Patent Description:
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.

The filling of pharmaceutical containers with fluid pharmaceuticals specifically requires the aseptic handling of both the containers and the fluid pharmaceutical itself. This leads to complex mechanisms and procedures, many of which may be automated to one degree or another. Often, the production equipment for fluid pharmaceutical handling is bulky and expensive. This creates a problem for smaller operations, particularly in the small-scale production and development environments. As the field has developed, the need for smaller, more compact equipment, particularly in the filling and compounding of fluid pharmaceuticals, has become evident.

The prior art is typically characterized by the use of vibratory bowls and escapements. Many prior art systems also employ gloves for use by the operator to access the interior of the chamber.

<CIT> describes in one general aspect, a system for aseptically filling a tray of pharmaceutical containers with a pharmaceutical product, which consists of an aseptic chamber, one or more articulated arms within the chamber, a sensor aseptically disposed with respect to the chamber, and a controller. The controller determines the locations of openings of the containers based on the image information from the sensor, and automatically guides one of the arms to fill the containers with the product. In order to obtain suitable contrast for accurately identifying the openings, an illuminator illuminates the tray with substantially collimated light. The sensor images the tray and containers using collimated light reflected from a reflective surface such as a retroreflector under the tray. To this end, the sensor may be disposed at a large enough distance from the retroreflector to collect largely the retroreflected light, or the sensor may employ a telecentric lens or a Fresnel lens. Further articulated arms move the tray and stopper the containers.

<CIT> describes a method and apparatus for controlling coating material deposition on to a medical device. Images of material drops in flight are captured and an average single drop volume value is calculated by conversion of the captured drop images to a volume measurement. The average single drop volume value is used to calculate a total number of drops necessary to apply a desired amount of coating. Alternately, material is applied and the amount of material deposited is accumulated and adjustments are made to deposit only a desired amount of coating material. A drop volume is determined for either every drop or a sampling of drops as the drops are being applied. Adjustments to the coating process include changing drop size and changing a number of drops to be deposited.

The invention to which this European patent relates is set out in the appended claims. In particular, the present invention is directed to a method for aseptically dispensing a pharmaceutical fluid into a pharmaceutical container as set out in claim <NUM>, a computer program as set out in claim <NUM>, and a system for aseptically dispensing a pharmaceutical fluid into a container as set out in claim <NUM>. Various related arrangements and example implementations are also described. Regardless of whether the terms "aspect", "embodiment" or "example" are used in reference to these arrangements, the scope of protection is defined by the claims.

In one general aspect, a method for filling nested pharmaceutical containers with a pharmaceutical fluid substance, such as a liquid, solution, or suspension having therapeutic properties is disclosed. The method includes providing a filling system comprising a sterilizable chamber capable of maintaining an aseptic condition, with the chamber comprising a filling station and a planar rotary stage having a destination fiducial locating structure including constraining surfaces. The method also includes transferring into the chamber at least one container tub sealed by a container tub cover and containing a container nest bearing a plurality of pharmaceutical containers, aseptically sealing the chamber, and establishing an aseptic condition within the chamber. The container nest bearing the plurality of pharmaceutical containers is transferred into the destination fiducial locating structure such that the container nest is held in place by the constraining surfaces, and the pharmaceutical fluid substance is dispensed into at least a portion of the plurality of pharmaceutical containers by operating both the rotary stage and the filling station.

In particular embodiments, the operating the filling station may include rotating the filling station. The dispensing the pharmaceutical fluid substance may comprise dispensing the pharmaceutical fluid substance on an iterative and serial basis into the containers. Providing a filling system may comprise providing a filing apparatus comprising at least one cover removal station within the chamber, with the transferring into the destination fiducial locating structure the container nest comprising removing the container tub cover from the container tub by operating both the rotary stage and the at least one cover removal station. Operating the at least one cover removal station may comprise rotating the at least one cover removal station. Providing the filling system may comprise providing within the chamber at least one cover removal station having an engagement tool, transferring into the chamber at least one container tub may comprise attaching to the container tub cover a cover removal fixture, and operating the at least one cover removal station may comprise engaging the engagement tool with the cover removal fixture.

The method may further comprise transferring into the chamber a container closure tub sealed by a container closure tub cover and containing at least one container closure nest bearing a plurality of pharmaceutical container closures. The method may further comprise positioning one of the at least one closure nests to align closures in the at least one closure nest with corresponding containers in the container nest, transferring the nests of aligned closures and containers to the ramming station by rotating the rotary stage, and forcing the closures into the corresponding containers. Positioning one of the at least one closure nests may comprise obtaining image information about the one of the at least one closure nest, and positioning the one of the at least one closure nests based on the image information.

Positioning one of the at least one closure nest may comprise applying a vacuum to suction cups, lifting the container closure nest with the suction cups, and operating the rotary stage. Transferring into the destination fiducial locating opening the container nest may comprise applying a vacuum to suction cups, lifting the container nest with the suction cups, and operating the rotary stage. Dispensing the pharmaceutical fluid substance may comprise simultaneously and/or serially operating the rotary stage and the filling station, and removing the container tub cover may comprise simultaneously and/or serially operating the rotary stage and the at least one cover removal station.

In another general aspect, a system for filling nested pharmaceutical containers with a pharmaceutical fluid substance comprising a sterilizable chamber capable of maintaining an aseptic condition is disclosed. The chamber includes a filling station, and a planar rotary stage having a rotary stage rotation axis and comprising a destination fiducial locating structure including constraining surfaces disposed and shaped to receive and hold a pharmaceutical container nest bearing a plurality of pharmaceutical containers.

In particular embodiments, the filling station may comprise a fluid product dispenser head, with the filling station being configured to be rotatable about a filling station rotation axis parallel to the rotary stage rotation axis to position in combination with rotation of the rotary stage the dispenser head over any one of the plurality of pharmaceutical containers held in the container nest in the destination fiducial locating structure. The chamber may further comprise at least one cover removal station and the rotary stage may further comprise a first source fiducial locating structure including constraining surfaces disposed and shaped to receive and hold a pharmaceutical container closure tub sealed by a container closure tub cover and containing at least one pharmaceutical container closure nest bearing a plurality of pharmaceutical container closures, and at least one second source fiducial locating opening disposed and shaped to receive and hold a pharmaceutical container tub sealed by a container tub cover and containing a pharmaceutical container nest bearing a plurality of pharmaceutical containers.

The at least one cover removal station may be disposed and configured to be rotatable about a cover removal station rotation axis parallel to the rotary stage rotation axis to remove in combination with rotation of the rotary stage the container tub cover from the at least one container tub and the container closure tub cover from the container closure tub. At least one cover removal station may comprise an engagement tool disposed and configured to engage with engagement fixtures pre-attached to the container tub cover and to the container closure tub cover.

The system may further comprise at least one camera disposed to obtain image information about at least one of the container nest and the closure nest, and a controller, with the chamber further comprising at least one vacuum pickup system comprising suction cups disposed to engage with the container nests and the container closure nests, the at least one vacuum pickup system being configured in combination with rotation of the rotary stage to lift a pharmaceutical container nest from a pharmaceutical container tub held in one of the at least one second source fiducial locating openings and to deposit the pharmaceutical container nest in the destination fiducial locating opening in combination with rotation of the rotary stage and to lift a pharmaceutical container closure nest from a pharmaceutical container closure tub held in the first source fiducial locating opening and to deposit the container closure nest on top of the pharmaceutical container nest under control of the controller.

The controller may be operative to instruct the at least one camera to provide to the controller the image information and the controller may be operative to control the rotation of the rotary stage to place the closures in the closure nest in correspondence with containers in the container nest. The system may further comprise a ram system configured for forcing the closures into the corresponding containers.

The system may further comprise at least one rotatable cover removal station having a cover removal station rotation axis parallel to the rotary stage rotation axis, at least one vacuum pickup system for placing the container closure nest on the container nest with closures in the closure nest in correspondence with containers in the container nest, and a ram system for forcing the closures into the containers, with the filing station being a rotatable filling station having a filling station rotation axis parallel to the rotary stage rotation axis and comprising a fluid product dispenser head. The system may further comprise at least one camera for obtaining image information of at least one of the container nest and the closure nest, and a controller comprising a memory and a processor. The controller may be operative to instruct the rotary stage to rotate to angular positions that are one of predetermined and based on the image information and to control the at least one cover removal station, the filling station, the at least one vacuum pickup system, and the ram system to operate in conjunction with the rotary stage.

In a further general aspect, a system for filling nested pharmaceutical containers with a pharmaceutical fluid substance is disclosed that includes means for establishing and maintaining an aseptic condition in a chamber, means for constraining a container nest bearing a plurality of pharmaceutical containers in the chamber, and means for transferring a container nest to the means for constraining from a container tub in the chamber. It also includes means for rotating the means for constraining in the chamber; and means for dispensing the pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers in the container nest while the container nest is constrained by the means for constraining.

In a further aspect, a system is provided for filling nested pharmaceutical containers with a pharmaceutical fluid substance, the system comprising a sterilizable chamber capable of maintaining an aseptic condition, the chamber comprising: a planar rotary stage having a rotary stage rotation axis, a plurality of locating structures positioned with respect to the rotary stage at different positions around the rotary stage rotation axis, for holding nests of pharmaceutical container parts at the different positions around the rotary stage rotation axis, and a container filling station having a dispensing head for filling the containers while they are held in a nest at one of the locating structures. The locating structures may include surfaces associated with a first tub-holding opening in the rotary stage for holding a first tub containing at least one nest of containers, surfaces associated with a second tub-holding opening in the rotary stage for holding a second tub containing at least one nest of closures, and surfaces associated with a destination nest-holding opening in the rotary stage for holding at least one nest.

The chamber may further comprise at least one vacuum pickup system comprising suction cups disposed to engage with the container nest and container closure nest held on the rotary stage, the at least one vacuum pickup system being configured in combination with rotation of the rotary stage to lift a pharmaceutical container nest from a pharmaceutical container tub and to deposit the pharmaceutical container nest in the destination opening in combination with rotation of the rotary stage and to lift a pharmaceutical container closure nest from a pharmaceutical container closure tub and to deposit the container closure nest on top of the pharmaceutical container nest.

At least one of the locating structures may include a reconfigurable locating structure with one or more adjustable positioning surfaces to position a tub with respect to the rotary stage. The reconfigurable locating structure may include at least one pair of a reconfigurable stopping member and a restraining member disposed opposite each other across an opening in the rotary stage to precisely position at a first predetermined position a tub that contains at least one nest. The stopping member may be adjustable to stop the tub at the first predetermined position by a rotary adjustment and the restraining member may be disposed to restrain the tub in the first predetermined position.

At least a first of the reconfigurable locating structures may include a rotary positioning element having an axis of rotation parallel to a plane of the rotary stage and includes a plurality of different positioning surfaces that are selectable by rotating the rotary positioning element. At least one of the reconfigurable locating structures may include a pair of opposing rotary positioning elements each having an axis of rotation parallel to a plane of the rotary stage and each may include a plurality of different positioning surfaces that are selectable by rotating the rotary positioning elements to accommodate different nest widths.

At least one of the reconfigurable locating structures may include at least a first pair of opposing positioning elements that define positioning surfaces that oppose each other along a first positioning axis that is at least generally parallel to a plane of the rotary stage and at least a second pair of opposing positioning elements that define positioning surfaces that oppose each other along a second positioning axis that is at least generally parallel to a plane of the rotary stage and at least generally perpendicular to the first positioning axis. The at least one of the positioning elements in each of the first and second pairs of positioning elements may include a rotary positioning element having an axis of rotation parallel to a plane of the rotary stage and including a plurality of different positioning surfaces.

The system may further include a reconfigurable vacuum pickup system comprising: a first set of suction cups arranged in a first pattern, a second set of suction cups arranged in a second pattern different from the first pattern, and a selection mechanism operative to position either the first set of suction cups or the second set of suction cups to engage with the at least a first of the nests of pharmaceutical container parts while it is held by one of the plurality of locating structures. The selection mechanism of the reconfigurable vacuum pickup system may include a rotary mechanism operative to position the first or second sets of suction cups in an engagement position.

The system may further include at least one cover removal station positioned to remove covers from tubs containing at least one nest of pharmaceutical packaging materials held in one of the locating structures. The at least one cover removal station may be rotatable about a cover removal station rotation axis parallel to the rotary stage rotation axis to remove the tub covers in combination with rotation of the rotary stage. The at least one cover removal station may comprise an engagement tool disposed and configured to engage with a cover removal fixture on the tub cover.

The filling station may be configured to be rotatable about a filling station rotation axis parallel to the rotary stage rotation axis to position in combination with rotation of the rotary stage the dispenser head over any one of the plurality of pharmaceutical containers held by one of the one of the locating structures.

The system may further comprise at least one camera disposed to obtain image information about at least one of the nests of pharmaceutical container parts. The system may further comprise a ram system configured for forcing nested closures into corresponding nested containers.

The system may further comprise at least one rotatable cover removal station having a cover removal station rotation axis parallel to the rotary stage rotation axis; at least one vacuum pickup system for placing a container closure nest on a container nest with closures in the closure nest in correspondence with containers in the container nest; a ram system for forcing the closures into the containers; and wherein the filing station is a rotatable filling station having a filling station rotation axis parallel to the rotary stage rotation axis and comprising a fluid product dispenser head.

The system may further comprise at least one camera for obtaining image information of at least one of the container nest and the closure nest, a controller comprising a memory and a processor, and wherein the controller is operative to instruct the rotary stage to rotate to angular positions that are one of predetermined and based on the image information and to control the at least one cover removal station, the filling station, the at least one vacuum pickup system, and the ram system to operate in conjunction with the rotary stage.

In another aspect, a system is provided for filling nested pharmaceutical containers with a pharmaceutical fluid substance, comprising: means for establishing and maintaining an aseptic condition in a chamber; means for constraining a container nest bearing a plurality of pharmaceutical containers in the chamber; means for transferring to the means for constraining a container nest from a container tub in the chamber; means for rotating the means for constraining in the chamber; and means for dispensing the pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers in the container nest while the container nest is constrained by the means for constraining.

In a further aspect, a method is provided for filling nested pharmaceutical containers with a pharmaceutical fluid substance, the method comprising: providing a filling system comprising a sterilizable chamber capable of maintaining an aseptic condition, the chamber comprising a filling station and a planar rotary stage having a destination locating structure; transferring into the chamber at least one container tub sealed by a container tub cover and containing a container nest bearing a plurality of pharmaceutical containers; aseptically sealing the chamber; establishing an aseptic condition within the chamber; transferring into the destination locating structure the container nest bearing the plurality of pharmaceutical containers such that the container nest is held in place; and dispensing the pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers by operating both the rotary stage and the filling station. The operating the filling station may include rotating the filling station. The dispensing the pharmaceutical fluid substance may comprise dispensing the pharmaceutical fluid substance on an iterative and serial basis into the containers.

The providing a filling system may comprise providing a filing apparatus comprising at least one cover removal station within the chamber and wherein the transferring into the destination locating structure the container tub comprises removing the container tub cover from the container tub by operating both the rotary stage and the at least one cover removal station. The operating the at least one cover removal station may comprise rotating the at least one cover removal station. The providing the filling system may comprise providing within the chamber at least one cover removal station having an engagement tool, the transferring into the chamber at least one container tub may comprise attaching to the container tub cover a cover removal fixture; and wherein the operating the at least one cover removal station comprises engaging the engagement tool with the cover removal fixture.

The method may further comprise transferring into the chamber a container closure tub sealed by a container closure tub cover and containing at least one container closure nest bearing a plurality of pharmaceutical container closures. The method may further comprise positioning one of the at least one closure nests to align closures in the at least one closure nest with corresponding containers in the container nest; transferring the nests of aligned closures and containers to a ramming station by rotating the rotary stage; and forcing the closures into the corresponding containers. The method may further include adjusting a tub locating structure to accommodate a size of the closure nest tub. The positioning one of the at least one closure nest may comprise: obtaining image information about the one of the at least one closure nests; and positioning the one of the at least one closure nests based on the image information. The positioning one of the at least one closure nest may comprise: applying a vacuum to suction cups; lifting the container closure nest with the suction cups; and operating the rotary stage.

The transferring into the destination locating opening the container nest may comprise: applying a vacuum to suction cups; lifting the container nest with the suction cups; and operating the rotary stage. The method may further include selecting one of a plurality of sets of suction cups and wherein the applying a vacuum to suction cups is performed for the selected set of suction cups. The selecting may include rotating one of the plurality of sets of suction cups into position. The method may further include the destination locating structure to accommodate a size of the container nest. The adjusting may be performed in two at least generally orthogonal directions. The method may further include adjusting a tub locating structure to accommodate a size of the container nest tub.

In another general aspect, a container assembly for holding nested pharmaceutical container parts is disclosed. It includes a container comprising a bottom, a top lip that provides a horizontal top sealing surface that has a peripheral outline, and sidewalls located between the bottom and the top lip. It also includes a peelable container cover consisting of a sheet of flexible material sealed to the sealing surface of the top lip of the rectangular container to seal the contents of the container, and a cover removal fixture on the container cover.

The sealed peelable container cover may include a portion that extends outside of the peripheral outline of the top sealing surface of the container, and the cover removal fixture may be on the portion of the peelable container cover that extends outside of the peripheral outline of the top sealing surface of the container. The container may be rectangular and includes four sidewalls. The cover removal fixture may include an appendage to allow it to be engaged by an engagement tool. The cover removal fixture may include a ball-shaped appendage to allow it to be engaged by an engagement tool. The peelable container cover may be heat sealed to the sealing surface of the top lip of the rectangular container to seal the contents of the container against decontamination. The peelable container cover may be sealed to the sealing surface of the top lip of the rectangular container to seal the contents of the container against decontamination using a chemical agent. The peelable container cover may sealed to the sealing surface of the top lip of the rectangular container to seal the contents of the container against decontamination using a radiation. The peelable container cover may be sealed to the sealing surface of the top lip of the rectangular container to seal the contents of the container against decontamination using plasma. The peelable cover may be made of a plastic material. The peelable cover may be made of an impermeable laminated foil. The peelable cover may be made of a polymeric membrane. The cover removal fixture may be clipped to a portion of the peelable container cover that extends outside of the peripheral outline of the top sealing surface of the container. The sealed container may hold sterilized pharmaceutical containers or closures.

In a further aspect, a method is provided for removing within a controlled environment enclosure a container cover from a sealed container, the sealed container being sealed by the container cover, the method comprising: providing the container in the controlled environment enclosure with the cover sealed to a sealing surface of a lip of the container to seal the contents of the container against decontamination, the cover having a cover removal fixture, decontaminating the sealed container in the controlled environment enclosure, engaging the cover removal fixture with an engagement tool, and removing the cover from the container using the engagement tool. The engaging may engage the cover removal fixture with a fork-shaped engagement tool. The engaging may engage a ball-shaped appendage on the cover removal fixture.

The providing may include providing sterilized pharmaceutical containers or closures in the sealed container before the decontaminating. The attaching may take place before the container is in the controlled environment enclosure. The decontaminating the sealed container in the controlled environment enclosure may take place before the removing the cover. The removing the cover may include moving the engagement tool relative to the container. The removing the cover may include moving both the container and the engagement tool. The method may further comprise attaching the cover removal fixture to the cover before providing the container in the controlled environment enclosure.

In a further aspect, a method is provided for aseptically dispensing a pharmaceutical fluid into a container, the method comprising: providing a sterilizable chamber capable of maintaining an aseptic condition, the chamber comprising a pharmaceutical fluid dispensing head configured for producing droplets of the pharmaceutical fluid and a droplet monitoring system comprising a digital imager; establishing within the sterilizable chamber an aseptic condition; providing within the sterilizable chamber an aseptic pharmaceutical container; moving at least one of the dispensing head and the container to position an opening of the container under the dispensing head to receive the droplets along a droplet path; dispensing a plurality of droplets of the fluid from the dispensing head along a droplet path into the container; obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path; and determining from the plurality of images a volume of fluid dispensed into the container. The method may further comprise ceasing the dispensing of the fluid based on the volume of fluid dispensed into the container.

The determining from the plurality of images a volume of fluid dispensed into the container may comprise determining a volume of at least one of the plurality of droplets. The determining the volume of the at least one of the plurality of droplets may comprise: identifying first and second total portions of the at least one droplet appearing respectively to the left and to the right of the droplet path in at least one image of the at least one droplet; calculating first and second volumes of the at least one of the plurality of droplets by separately mathematically rotating respectively the first and second total portions of the droplet through 2π about the droplet path; and equating the volume of the at least one of the plurality of droplets to the average of the first and second volumes.

The obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path may comprise obtaining the plurality of images over a predetermined portion of the droplet path. Alternatively, the obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path may comprise: determining from the plurality of images a portion of the droplet path where droplets have a stable shape; and selecting the at least one image of the at least one droplet to be from among images of the droplet taken when the droplet is in the portion of the droplet path where droplets have a stable shape.

The determining from the plurality of images a volume of fluid dispensed into the container may comprise determining a volume of each droplet dispensed into the container. The ceasing the dispensing of the fluid based on the volume of fluid dispensed into the container may comprise ceasing the dispensing of the fluid when a total amount of fluid dispensed into the container equals a predetermined volume. The obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path may comprise obtaining the plurality of images employing light reflected to the imager by a retroreflector. The obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path may comprise obtaining the plurality of images by means of a telecentric lens. The providing within the sterilizable chamber an aseptic pharmaceutical container comprises providing the aseptic pharmaceutical container within a container nest.

The method may further comprise moving at least one of the dispensing head and the container to position an opening of the container under the dispensing head to receive the droplets along a droplet path. The moving the container may comprise operating a robotic arm. Operating the robotic arm may comprise operating an articulated robotic arm. Moving the dispensing head may comprise operating a robotic arm, which arm may be an articulated robotic arm.

In a further aspect, a system is provided for aseptically dispensing a pharmaceutical fluid into a container, the system comprising: a sealable and sterilizable chamber capable of maintaining an aseptic condition; in the chamber a pharmaceutical fluid dispensing head configured for producing droplets of the pharmaceutical fluid; in the chamber a droplet monitoring system comprising a digital imager disposed to obtain images of droplets dispensed by the fluid dispensing head; a controller comprising a memory and a processor, the controller in communication with the fluid dispensing head and the digital imager; and software configured for controlling dispensing of the pharmaceutical fluid droplets by the fluid dispensing head and for collection of images of the pharmaceutical fluid droplets along a droplet path when the software is loaded in the memory and executed by the processor.

The system may further comprise in communication with the controller at least one of a fluid dispensing head positioning system and a container positioning system, the software further configured for controlling the at least one of a fluid dispensing head positioning system and a container positioning system. The fluid dispensing head positioning system may comprise a robotic arm that may be an articulated robotic arm. The articulated robotic arm may be hermetically sealed to the chamber. The container positioning system may comprise a robotic arm. The robotic arm used in the container positioning system may comprise an end effector arranged for holding a container nest. The robotic arm used in the container positioning system may comprise an articulated robotic arm which may, in some embodiments, be hermetically sealed to the chamber. The droplet monitoring system may comprise a retroreflector disposed to reflect light through the droplets to the digital imager. The digital imager may comprise a telecentric lens.

Systems and methods according to the invention need not employ either vibratory bowls or escapements. Nor do such systems or method require gloves. Systems and methods according to the invention may therefore address needs for compact, small-scale filling and compounding of fluid pharmaceuticals.

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:.

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 flow charts are also representative in nature, and actual embodiments of the invention may include further features or steps not shown in the drawings. The exemplifications set out herein illustrate embodiments of the invention, in one or more forms, and such exemplifications are not to be construed as limiting the scope of the invention in any manner.

The embodiments disclosed below are illustrative and not intended to be exhaustive or limit the invention to the precise form disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may utilize their teachings.

The present invention relates to an apparatus and method for filing pharmaceutical containers with a pharmaceutical fluid substance in a spatially constrained environment. In <FIG>, filling system <NUM> comprises sealable chamber <NUM> in communication with an ambient environment, sealable chamber <NUM> being capable of having an aseptic environment established within its interior and capable of maintaining that aseptic environment within its interior. The interior of sealable chamber <NUM> may be rendered aseptic by any one or more of treatments, including but not limited to treatment with a sterilant, such as steam, hydrogen peroxide vapor, ozone, nitrogen dioxide, and ethylene oxide. The structures and mechanisms to perform such sterilization steps are well known in the art and are not shown in <FIG>.

Chambers <NUM> and <NUM> are separated from chamber <NUM> by upper wall <NUM> and lower wall <NUM> respectively and are not required to be capable of maintaining aseptic environments within their interiors. The communication of chamber <NUM> with the ambient environment may be via suitable aseptically sealable access door <NUM>, schematically shown in broken outline in <FIG>. Suitable sealable doors and ports are well known in the art and will not be dwelt upon further in this specification. The ambient environment may be, for example, a clean room adapted for the handling of pharmaceuticals during production. Since space is at a premium in such spatially constrained clean environments, there is much merit in reducing the so-called "footprint" of equipment to be housed in the clean environment.

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 a chamber shall be understood to mean establishing that condition throughout the internal atmosphere of the chamber as well as on substantially all exposed interior surfaces of the chamber. This shall include the surfaces of all items, containers, subsystems and the like exposed to the interior atmosphere of the chamber. To the extent that extremely tight crevices or microscopic crevices may exist in the interior of the chamber such that a sterilizing gas or vapor may not perfectly penetrate into such tight regions, for example, the degree of sterilization in practical cases may 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 chamber and "sterilizing the interior of the chamber" shall have the same meaning in this specification.

Introducing into the interior of a chamber with an aseptic condition an item of which the surfaces are not suitably sterilized destroys the existing aseptic condition within the chamber. Conversely, introducing an aseptic or sterilized item into an interior of a chamber 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 chamber does not in any way sterilize the chamber or render it aseptic to a degree acceptable in the pharmaceutical industry. The reason is that the interior surfaces of the chamber 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 chamber.

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 chambers. 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 chamber 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 chamber.

In some prior art systems, containers introduced into a chamber 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 chamber when the chamber itself is not aseptic the containers lose their aseptic condition as biological species contained within the chamber will deposit on the previously aseptic containers.

It should also be pointed out that pharmaceutical or semiconductor clean rooms of any quality level, including "Class <NUM>", "Class <NUM>" or "Class <NUM>", 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 chamber because they do not have an assurable means to render the surfaces of the room sterile or aseptic. Standards for clean rooms exist from both the United States Federal Government 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 a chamber cannot be rendered aseptic by the management of its atmosphere or airflow only. Nor, conversely, can the chamber be rendered aseptic by the sterilization of only the surfaces of its interior.

The text "<NPL>et al from the Center for Disease Control lists a compendium of mechanisms and methods for sterilization. Our concern in this specification is specifically with those mechanisms for sterilizing the interior of a chamber; that is, sterilizing both the interior surfaces and the atmosphere within the chamber. 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 chamber is employed in the filling of pharmaceutical containers.

The subsystems of apparatus <NUM> contained with sealable chamber <NUM> will now be described at the hand of <FIG>. Due to the compactness and density of components and subsystems of apparatus <NUM>, certain components and subsystems are omitted from the drawings of <FIG> in the interest of clarity and the focus is placed on components and subsystems most relevant to the supporting text in this specification. Planar rotary stage <NUM> is fully rotatable through <NUM>° (degrees) in a horizontal plane parallel to lower wall <NUM> about rotary stage rotation axis <NUM> and may be raised and lowered by means of bellows feed-through <NUM>. The use of bellows feed-through <NUM> allows chamber <NUM> to retain its aseptic condition during the motion of rotary stage <NUM>. A suitable engine and gearing system <NUM> may be housed within chamber <NUM>. Engines, for example stepper motors, as well as gearing systems suitable for rotating rotary stage <NUM> with suitable angular precision and repeatability are well known in the art and are not further discussed in this specification.

As shown in <FIG>, at least three fiducial locating openings <NUM>, <NUM>, and <NUM> are provided in rotary stage <NUM>. Fiducial locating opening <NUM> is employed for receiving container tubs <NUM> holding sterilized pharmaceutical containers <NUM> pre-packed in a predetermined pattern in container nests <NUM>. Container tubs <NUM> are typically substantially rectangular and are sealed with peelable covers <NUM>. Suppliers of pharmaceutical containers provide their product in this format to users of the apparatus of the present specification. Fiducial locating opening <NUM> is employed for receiving container closure tubs <NUM> holding sterilized pharmaceutical containers closures <NUM> pre-packed in a predetermined pattern in container closure nests <NUM>. Container closure tubs <NUM> are typically substantially rectangular and are sealed with peelable tub covers not shown in <FIG>. The peelable covers of tubs <NUM> are functionally identical to peelable covers <NUM>. Suppliers of pharmaceutical containers provide their product in this format to users of the apparatus of the present specification. In the interest of the compactness of system <NUM>, the rectangular axes of locating openings <NUM>, <NUM>, and <NUM> may be oriented at an angle with respect to the radial direction of rotary stage <NUM> in order to ensure a suitably small radius for rotary stage <NUM>.

Suitable container nests <NUM> and container closure nests <NUM>; container tubs <NUM> and container closure tubs <NUM>; and peelable tub covers <NUM> are described in <CIT>, the disclosures of which is hereby incorporated in full. Alternative cover gripping arrangements for the removal of tub covers from tubs are also described in <CIT>, the disclosures of which is hereby incorporated in full. The removal of tub covers may be controlled and monitored by the subsystem and method described in <CIT>, the disclosures of which is hereby incorporated in full.

In the interest of clarity, <FIG> show, and the associated text to follow below will describe, the use of single tub <NUM> of pharmaceutical containers <NUM> along with single tub <NUM> of container closures <NUM>. In practice, container closures <NUM> are provided as multiple nests <NUM> per container closure tub <NUM>. To this end rotary stage <NUM> may contain more than one fiducial locating opening <NUM> to each receive container tub <NUM> holding sterilized pharmaceutical containers <NUM> pre-packed in one container nest <NUM>. In yet other implementations, more than one nest <NUM> of containers <NUM> may be present in a single pharmaceutical container tub <NUM>.

Fiducial locating opening <NUM> is specifically arranged to receive container nests <NUM> bearing pharmaceutical containers <NUM>. Whereas tubs <NUM> and <NUM> naturally locate in fiducial locating openings <NUM> and <NUM> and are suspended by their own rims once in opening <NUM> and <NUM>, containers <NUM> are correctly located in opening <NUM> and retained in position by some other mechanism. To this end, fiducial locating opening <NUM> comprises four fiducial retaining guides <NUM>. Baseplate <NUM> is located within fiducial locating opening <NUM> as a loose component of system <NUM>, and rests on the horizontal portions at the bottoms of each of the four fiducial retaining guides <NUM> (see <FIG>). This arrangement allows baseplate <NUM> to move freely, guided by fiducial retaining guides <NUM>. We shall return to this arrangement when discussing the closing of containers with container closures.

<FIG> shows fiducial locating opening <NUM> as empty, while cover <NUM> is being peeled from container tub <NUM> in fiducial locating opening <NUM> (not visible) to expose nest <NUM> bearing pharmaceutical containers <NUM>. At this point in the operation of system <NUM>, a cover similar to cover <NUM> has already been pealed from tub <NUM> in fiducial locating opening <NUM> (not visible) to expose nest <NUM> bearing container closures <NUM>. <FIG> shows a close-up detailed view of the peeling of cover <NUM>. Cover removal station <NUM> is rotatable about cover removal station rotation axis <NUM> parallel to rotary stage rotation axis <NUM> and comprises engagement tool <NUM>, which, in this particular embodiment, is fork-shaped in order to engage with cover removal fixture <NUM> attached to cover <NUM>. Cover removal fixture <NUM> is pre-attached to cover <NUM> before tub <NUM> is transferred into system <NUM> via door <NUM> (See <FIG>). In the embodiment shown in <FIG> and <FIG>, cover removal fixture <NUM> is clipped to cover <NUM> and has a ball-shaped appendage to allow it to be engaged by engagement tool <NUM>. Other combinations of cover removal fixtures and engagement tools are contemplated and system <NUM> is not limited to the particular combination of cover removal fixture and engagement tool shown in <FIG>, <FIG> and <FIG>. Cover removal fixture <NUM>, for example, may be manufactured as an integral part of cover <NUM> for use in filling systems such as filling system <NUM>. Or it may be clipped to cover <NUM> during the placement into tub <NUM> of nests <NUM> bearing containers <NUM> and during the placement into tub <NUM> of nests <NUM> bearing container closures <NUM>.

Rotary stage <NUM> may be lowered to assist in obtaining a less acute angle between cover <NUM> and tub <NUM>. Too acute an angle may lead to the tearing of cover <NUM>. Cover removal station <NUM> may be rotated while rotary stage <NUM> rotates so that the combined motions of cover removal station <NUM> and rotary stage <NUM> provide a low stress path for the removal of cover <NUM>, thereby limiting the chances of tearing of cover <NUM>. In particular, cover removal station <NUM> may be rotated to ensure that engagement tool <NUM> is not present above fiducial locating opening <NUM> when container tub <NUM> is placed in or removed from fiducial locating opening <NUM>.

In some embodiments, system <NUM> comprises single cover removal station <NUM> for sequentially removing covers from tubs <NUM> and <NUM>. In other embodiments, system <NUM> may be equipped with two or more cover removal stations <NUM> for dedicated removal of covers from tubs <NUM> and <NUM> and other additional tubs. In some embodiments covers are simultaneously removed from tubs <NUM> and <NUM> and from other tubs, all the removal processes benefiting from a single rotary motion of rotary stage <NUM>.

In <FIG>, <FIG>, and <FIG> filling station <NUM> for filling pharmaceutical containers <NUM> with pharmaceutical fluid product comprises pharmaceutical fluid product feed line <NUM> supplying pharmaceutical fluid product to pharmaceutical fluid product dispenser head <NUM> (See <FIG>). Filling station <NUM> is rotatable about filling station rotation axis <NUM> parallel to rotary stage rotation axis <NUM>. Filling station <NUM> and rotary stage <NUM> may simultaneously or sequentially rotate to place dispenser head <NUM> over an opening of any selected container <NUM> in nest <NUM> when nest <NUM> is seated in fiducial locating opening <NUM>. This allows every container <NUM> in nest <NUM> to be filled with pharmaceutical fluid product by product dispenser head <NUM>. When not engaged in filling containers <NUM>, filling station <NUM> may be rotated to swing dispenser head <NUM> completely away from fiducial locating opening <NUM>, thereby allowing nests <NUM> bearing container closures <NUM> to be placed on top of nest <NUM> with closure <NUM> directly on top of an opening of every container <NUM> residing in fiducial locating opening <NUM>.

Another term employed to describe dispenser head <NUM> is "filling needle". Suitable filling needles and protective sheathing arrangements for such filling needles are described in co-pending <CIT>and <CIT>, and August <NUM>, <NUM>, respectively, the disclosures of which are hereby incorporated in full.

<FIG> and <FIG> show two vacuum pickup systems <NUM> and <NUM>, each respectively comprising a plurality of suction cups <NUM> and <NUM> (See <FIG>). Vacuum pickup system <NUM> is arranged to pick up nests <NUM> of containers <NUM> by means of suction cups <NUM>, and vacuum pickup system <NUM> is arranged to pick up nests <NUM> of containers <NUM> by means of suction cups <NUM>. Vacuum pickup system <NUM> may be raised and lowered in order to allow suction cups <NUM> to engage with different nests <NUM> of container closures <NUM> contained at differing depths inside tub <NUM>. To this end, vacuum pickup system <NUM> may comprise a bellows feed-through allowing vertical motion whilst maintaining the aseptic integrity of chamber <NUM>. Suitable vacuum pumps, or vacuum lines from a vacuum source external to system <NUM>, may be connected to vacuum pickup systems <NUM> and <NUM>, and ensure suitable vacuum at suction cups <NUM> and <NUM>.

Cameras <NUM> and <NUM> are disposed to view and record the positioning of suction cups <NUM> and <NUM> on nests <NUM> and <NUM> respectively. In the embodiment shown in <FIG>, cameras <NUM> and <NUM> are disposed within chamber <NUM> and view nests <NUM> and <NUM> through sealed windows <NUM> and <NUM> respectively. In other embodiments, cameras <NUM> and <NUM> may be disposed within chamber <NUM> and view nests directly from within chamber <NUM>.

Container closing ram system <NUM>, shown in <FIG>, <FIG>, and <FIG>, comprises upper ram plate <NUM> disposed within chamber <NUM> above rotary stage <NUM>, lower ram plate <NUM> disposed within chamber <NUM> below rotary stage <NUM>, and ram drive <NUM> within chamber <NUM>. Ram drive <NUM> is disposed for driving lower ram plate <NUM> vertically toward upper ram plate <NUM> via bellows feed-through <NUM>. Loose base plate <NUM> of fiducial locating opening <NUM>, when located above lower ram plate <NUM> by suitably rotating rotary stage <NUM>, is pushed upward by ram plate <NUM> and is guided in the process by fiducial retaining guides <NUM> (See <FIG>). When closures <NUM> in closure nest <NUM> are ultimately pushed against upper ram plate <NUM>, they are forced into the openings of containers <NUM> in nest <NUM>. This creates a sandwiched nest of closed containers <NUM>, each closed by a corresponding closure <NUM>. As shown in <FIG>, nests <NUM> and <NUM> are forced together in the process to create a compound nest <NUM>/<NUM>.

Controller <NUM>, shown in <FIG> and <FIG>, may communicate with the rest of system <NUM> via control communications line <NUM>, or may be contained physically within system <NUM>, for example, within chamber <NUM>. Controller <NUM> may have suitable memory and a processor containing suitable software programming instructions which, when loaded in the memory executed by the processor, control the motions of ram system <NUM>, vertical motion and rotating action of rotary stage <NUM>, the application of vacuum to vacuum pickup systems <NUM> and <NUM>, the imaging by cameras <NUM> and <NUM>, the vertical motion of vacuum pickup system <NUM>, any rotational or vertical motions required from cover removal stations <NUM> and filling station <NUM>, as well as the on-and-off valving of pharmaceutical fluid product supply to dispenser head <NUM>. Suitable valves and pumps, typically peristaltic pumps, required for pharmaceutical fluid product supply to dispenser head <NUM> are well known in the art and may be housed in chamber <NUM> or may be located outside system <NUM>. The various mechanical drives for the subsystems described above are well-known in the art, will not be discussed here in detail. These may typically be housed in chamber <NUM> of system <NUM>. The software, when executed by the processor, instructs the rotary stage to rotate to angular positions that are either predetermined or based on image information from the cameras and controls the cover removal stations, the filling station, the vacuum pickup systems, and the ram system to operate specifically in conjunction with the rotary stage.

A method based on system <NUM> for filling nested pharmaceutical containers with a pharmaceutical fluid product will now be described at the hand of the flow chart given in <FIG>, and which is continued in <FIG>. The method comprises providing [<NUM>] filling apparatus <NUM> comprising sterilizable chamber <NUM> capable of maintaining an aseptic condition, the chamber comprising rotary stage <NUM> with destination fiducial locating opening <NUM> and at least two source fiducial locating openings (<NUM> and <NUM>); filling station <NUM>; at least one cover removal station <NUM>; vertically oriented container ramming system <NUM>; and at least one vacuum pickup system (for example <NUM> and/or <NUM>). The method further comprises transferring [<NUM>] into at least a first of the at least two source fiducial locating openings (<NUM> and <NUM>) at least one container tub <NUM> sealed by container tub cover <NUM> and containing container nest <NUM> bearing a plurality of pharmaceutical containers <NUM>; and transferring [<NUM>] into a second of the at least two source fiducial locating openings (<NUM> and <NUM>) container closure tub <NUM> sealed by a closure tub cover and containing at least one container closure nest <NUM> bearing a plurality of pharmaceutical container closures <NUM>.

The method further comprises aseptically sealing [<NUM>] chamber <NUM> and establishing [<NUM>] an aseptic condition within chamber <NUM>. Establishing [<NUM>] an aseptic condition within chamber <NUM> may comprise treating the interior of chamber <NUM> with any one or more of steam, hydrogen peroxide vapor, ozone, nitrogen dioxide, and ethylene oxide.

The method further comprises operating [<NUM>] the at least one cover removal station <NUM> and rotating rotary stage <NUM> to remove container tub cover <NUM> from the at least one container tub <NUM> and remove the closure tub cover from closure tub <NUM>; operating [<NUM>] rotary stage <NUM> and one of the at least one vacuum pickup systems (for example <NUM> and/or <NUM>) to transfer to destination fiducial locating opening <NUM> container nest <NUM> bearing the plurality of pharmaceutical containers <NUM>; and dispensing [<NUM>] on an iterative and serial basis a pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers <NUM> by operating rotary stage <NUM> and filling station <NUM>. The phrase "iterative and serial" is employed in this specification to describe the fact that the same operational steps are repeatedly used to fill the various containers and the fact that the containers are filled one after another, as opposed to simultaneously. In some embodiments multiple containers may be simultaneously filled using a filling station with multiple dispenser heads.

Steps [<NUM>], [<NUM>], and [<NUM>] each involves rotating rotary stage <NUM> and operating another device, being respectively cover removal station <NUM>, one of the at least one vacuum pickup systems (for example <NUM> and/or <NUM>), and filling station <NUM>. The motions involved may be simultaneous in some cases or embodiments, and serial in other cases or embodiments. In some embodiments some of the motions may be simultaneous and others may be serial.

Operating [<NUM>] the at least one cover removal station <NUM> may comprise engaging an engagement tool (for example tool <NUM>) with a cover removal fixture (for example fixture <NUM>) pre-attached to the cover being removed. Operating [<NUM>] one of the at least one vacuum pickup systems may comprise contacting container nest <NUM> with a plurality of suction cups <NUM> while applying a vacuum to suction cups <NUM>. Dispensing [<NUM>] a pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers may comprise disposing on an iterative and serial basis fluid product dispenser head <NUM> of filling station <NUM> over the openings of the at least a portion of the plurality of pharmaceutical containers <NUM>. Operating [<NUM>] rotary stage <NUM> and one of the at least one vacuum pickup systems may comprise operating camera <NUM> to obtain image information of container nest <NUM> bearing the plurality of pharmaceutical containers <NUM> and to position the one of the at least one vacuum pickup systems over container nest <NUM>.

The method further comprises operating [<NUM>] one of the at least one vacuum pickup systems (for example <NUM> and/or <NUM>) and rotary stage <NUM> to transfer to destination fiducial locating opening <NUM> one of the at least one container closure nests <NUM> bearing the plurality of pharmaceutical container closures <NUM> and positioning the at least one closure nest <NUM> to align closures <NUM> with containers <NUM>; operating [<NUM>] rotary stage <NUM> to jointly position aligned container nest <NUM> and closure nest <NUM> in ramming system <NUM>; and operating [<NUM>] ramming system <NUM> to force the plurality of container closures <NUM> into the plurality of containers <NUM>.

Operating [<NUM>] one of the at least one vacuum pickup systems may comprise contacting container closure nest <NUM> with a plurality of suction cups <NUM> while applying a vacuum to suction cups <NUM>. Operating [<NUM>] ramming system <NUM> may comprise driving the plurality of pharmaceutical containers <NUM> toward upper ram plate <NUM> of ramming system <NUM>.

The operating [<NUM>] rotary stage <NUM> and one of the at least one vacuum pickup systems may comprise operating camera <NUM> to obtain image information of the one of the at least one container closure nests <NUM> bearing the plurality of pharmaceutical container closures <NUM> and to position the one of the at least one vacuum pickup systems over the one of the at least one container closure nests <NUM>.

Providing [<NUM>] a filling apparatus may comprise providing a filling apparatus further comprising controller <NUM> and a software program executable by controller <NUM>. Any one or more of the aseptically sealing [<NUM>] chamber <NUM>; establishing [<NUM>] an aseptic condition within chamber <NUM>; operating rotary stage <NUM>; operating the at least one cover removal station <NUM>; operating [<NUM>] one of the at least one vacuum pickup systems (<NUM> and/or <NUM>); operating filling station <NUM>; and operating [<NUM>] ramming system <NUM> may be done automatically by executing the software program in controller <NUM>.

In the embodiment described at the hand of <FIG>, each of steps [<NUM>], [<NUM>], [<NUM>], [<NUM>], and [<NUM>] comprises rotating a rotary stage, for example rotary stage <NUM>, bearing the container nests and container closure nests.

In other embodiments, a plurality of the steps of removing a container tub cover from at least one container tub <NUM>; removing a container tub cover from at least one container closure tub <NUM>; transferring to destination fiducial locating opening <NUM> container nest <NUM>; dispensing a pharmaceutical fluid substance into pharmaceutical containers <NUM>; transferring to destination fiducial locating opening <NUM> one of the at least one container closure nests <NUM>; and positioning aligned container nest <NUM> and closure nest <NUM> in ramming system <NUM> comprises rotating a rotary stage bearing the container nests and container closure nests.

In a general embodiment, at least one of the steps of removing a container tub cover from at least one container tub <NUM>; removing a container tub cover from at least one container closure tub <NUM>; transferring to destination fiducial locating opening <NUM> container nest <NUM>; dispensing a pharmaceutical fluid substance into pharmaceutical containers <NUM>; transferring to destination fiducial locating opening <NUM> one of the at least one container closure nests <NUM>; and positioning aligned container nest <NUM> and closure nest <NUM> in ramming system <NUM> comprises rotating a rotary stage bearing the container nests and container closure nests.

It is to be noted that neither filling system <NUM>, nor the associated method, needs to employ the vibratory bowls or escapements that are typical of the prior art. Unlike many prior art systems, filling system <NUM> also does not require the use of gloves for use by an operator to access the interior of the chamber.

The system above has been described as employing a controller that runs stored software running on a general-purpose computer platform, but it could also be implemented in whole or in part using special-purpose hardware.

The system described above also employs fiducial openings defined in the rotary stage to hold tubs and nests, but it could also employ other types of fiducial structures that include other configurations of constraining surfaces sufficient to hold tubs and nests in place. Notched posts mounted on the rotary stage may hold tubs and/or nests above the rotary stage, for example. Further fiducial locating structures for holding tubs of nests for containers or container closures are described below at the hand of <FIG>, <FIG>, <FIG>, and <FIG>.

Another embodiment of a filling system according to the invention may be in all respects identical to the embodiments described above at the hand of <FIG> and <FIG>, with the exception of vacuum pickup system(s) <NUM> or <NUM>. <FIG> and <FIG> show a portion of a filling system as described above. <FIG>, in particular, focuses on the general area of one of the vacuum pickup systems, by way of example, vacuum pickup system <NUM>. In this alternative embodiment, vacuum pickup system <NUM> is replaced by reconfigurable vacuum pickup system <NUM>'. Vacuum pickup system <NUM> of <FIG> and <FIG> may similarly be replaced by reconfigurable vacuum pickup system <NUM>' of the same arrangement as vacuum pickup system <NUM>'. In the interest of clarity, vacuum pickup system <NUM>' is not shown in <FIG> or <FIG>. In other embodiments, single reconfigurable vacuum pickup system <NUM>' may be employed to pick up both container nests and container closure nests. Vacuum pickup system <NUM>' may access the container nests and container closure nests by rotation of rotary stage <NUM>.

Vacuum pickup system <NUM>' comprises two rotary arms 154a' and 154b', in their turn respectively comprising pluralities of suction cups 152a' and 152b'. Vacuum pickup system <NUM>' is arranged to pick up nests <NUM> of containers <NUM> by means of suction cups 152a' and 152b'. Vacuum pickup system <NUM>' may also be arranged to pick up nests <NUM> of container closures <NUM> by means of suction cups 152a' and 152b'. As with vacuum pickup system <NUM>, vacuum pickup system <NUM>' may be raised and lowered in order to allow suction cups 152a' and 152b' to engage with different nests <NUM> of container closures <NUM> contained at differing depths inside tub <NUM>.

Suction cups 152a' and 152b' are arranged on rotary arms 154a' and 154b' as pluralities of sets of linearly arranged suction cups 152a' and 152b', each set of linearly arranged suction cups 152a' and 152b' being arranged at a different angle perpendicular to the longitudinal axes of rotary arms 154a' and 154b'. This arrangement allows rotary arms 154a' and 154b' to be rotated about their longitudinal axes in order to orient different sets of linearly arranged suction cups 152a' and 152b' to engage with different nests <NUM> of containers <NUM>. This allows the sets of suction cups 152a' and 152b' to be individually selectable for use. Rotation of rotary arms 154a' and 154b' may be performed manually. In other embodiments, rotation of rotary arms 154a' and 154b' may be by means of a suitable motorized drive incorporated in vacuum pickup system <NUM>' and controlled by controller <NUM> shown in <FIG>.

By selecting different sets of linearly arranged suction cups 152a' and 152b' via the rotation of rotary arms 154a' and 154b', the sets of suction cups 152a' and 152b' may be disposed to engage with different container nests <NUM> bearing containers <NUM>, or container closure nests <NUM> bearing container closures <NUM>.

<FIG> and <FIG> show vacuum pickup system <NUM>' as comprising two rotary arms, being rotary arms 154a' and 154b'. In other embodiments, one or more arms may be employed, all embodiments sharing the concept of a selectable configuration of suction cups. Whereas the selection of suction cup configurations in <FIG> and <FIG> is by means of rotation of arms 154a' and 154b' bearing suction cups 152a' and 152b', the selecting in other embodiments may be on a different basis of configuration, including, for example without limitation, lateral translation of suction-cup-bearing arms in a plane parallel to the rotation plane of rotary stage <NUM> in order to engage different sets of suction cups with container nests or container closure nests. In <FIG> and <FIG> suction cups are arranged in linear sets. In other embodiments non-linear arrangements of suction cups may be employed.

Turning now to <FIG> specifically, we consider members <NUM> and <NUM> in more detail. In one embodiment, reconfigurable stopping member <NUM> is shown as having two different ends of which a first end may be selected for use by suitable rotation of reconfigurable stopping member <NUM> about stopping member rotation axis <NUM> to a predetermined set position. In the set position, reconfigurable stopping member <NUM> provides a hard stop for a proximal end of container <NUM> against the selected end of reconfigurable stopping member <NUM> along a direction parallel to the longitudinal axes of rotary arms 154a' and 154b'. In this embodiment, reconfigurable stopping member <NUM> may be rotated through <NUM>° (degrees) to dispose the second end of reconfigurable stopping member <NUM> to stop container <NUM>. The second end of reconfigurable stopping member <NUM> may be configured to stop the proximal end of container <NUM> at a different point than where the first end of reconfigurable stopping member <NUM> stops the proximal end of container <NUM>.

Restraining member <NUM> is configured to push against a distal end of container <NUM>. While different mechanisms are contemplated to ensure the pushing action of restraining member <NUM>, one particular suitable mechanism involves providing restraining member <NUM> with suitable spring loading to rotate about axis <NUM>. By the above operation, reconfigurable stopping member <NUM> and restraining member <NUM> together allow container <NUM> to be positioned at an exact location parallel to the longitudinal axes of rotary arms 154a' and 154b'. The particular exact location is selectable by selecting the appropriate end of reconfigurable stopping member <NUM> to stop container <NUM>. This arrangement allows containers <NUM> of different dimensions parallel to the longitudinal axes of rotary arms 154a' and 154b' to be located at exact predetermined locations with respect to sets of suction cups 152a' and 152b'.

A particular set of suction cups 152a' and 152b' may be selected to match the selection of the particular end of reconfigurable stopping member <NUM>. In this way, vacuum pickup system <NUM>' may be set to a configuration that ensures that a selected size of container <NUM> is precisely positioned to allow container nests <NUM> within container <NUM> to be engaged by specific sets of suction cups 152a' and 152b'. Vacuum pickup system <NUM>' is thereby reconfigurable to engage with nests of different sizes within containers of different sizes.

In the interest of clarity, the description above, as well as <FIG> and <FIG>, show an arrangement that allows for the exact positioning of containers <NUM> along only one dimension in the rotation plane of rotary stage <NUM>, the dimension of the containers perpendicular to the one dimension being assumed to be identical. In such an arrangement, fiducial locating openings <NUM> and <NUM> are sized to constrain containers <NUM> in the perpendicular dimension in the rotation plane of rotary stage <NUM>.

In another embodiment, a further reconfigurable stopping member and restraining member may be added to the arrangement of <FIG> and <FIG> in order to address the positioning of container <NUM> in the perpendicular direction within the rotation plane of rotary stage <NUM>. To allow the positioning of container <NUM> in this perpendicular direction, fiducial locating openings <NUM> and <NUM> are not sized to constrain containers in any direction within the rotation plane of rotary stage <NUM>.

In the embodiments described above, reconfigurable stopping member <NUM> has been described as having two ends of which one is selected for use at any one time by rotating reconfigurable stopping member <NUM> about stopping member rotation axis <NUM>. In other embodiments, reconfigurable stopping member <NUM> may be shaped or configured to have more than two stopping ends, the ends being selectable by suitable rotation of reconfigurable stopping member <NUM> about stopping member rotation axis <NUM>. In one embodiment, in which the reconfigurable stopping member has a very large number of stopping ends, the reconfigurable stopping member may assume the shape of a cam, representing a large plurality of possible stopping ends that may be selected via rotation of the reconfigurable stopping member about a suitable stopping member rotation axis.

In general, the system described at the hand of <FIG> and <FIG> comprises a reconfigurable fiducial nest positioning system. The reconfigurable fiducial nest positioning system comprises a movable platform comprising fiducial locating opening <NUM>, reconfigurable stopping member <NUM>, and restraining member <NUM>. In the case of the system of <FIG> and <FIG>, the movable platform is rotary stage <NUM>. As explained later, other movable platforms are also contemplated. To the extent that, for example, tub <NUM> positionally constrains and locates nest <NUM> inside tub <NUM>, any system that fiducially locates tub <NUM> inherently also fiducially locates nest <NUM>.

The various embodiments contemplated all comprise a reconfigurable vacuum pickup system that may be configured to engage its suction cups with corresponding areas on a pharmaceutical container nest. The containers in the container nest may be closed by corresponding container closures suspended in a container closure nest. The planar surface of the container closure nest may have an outline that leaves pass-throughs on its perimeter for the suction cups to pass through to engage with the container nest. By way of example, in <FIG> pass-throughs <NUM> are shown on the perimeter of closure nest <NUM>. Alternatively or additionally, the container closure nest may have suitable openings in its planar interior to serve as pass-throughs for the suction cups to pass through to engage with the container nest. The vacuum pickup systems contemplated are further configured and disposed to pick up the combination of nested containers and their closures by the container nest, as opposed to by the closure nest.

In a general embodiment, a nest handling subsystem comprises a reconfigurable vacuum pickup system for picking up container nests and/or container closure nests may comprise one or more arms bearing a plurality of sets of suction cups. By reconfiguration of the vacuum pickup system a set of suction cups may be selected from among the plurality of sets of suction cups, the selected set of suction cups being pre-arranged to engage with a particular container nest or container closure nest. The selection may be on the basis of one or both of the size and the shape of the nest. The nest handling system may further comprise at least one pair of a reconfigurable stopping member <NUM> and a restraining member <NUM> disposed proximate opposing ends of a fiducial locating opening <NUM> for holding a tub <NUM> containing container nests <NUM> bearing containers <NUM> in order to engage with opposing ends of tub <NUM>. The stopping and restraining members are disposed to position tub <NUM> in a predetermined position that ensures that the selected set of suction cups may engage with the container nests and/or container closure nests.

As is the case with opening <NUM>, opening <NUM> of <FIG> may also be served by at least one set of a reconfigurable stopping member, being member <NUM> in this case, and a restraining member, being member <NUM> in this case. Reconfigurable stopping member <NUM> and restraining member <NUM> function with respect any tub in opening <NUM> in the same way as reconfigurable stopping member <NUM> and restraining member <NUM> function with respect any tub in opening <NUM>.

The various embodiments above have been described in terms of <FIG> and <FIG>, and <FIG> in which the vacuum pickup system <NUM>, <NUM> is described as part of a pharmaceutical filling system <NUM>. However, vacuum pickup system <NUM>', <NUM>' may also be employed in its own right other apparatus not limited to the filling system of <FIG>, or, in fact, to filling systems in general. Some other example applications include, without limitation, lyophilizing systems. It may be applied to suitable nests of any objects arranged in a predetermined pattern. Furthermore, while system <NUM> of <FIG> employs rotary stage <NUM>, reconfigurable vacuum pickup system <NUM>' may employ any suitable movable platform comprising suitable fiducial locating openings.

The method described above at the hand of <FIG> and <FIG> may now also be described in more detail with reference to <FIG> and <FIG>. Providing at least one vacuum pickup system as part of the providing a filling apparatus step [<NUM>] may comprise providing at least one reconfigurable vacuum pickup system <NUM>', the at least one reconfigurable vacuum pickup system <NUM>' comprising a plurality of sets of suction cups 152a' and 152b'.

Providing a filling apparatus step [<NUM>] may comprise providing rotary stage <NUM> with destination fiducial locating opening <NUM> and at least two source fiducial locating openings <NUM>, <NUM>, each source fiducial opening having at least one pair of reconfigurable stopping member <NUM> and restraining member <NUM>.

Transferring step [<NUM>] may comprise operating at least a first reconfigurable stopping member <NUM> to stop container tub <NUM> at a predetermined container tub position and operating at least first restraining member <NUM> to restrain container tub <NUM> at the predetermined container tub position.

Transferring step [<NUM>] may comprise operating at least a second reconfigurable stopping member <NUM> to stop container closure tub <NUM> at a predetermined closure tub position and operating at least second restraining member <NUM> to restrain container tub <NUM> at the predetermined closure tub position.

Operating [<NUM>] the at least one vacuum pickup system <NUM>', <NUM>' may comprise configuring the at least one reconfigurable vacuum pickup system <NUM>', <NUM>' to select a first predetermined set of suction cups disposed to engage with container nest <NUM>.

Operating [<NUM>] of one of the at least one vacuum pickup system <NUM>', <NUM>' may comprise configuring the at least one reconfigurable vacuum pickup system <NUM>', <NUM>' to select a second predetermined set of suction cups disposed for engaging with container closure nest <NUM>.

The method may further comprise operating [<NUM>] the at least one vacuum pickup system <NUM>', <NUM>' with the first predetermined set of suction cups selected to engage with container nest <NUM> and jointly remove container nest <NUM> and container closure nest <NUM> from ramming system <NUM>.

We have considered in <FIG> and <FIG> alternative embodiments of the arrangements of vacuum pickup systems <NUM> and <NUM> of <FIG> in the form of vacuum pickup systems <NUM>' and <NUM>'; and the positioning arrangements associated with source openings <NUM> and <NUM> in the form of elements <NUM>, <NUM>, <NUM>, and <NUM>. We now turn our attention to alternative embodiments for the arrangements around destination opening <NUM> of <FIG> and <FIG>. <FIG> and its close up view in <FIG> show the system of <FIG> with a different embodiment of the arrangement around destination opening <NUM>. While cameras <NUM> and <NUM> of <FIG> may be employed in conjunction with controller <NUM> and rotation of rotary stage <NUM> to position nest <NUM> at opening <NUM>, and to position nest <NUM> over nest <NUM> at opening <NUM>, the adjustable destination fiducial positioning system of <FIG> and <FIG> comprising rotary positioning elements 164a and 164b may be alternatively or additionally employed to accurately position nests <NUM> and <NUM>.

Typical industrial container nests are not manufactured to a dimensional standard, and, as a result, any system for filling and closing nested containers <NUM> should have a mechanism to accurately position differently sized nests <NUM> bearing containers <NUM>. To this end, rotary positioning elements 164a and 164b may have different sets of paired positioning surfaces 167a, 167b and 163a, 163b allowing nests <NUM> of specific dimensions to be accurately fitted between such paired positioning surfaces. In <FIG>, nest <NUM> fits such that its two opposing ends in a first dimension touch mutually facing surfaces 167a and 167b of rotary positioning elements 164a and 164b respectively. By mutually counter-rotating elements 164a and 164b about respectively axes 166a and 166b, surfaces 167a and 167b may be made to face each other and may thereby allow the precise positioning between them of a nest of different length in the first dimension.

As is evident from <FIG>, when surfaces 167a and 167b face each other, the nest positioned snugly between them may be retained in a precise and predetermined vertical position by resting on surfaces 165a and 165b of rotary positioning elements 164a and 164b respectively. When surfaces 163a and 163b face each other, the alternative nest positioned snugly between them may retained in a precise and predetermined vertical position by resting on surfaces 161a and 161b of rotary positioning elements 164a and 164b respectively. Elements 164a and 164b may be rotated manually about axes 166a and 166b respectively. In some embodiments, the rotation of elements 164a and 164b may be done automatically, for example, by motorized drives controlled by controller <NUM> and suitable control software. That control may be based on predetermined dimensional data relating to the nest being positioned between the surfaces of elements 164a and 164b. It may also be based, independently or in combination, on input data derived from imaging data obtained from cameras <NUM> and/or <NUM>. Further, the rotation may take place as nest <NUM> is lowered into position so that the particular surfaces of elements 164a and 164b destined to engage with the opposing ends of nest <NUM> along the first dimension may serve as closing horizontal grip on nest <NUM> as the surfaces rotate toward the position in which they face each other. In this embodiment, the horizontal positioning and vertical positioning of a nest between elements 164a and 164b are not mutually independent.

Another arrangement as shown in <FIG> and <FIG> for the first dimension of nest <NUM>, may also be established for the second planar dimension of nest <NUM> perpendicular to the first dimension. This allows any nest <NUM> placed at opening <NUM> to be accurately located in a location predetermined by the choice of setting of rotary positioning elements 164a and 164b.

Another embodiment of rotary positioning elements is shown in <FIG> and <FIG>. In contrast with the embodiment of <FIG> and <FIG> described immediately above, the horizontal positioning and vertical positioning of a nest between two mutually counter-rotatable elements 164a' and 164b' in <FIG> and <FIG> are mutually independent positioning actions. This is achieved by employing, in each of the two mutually perpendicular planar dimensions addressed in the embodiment immediately above, a pair of fixed opposing planar tabs 165a' and 165b' to position nest <NUM> in the vertical dimension, and a pair of rotary positioning elements 164a' and 164b' to position nest <NUM> in the first horizontal dimension. In this embodiment, each of elements 164a' and 164b' comprises two rotatable elements ganged on axles 166a' and 166b' respectively to rotate in unison and mutual alignment either side of planar tabs 165a' and 165b' within bosses 169a' and 169b' respectively. The sets of rotary elements 164a' and 164b', beyond each being divided in to two ganged elements, serve to confine nest <NUM> in the horizontal dimension in the same fashion as rotary elements 164a and 164b in the embodiment of <FIG> and <FIG> described immediately above.

While elements 164a' and 164b' may be designed to be of more complex shape, we show in <FIG> and <FIG> a very simple implementation in which surfaces 167a' of rotary elements 164a' and surfaces 167b' of rotary elements 164b' serve to position nest <NUM> in the first horizontal dimension. By rotating elements 164a' joined by axle 166a' counter-clockwise within boss 169a' and rotating elements 164b' joined by axle 166b' clockwise within boss 169b', surfaces 163a' and 163b' may be made to face each other and thereby a nest of different length in the first horizontal dimension may be positioned and accurately located between elements 164a' and 164b'.

Ganged elements 164a' and 164b' may be rotated manually about the axes of axles 166a' and 166b' respectively inside bosses 169a' and 169b' respectively. In some embodiments, the rotation of elements 164a' and 164b' may be done automatically by motorized drives controlled by controller <NUM> and suitable control software. That control may be based on predetermined dimensional data relating to the nest being positioned between the surfaces of elements 164a' and 164b'. It may also be based, independently or in combination, on input data derived from imaging data obtained from cameras <NUM> and/or <NUM>. Further, the rotation may take place as nest <NUM> is lowered into position so that the particular surfaces of elements 164a' and 164b' destined to engage with the opposing ends of nest <NUM> along the first dimension may serve as closing horizontal grip on nest <NUM> as the surfaces rotate toward the position in which they face each other.

<FIG> and <FIG> show a further set of paired mutually counter-rotatable rotary positioning elements, not numbered for the sake of clarity, ganged similarly to rotary elements 164a' and 164b', and disposed to accurately locate nest <NUM> independently in the vertical dimension and in a second planar dimension of nest <NUM> perpendicular to the first dimension.

In a further aspect, described at the hand of <FIG>, a method is provided for filling nested pharmaceutical containers <NUM> with a pharmaceutical fluid substance, the method comprising: providing [<NUM>] filling system <NUM> comprising sterilizable chamber <NUM> capable of maintaining an aseptic condition, chamber <NUM> comprising filling station <NUM> and planar rotary stage <NUM> having destination locating structure <NUM>, 164a, 164b, 164a', 164b'; transferring [<NUM>] into chamber <NUM> at least one container tub <NUM> sealed by container tub cover <NUM> and containing container nest <NUM> bearing a plurality of pharmaceutical containers <NUM>; aseptically sealing [<NUM>] chamber <NUM>; establishing [<NUM>] an aseptic condition within chamber <NUM>; transferring [<NUM>] into destination locating structure <NUM>, 164a, 164b, 164a', 164b' container nest <NUM> bearing the plurality of pharmaceutical containers <NUM> such that container nest <NUM> is held in place; and dispensing [<NUM>] the pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers <NUM> by operating both rotary stage <NUM> and filling station <NUM>. Operating filling station <NUM> may include rotating filling station <NUM>. Dispensing the pharmaceutical fluid substance may comprise dispensing the pharmaceutical fluid substance on an iterative and serial basis into containers <NUM>.

Providing [<NUM>] filling system <NUM> may comprise providing a filing apparatus comprising at least one cover removal station <NUM> within chamber <NUM> and wherein transferring into the destination locating structure container tub <NUM> comprises removing container tub cover <NUM> from container tub <NUM> by operating both rotary stage <NUM> and the at least one cover removal station <NUM>. Operating the at least one cover removal station <NUM> may comprise rotating the at least one cover removal station <NUM>. Providing [<NUM>] filling system <NUM> may comprise providing within chamber <NUM> at least one cover removal station <NUM> having engagement tool <NUM>, transferring [<NUM>] into chamber <NUM> at least one container tub <NUM> may comprise attaching to container tub <NUM> cover removal fixture <NUM>; and wherein operating the at least one cover removal station <NUM> comprises engaging engagement tool <NUM> with cover removal fixture <NUM>.

The method may further comprise transferring [<NUM>] into chamber <NUM> container closure tub <NUM> sealed by a container closure tub cover and containing at least one container closure nest <NUM> bearing a plurality of pharmaceutical container closures <NUM>. The method may further comprise positioning [<NUM>] one of the at least one closure nests <NUM> to align closures <NUM> in the at least one closure nest <NUM> with corresponding containers <NUM> in container nest <NUM>; transferring [<NUM>] nests <NUM>, <NUM> of aligned closures <NUM> and containers <NUM> to a ramming station by rotating rotary stage <NUM>; and forcing [<NUM>] closures <NUM> into corresponding containers <NUM>. The method may further include adjusting tub locating structure <NUM>, <NUM> to accommodate a size of closure nest tub <NUM>. Positioning [<NUM>] one of the at least one closure nest <NUM> may comprise: obtaining image information about the one of the at least one closure nests <NUM>; and positioning the one of the at least one closure nests <NUM> based on the image information. Positioning [<NUM>] one of the at least one closure nest <NUM> may comprise: applying a vacuum to suction cups <NUM>, 152a, 152b, 152a', 152b'; lifting container closure nest <NUM> with the suction cups; and operating rotary stage <NUM>.

Transferring [<NUM>] into the destination locating opening container nest <NUM> may comprise: applying a vacuum to the suction cups; lifting container nest <NUM> with the suction cups; and operating rotary stage <NUM>. The method may further include selecting one of a plurality of sets of suction cups and wherein the applying a vacuum to suction cups is performed for the selected set of suction cups. The selecting may include rotating one of the plurality of sets of suction cups into position. The method may further include adjusting destination locating structure <NUM>, 164a, 164b, 164a', 164b' to accommodate a size of container nest <NUM>. The adjusting may be performed in two at least generally orthogonal directions. The method may further include adjusting tub locating structure <NUM>, <NUM> to accommodate a size of container nest tub <NUM>.

In a further aspect, a method is provided (see <FIG>) for removing within a controlled environment enclosure a container cover from a sealed container, for example tub <NUM> or tub <NUM>, the sealed container being sealed by the container cover, for example cover <NUM>, the method comprising: providing the container in controlled environment enclosure <NUM> with cover <NUM> sealed to a sealing surface of a lip of the container to seal the contents of the container against decontamination, cover <NUM> having cover removal fixture <NUM>, decontaminating the sealed container in controlled environment enclosure <NUM>, engaging cover removal fixture <NUM> with engagement tool <NUM>, and removing the cover from the container using engagement tool <NUM>. Engaging may involve engaging cover removal fixture <NUM> with fork-shaped engagement tool <NUM>. Engaging may involve engaging a ball-shaped appendage on cover removal fixture <NUM>.

Providing may include providing sterilized pharmaceutical containers <NUM> or closures <NUM> in the sealed container, for example tub <NUM> or <NUM>, before the decontaminating. Attaching may take place before the container is in controlled environment enclosure <NUM>. Decontaminating the sealed container in controlled environment enclosure <NUM> may take place before removing cover <NUM>. Removing cover <NUM> may include moving engagement tool <NUM> relative to container <NUM>. Removing cover <NUM> may include moving both container <NUM> and engagement tool <NUM>. The method may further comprise attaching cover removal fixture <NUM> to cover <NUM> before providing container <NUM> in the controlled environment enclosure.

<FIG> shows a drawing of subsystems of a further embodiment of an apparatus for filling pharmaceutical containers with a pharmaceutical fluid product, based on the subsystems shown in <FIG>, <FIG>, <FIG>, <FIG> and <FIG>. For the sake of clarity, several subsystems have been omitted in order to show only aseptic sealable chamber <NUM> of <FIG>; rotary stage <NUM> of <FIG> and <FIG>; openings <NUM>, <NUM>, and <NUM> of <FIG>; with container nest <NUM> bearing pharmaceutical containers <NUM>, nest <NUM> held in position by the arrangement shown in <FIG>. In <FIG>, fill arm <NUM> of <FIG> is replaced by articulated robotic fill arm <NUM>'. Any alternative fiducial arrangement for holding nest <NUM> may be employed as long as it allows the opening of each container <NUM> to be known with suitable accuracy and precision for reliably dispensing droplets of pharmaceutical fluid into containers <NUM>.

To the aforementioned elements in <FIG> is added a droplet monitoring subsystem <NUM>, shown separately in <FIG>, comprising illuminating imager system <NUM>, mirror <NUM>, and retroreflector <NUM>. Droplet monitoring subsystem <NUM> may be controlled by controller <NUM>, to which end controller <NUM> is in communication with droplet monitoring subsystem <NUM>. Controller <NUM> may comprise a memory and a processor. As in the case of fill arm <NUM> of <FIG> and <FIG>, articulated robotic fill arm <NUM>' is supplied with pharmaceutical fluid via a pharmaceutical fluid product feed line <NUM>. In <FIG>, fill arm <NUM>' is equipped with a pharmaceutical fluid product dispenser head <NUM>'. Dispenser head <NUM>' is arranged and configured to produce droplets of pharmaceutical fluid of consistent volume and within a limited range of droplet shapes to travel down along droplet path <NUM>. To this end, dispenser head <NUM>' may be equipped with a suitable nozzle. Controller <NUM> may control the dispensing action of dispenser head <NUM>', to which end controller <NUM> may be in communication with dispenser head <NUM>' or a pump supplying dispenser head <NUM>' with pharmaceutical fluid. Imager system <NUM> may comprise a telecentric lens, thereby to render imager system <NUM> capable of making consistent size measurements of droplets produced by dispenser head <NUM>'.

Illuminating imager system <NUM> is arranged and disposed to illuminate retroreflector <NUM> and to obtain high speed images of droplets <NUM> dispensed by dispenser head <NUM>' to travel along droplet path <NUM> into any container <NUM>. The line a-a' in <FIG> indicates the light beam path. Since rotary stage <NUM> moves every container <NUM> along a circular path around the rotation axis of rotary stage <NUM>, articulated robotic fill arm <NUM>' is operated to move dispenser head <NUM>' along a linear trajectory following the imaging path a-a' of droplet monitoring subsystem <NUM>. In this implementation, therefore, both rotary stage <NUM> and articulated robotic fill arm <NUM>' are operated to position any container <NUM> for filling by dispenser head <NUM>'. Any operating of fill arm <NUM>' may, in addition to the operating of rotary stage <NUM>, be controlled via controller <NUM>. To this end, controller <NUM> is in communication with both fill arm <NUM>' and rotary stage <NUM>, allowing controller <NUM> to coordinate the motion of fill arm <NUM>' and rotary stage <NUM>.

Software may be supplied for loading into the memory of controller <NUM> and configured, when executed by the processor, for controlling dispensing of the pharmaceutical fluid droplets <NUM> by fluid dispensing head <NUM>', and for collection of images of pharmaceutical fluid droplets <NUM> along droplet path <NUM>. The software may also allow controller <NUM>' to control robotic fill arm <NUM>' and rotary stage <NUM>.

An alternative embodiment, shown in <FIG>, shows another articulated robotic fill arm <NUM>" into which alternative droplet monitoring subsystem <NUM>' has been integrated. This particular embodiment employs two mirrors <NUM>' and <NUM>' along with illuminating imager system <NUM>' and retroreflector <NUM>'. We retain the same numbering, namely <NUM>', for dispenser head and <NUM> for pharmaceutical fluid product feed line. Illuminating imager system <NUM>' is arranged and disposed to illuminate retroreflector <NUM>' and to obtain via mirrors <NUM>' and <NUM>' high speed images of droplets <NUM> dispensed by dispenser head <NUM>' to travel along droplet path <NUM> into any container <NUM>. In this particular implementation, only articulated robotic fill arm <NUM>" needs to be operated in order to position any container <NUM> held in nest <NUM> for filling by dispenser head <NUM>' and rotary stage <NUM> may be held stationary during the positioning of filling of all containers <NUM> held in nest <NUM>. In a more general case, both rotary stage <NUM> and articulated robotic fill arm <NUM>" may be operated to position any container <NUM> for filling by dispenser head <NUM>'. Any operating of fill arm <NUM>" may, in addition to the operating of rotary stage <NUM>, be controlled via controller <NUM>. To this end, controller <NUM> is in communication with both fill arm <NUM>" and rotary stage <NUM>. Imager system <NUM>' may comprise a telecentric lens, thereby to render imager system <NUM>' capable of making consistent size measurements of droplets produced by dispenser head <NUM>'.

The use of droplet monitoring subsystems of the present invention is not limited to the rotary stage pharmaceutical filling systems of <FIG>. They may also be employed in any system in which any fluid is dropwise dispensed into containers, whether nested or not. One group of filling systems suitable for filling pharmaceutical containers with a pharmaceutical fluid in an aseptic chamber using the droplet monitoring system of the present invention employs robotic arms to hold containers by means of a suitable end effector. The robotic arms may be articulated robotic arms and may be hermetically sealed to chamber <NUM>. Suitable examples of such systems are provided in <CIT>, <CIT>, <CIT>, <CIT>, and <CIT>, the disclosures of which are all wholly incorporated herein by reference. We describe below embodiments of the droplet monitoring subsystem of the present invention used in conjunction with an articulated arm of the type described in more detail in these four listed publications.

<FIG> shows droplet monitoring system <NUM> of <FIG> implemented in a pharmaceutical container filling system having aseptic sealable chamber <NUM>' in which container nest <NUM> bearing pharmaceutical containers <NUM> is held by end effector <NUM> of articulated arm <NUM>. Articulated arm <NUM> may be a robotic articulated arm. In some embodiments, articulated robotic arm <NUM> may be controlled by suitable controller <NUM>'. To this end, as shown in <FIG>, controller <NUM>' is in communication with robotic arm <NUM>. Robotic arm <NUM> may be of the type described in detail in the publications listed above and incorporated by reference. Controller <NUM>' may be, for example without limitation, controller <NUM> used by the filling system described at the hand of <FIG> of <CIT> or controller <NUM> of <FIG> of <CIT>. Articulated arm <NUM> may be, for example without limitation, articulated arm <NUM> of <FIG> of <CIT>, articulated arm <NUM> of <FIG> of <CIT>, or articulated arm <NUM> of <FIG> of <CIT>. Controller <NUM>' may also be used to control droplet monitoring system <NUM>, to which end it is in communication with droplet monitoring system <NUM>.

<FIG> shows the droplet monitoring system <NUM>' of <FIG> employed in the same pharmaceutical container filling system as described at the hand of <FIG>. Controller <NUM>' may also be used to control droplet monitoring system <NUM>', to which end it is in communication with droplet monitoring system <NUM>'.

In further embodiments of the system, both dispensing head <NUM>' and container(s) <NUM> may be moved by robotic arms, being robotic arms <NUM>', <NUM>" on the one hand and <NUM> on the other. Either or both of the robotic arms may be articulated robotic arms of the types described in the incorporated United States Patent Publications listed above. In yet further embodiments, both dispensing head <NUM>' and container <NUM> may be in fixed positions, these particular embodiments pertaining, for example, to the filling of single container <NUM> at a time.

The embodiments shown in <FIG>, <FIG>, <FIG> and <FIG> all employ a retroreflector <NUM>, <NUM>' illuminated by a light source housed in the illuminating digital imager system <NUM>, <NUM>'. In other embodiments, droplets <NUM> may be backlit, or illuminated from any other angle. In such embodiments, the imager systems do not require an integrated illuminator and the illuminator may be disposed elsewhere separate from the imager.

We now turn to a method, described at the hand of the flowchart in <FIG>, for aseptically dispensing a pharmaceutical fluid into pharmaceutical container <NUM>, the method comprising: providing [<NUM>] sterilizable chamber <NUM>, <NUM>' capable of maintaining an aseptic condition, the chamber comprising pharmaceutical fluid dispensing head <NUM>' configured for producing droplets <NUM> of the pharmaceutical fluid and droplet monitoring system <NUM>, <NUM>' comprising digital imager <NUM>, <NUM>'; establishing [<NUM>] within sterilizable chamber <NUM>,<NUM>' an aseptic condition; providing [<NUM>] within sterilizable chamber <NUM>, <NUM>' aseptic pharmaceutical container <NUM>; dispensing [<NUM>] a plurality of droplets <NUM> of the fluid from dispensing head <NUM>' along droplet path <NUM> into container <NUM>; obtaining [<NUM>] from imager <NUM>,<NUM>' a plurality of images of at least one of the plurality of droplets <NUM> along droplet path <NUM>; and determining [<NUM>] from the plurality of images a volume of fluid dispensed into container <NUM>.

The method may, in some embodiments, further comprise ceasing [<NUM>] dispensing of the fluid based on the volume of fluid dispensed into container <NUM>. In other embodiments, ceasing may be based on the length of time of dispensing of the pharmaceutical fluid into container <NUM> or on weighing of the amount of pharmaceutical fluid dispensed into container <NUM>. The droplet information from the imager may therefore be used either in merely monitoring the pharmaceutical fluid dispensing process, or as a way of controlling the fluid dispensing process, as in when it forms the basis of the ceasing [<NUM>].

Determining [<NUM>] from the plurality of images a volume of fluid dispensed into container <NUM> may comprise determining a volume of at least one of the plurality of droplets <NUM>. Determining the volume of the at least one of the plurality of droplets <NUM> may comprise: identifying first and second total portions of the at least one droplet <NUM> appearing respectively to the left and to the right of droplet path <NUM> in at least one image of the at least one droplet <NUM>; calculating first and second volumes of the at least one of the plurality of droplets <NUM> by separately mathematically rotating respectively the first and second total portions of droplet <NUM> through 2π about droplet path <NUM>; and equating the volume of the at least one of the plurality of droplets <NUM> to the average of the first and second volumes. The term "total portion" is used in this specification to describe all of the side-on planar view of the droplet to either the left or the right side of droplet path <NUM>. The two total portions of the droplet will not in general be quite equal. The two planar total portions, or approximate "halves", are then taken and separately rotated in software about droplet path <NUM> to obtain two "droplet volumes", which are then averaged to obtain the assumed volume of the droplet.

Obtaining [<NUM>] from imager <NUM>, <NUM>' a plurality of images of at least one of the plurality of droplets <NUM> along the droplet path may comprise obtaining the plurality of images over a predetermined portion of the droplet path over which droplets <NUM> have a stable shape. In this specification, the shape of droplets may be considered "stable" when the droplets have distinctly detached from the dispensing head <NUM>' and have assumed a shape confined to a predetermined perimeter as viewed by the imager, the shape being allowed to vary within that predetermined perimeter.

Determining [<NUM>] from the plurality of images a volume of fluid dispensed into container <NUM> may comprise determining a volume of each droplet <NUM> dispensed into container <NUM>. Ceasing dispensing of the fluid based on the volume of fluid dispensed into container <NUM> may comprise ceasing dispensing of the fluid when a total amount of fluid dispensed into container <NUM> equals a predetermined volume. The predetermined volume may be, for example without limitation, a single adult human dosage volume of the pharmaceutical fluid. Other predetermined volumes may be integer multiples of dosages or volumes specified by a health authority, regulatory body, or MSDS sheet of the pharmaceutical fluid.

In other embodiments, determining [<NUM>] from the plurality of images a volume of fluid dispensed into container <NUM> may comprise determining a representative volume of droplet <NUM>, counting the total number of droplets dispensed into container <NUM>, and then multiplying the representative droplet volume with the number of droplets. Determining a representative volume of droplet <NUM> may comprise measuring only a first droplet and assuming it to be representative. In other embodiments, determining a representative volume of droplet <NUM> may comprise measuring a plurality of droplets and calculating an average droplet volume across the plurality of droplets.

Obtaining [<NUM>] from imager <NUM>, <NUM>' a plurality of images of at least one of the plurality of droplets <NUM> along droplet path <NUM> may comprise obtaining the plurality of images employing light reflected to the imager by retroreflector <NUM>, <NUM>'. Obtaining from imager <NUM>, <NUM>' a plurality of images of at least one of the plurality of droplets <NUM> along droplet path <NUM> may comprise obtaining the plurality of images by using a telecentric lens. The telecentric lens may be incorporated within imager <NUM>, <NUM>'. Providing within sterilizable chamber <NUM>, <NUM>' aseptic pharmaceutical container <NUM> may comprise providing aseptic pharmaceutical container <NUM> within container nest <NUM>.

The method may further comprise moving at least one of dispensing head <NUM>' and container <NUM> to position [<NUM>] an opening of container <NUM> under dispensing head <NUM>' to receive droplets <NUM> along droplet path <NUM>. Moving the container may comprise operating robotic arm <NUM>. Moving container <NUM> may comprise moving container nest <NUM> holding container <NUM>. Operating robotic arm <NUM> may comprise operating an articulated robotic arm. Moving dispensing head <NUM>' may comprise operating robotic arm <NUM>', <NUM>". Moving dispensing head <NUM>' may comprise operating articulated robotic arm <NUM>', <NUM>".

Claim 1:
A method for aseptically dispensing a pharmaceutical fluid into a pharmaceutical container (<NUM>), the method comprising:
providing a sterilizable chamber (<NUM>) capable of maintaining an aseptic condition, the chamber comprising a pharmaceutical fluid dispensing head (<NUM>) configured for producing droplets (<NUM>) of the pharmaceutical fluid and a droplet monitoring system (<NUM>, <NUM>') comprising a digital imager (<NUM>, <NUM>');
establishing within the sterilizable chamber an aseptic condition;
providing within the sterilizable chamber an aseptic pharmaceutical container (<NUM>);
dispensing a plurality of droplets of the fluid from the dispensing head into the container along a droplet path (<NUM>);
obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path; and
determining from the plurality of images a volume of fluid dispensed into the container.