US20130020727A1 - Modular cassette synthesis unit - Google Patents
Modular cassette synthesis unit Download PDFInfo
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- US20130020727A1 US20130020727A1 US13/550,026 US201213550026A US2013020727A1 US 20130020727 A1 US20130020727 A1 US 20130020727A1 US 201213550026 A US201213550026 A US 201213550026A US 2013020727 A1 US2013020727 A1 US 2013020727A1
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- cassettes
- reaction
- modular
- reagent
- reagent packs
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0006—Controlling or regulating processes
- B01J19/004—Multifunctional apparatus for automatic manufacturing of various chemical products
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- G—PHYSICS
- G05—CONTROLLING; REGULATING
- G05B—CONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
- G05B15/00—Systems controlled by a computer
- G05B15/02—Systems controlled by a computer electric
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00002—Chemical plants
- B01J2219/00004—Scale aspects
- B01J2219/00006—Large-scale industrial plants
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00002—Chemical plants
- B01J2219/00018—Construction aspects
- B01J2219/0002—Plants assembled from modules joined together
Definitions
- aspects of the present invention relate to methods and systems for reagent interaction in a modular context. More specifically, aspects of the present invention relate to methods and systems that effectuate and control reagent interaction through the remote action of pneumatic valves in a modular context
- Nuclear medicine is a branch of medical imaging that uses small amounts of radioactive materials to diagnose or treat a variety of diseases, including many types of cancers, heart disease, and other abnormalities within the body.
- PET positive emission tomography
- a radiopharmaceutical that includes a radionuclide tracer is introduced into the body where it eventually accumulates in an organ or area of the body being examined.
- the radionuclide gives off energy in the form of POSITRONS, which are detected by devices, including a PET scanner.
- radiopharmaceuticals that incorporate the radionuclide fluorine-18, such as fluorodeoxyglucose (FDG), 3′-deoxy-3′-[ 18 F]-pluorothymidine (FLT), [ 18 F]-fluoromisonidazol (F-MISO), (4-[ 18 F]-fluorobenzoyl)norbiotinamide (FBB) and PET Perfusion Agents (PPA), are commonly used.
- radioactive nature of radiopharmaceuticals Due to the radioactive nature of radiopharmaceuticals, special consideration must be taken in their preparation, handling, and delivery. Production of fluorine-18 for use in a radiopharmaceutical is often difficult and/or expensive, requiring specialized equipment, such as a cyclotron. The production of the radioisotope often occurs at a remote facility by a third party, from which the hospital or lab receives patient doses that are ready to inject. Even if the radioisotope happens to be produced on site, final production of the radiopharmaceuticals used in many diagnostic imaging procedures requires manual preparation in a special aseptic environment to ensure a safe injectable product that is free of environmental contaminants. In addition, precise accounting of the radioactive nature of the radionuclide to be used in the radiopharmaceutical for each procedure is required, while taking into account that the bulk radionuclide product continuously decays over time.
- Shielded containment systems for use in combining cyclotron-produced radionuclides with non-radionuclide components to produce radiopharmaceuticals have been developed. There are, however, many drawbacks of these systems. In particular, typically only one radiopharmaceutical may be produced in a production run. After a run, various radionuclide raw material components and physical system components must be replaced or decontaminated, which can greatly delay the production process and/or make the process much less efficient. Further, many aspects of production of radiopharmaceuticals in such related art systems are not automated and/or may require time-consuming and/or awkwardly controllable hand production steps.
- the radioactivity and/or quantities of the raw radionuclide and/or the produced radiopharmaceutical may be inaccurate and/or difficult to determine precisely.
- Necessary quality control to be performed on the output radiopharmaceutical products may be time-consuming, inaccurate, and/or require high levels of worker input/skill, further hampering production and/or timely delivery of the produced radiopharmaceuticals.
- a large and complex setup is sometimes needed to channel liquids, reagents and/or compounds towards a reactor vessel.
- Channeling various ingredients towards the reactor vessel generally involves the use of tubing, threaded connectors, valving and the like, which are often a source of fluid losses due to fluid being retained or trapped therein. The uncertainty and un-repeatability of such losses can create errors in determining the respective amounts of ingredients necessary to complete a desired reaction process with a desired specific yield.
- some ingredients or reagents may have a short shelf life and may have to be used very quickly after manufacture or after exposure to the environment, which further increases the need for complex reaction vessels.
- the radioactive input may be a radioactive isotope typically produced in a cyclotron.
- methods and systems that provide for chemical and/or physical interactions between a plurality of reagents and ingredients, while ensuring that subsequent reactions are not contaminated by remnants from previous reactions by providing, for example, one or more disposable reaction modules.
- reaction modules may be removably connected to one another, as such methods and systems may be useful in providing the ability to quickly and efficiently dispose a plurality of ingredients and/or reagents in contact with each other in a reaction vessel or chamber.
- systems and methods that provide for chemical and/or physical interactions between a plurality of reagents and ingredients when the reagents have a relatively short lifetime and must be mixed within a short period of time after being manufactured or exposed to the environment.
- a compact modular cassette system for the synthesis of radiopharmaceutical products including a modular unit having valve plates, a reaction cassette, a reagent pack, and other seal and connector plates, to ensure that reagents can be mixed together inside one or more chambers of the reaction cassette in a timely and efficient manner.
- a modular system where both the reaction cassette and the reagent pack are removable may be helpful, where either the reagent container, the reaction cassette, or both, can be removed from the modular cassette system and discarded after a desired reaction or process has taken place and, for example, the product of the reaction has been collected or further treated in a subsequent process.
- the physical connection between a reagent pack and the reaction cassette may be provided via one or more corresponding channels etched, molded or machined in at least one of the reagent pack and the reaction cassette.
- reagent transfer between a reagent pack and a chamber inside the reaction cassette may be controlled by a module located remotely from both the reagent pack and the reaction cassette, which remains part of the overall modular system.
- a broad side or broad face of the reaction cassette may be coupled to a corresponding broad side of the reagent pack or any other module that is part of the overall modular cassette system in order to allow for fluidic connections at various locations between neighboring cassettes, packs and other modules.
- the modular unit may include a number of power and fluid supply devices that are to remain stationary, and accordingly, the removable reaction cassette may be placed at a front end of the overall modular unit to facilitate operator interaction and, for example, to facilitate removal of the cassette to a disposal container.
- the modular unit may be coupled to the cassette so as to be located behind the cassette, which increases convenience of use of the modular unit when the modular unit includes communication lines coupling the cassette to supply lines located at a back portion of the modular unit.
- the module/cassette structure may also allow for an automatic ejection of the cassette. This may be advantageous in reducing operator exposure to the cassette and the hazardous radioactivity within waste droplets remaining within the cassette.
- the mini cell shielding structure may allow for the ejected cassettes to be guided to a shielded waste collection container. Further, future systems, with further development, may automatically install a fresh replacement cassette.
- FIG. 1 shows a system for radiopharmaceutical preparation according to an aspect of the invention
- FIGS. 2A-2C show perspective views of a multi-synthesis unit according to an aspect of the invention
- FIGS. 3A-3C show perspective views of a synthesis module according to an aspect of the invention.
- FIG. 4 is a perspective view of a modular cassette system, according to various aspects of the current invention.
- FIG. 5 is a perspective view of a synthesis module, according to various aspects of the current invention.
- FIGS. 6-7 are perspective views of components of a modular cassette system, according to various aspects of the current invention.
- FIG. 8 illustrates a principle of fluid transfer according to various aspects of the current invention
- FIG. 9 presents an example system diagram of various hardware components and other features, for use in accordance with an aspect of the present invention.
- FIG. 10 is a block diagram of various example system components, in accordance with an aspect of the present invention.
- FIG. 11 illustrates a flow diagram for performing a synthesis method in accordance with an aspect of the present invention.
- FIG. 1 shows a system for radiopharmaceutical preparation according to an aspect of the invention.
- the system 50 may include a shielded container, such as a mini-cell 52 .
- the mini-cell 52 may include compartments 54 , 56 , and 58 .
- Compartments 54 and 56 may each house a framework for mounting specific units, such as multi-synthesis units 60 .
- a multi-synthesis unit 60 may be about 26-30 inches wide, 18-22 inches tall, and 18-24 inches deep.
- a multi-synthesis unit 60 may be placed on a sliding track, for example, within a compartment so that the multi-synthesis unit 60 can easily be accessed for service or replacement of the modules or their components.
- Each multi-synthesis unit 60 may hold any number of modules as can be accommodated, while maintaining the overall compactness of the system 50 .
- the multi-synthesis units 60 may each incorporate up to six modules.
- the modules may include, but are not limited to, accessory modules 62 and synthesis modules 64 .
- the components of the modules 62 or 64 may be housed in a container that allows the modules to be removed easily from a multi-synthesis unit 60 .
- a radiopharmaceutical material may be prepared in a synthesis module 64 with reagents provided from the reagent pack.
- An additional compartment 58 may be used to store waste products of the radiopharmaceuticals synthesis process of the system 50 , for example.
- FIG. 2A is a perspective view of a six-module multi-synthesis unit, similar to the multi-synthesis unit 60 discussed in FIG. 1 , according to an aspect of the invention.
- the unit 60 may be sized to fit into a reduced mini-cell volume, and positioned on slides so that it may be pulled forward in, e.g., the mini-cell 52 , for service.
- individual modules 62 or 64 may be pulled forward in the multi-synthesis unit 60 for service or replacement.
- quick disconnects and hands-free connections between the modules and a multi-synthesis backplane/bus system may be implemented to facilitate rapid module replacement. For example, as shown in FIGS.
- the backplane/bus approach may allow individual modules to slide into the system and through “quick disconnects” tie into utilities to include power, gasses, solvents, control connections and the like.
- the overall electronics and control package may tie in to this bus and allow the control to be located remotely and shielded away from the sources of radioactivity, which traditionally has created reliability issues. This is due to the failure of electronic components exposed to high levels of radioactivity in traditionally packaged synthesis units combining electronics (controls) and electromechanical components.
- package of controls and electronics may be mounted in separate electrical box outside the shielded cell, and the package may be shared among a group of synthesis units (e.g., 6-12 synthesis units).
- a cable management scheme may permit the entire multi-synthesis unit 60 to be pulled forward in the mini-cell for service without disconnecting fluid, gas, and electrical lines from the mini-cell.
- FIGS. 3A-3C show a number of perspective views of a synthesis module, similar to the synthesis module 64 in FIG. 1 , according to an aspect of the invention. More specifically, each of the synthesis modules 64 may be configured to include, among other things, a group of radiation detectors 66 , fixed air/vacuum connections 68 , and floating luer connections (not shown).
- FIG. 4 is a perspective view of a valveless modular reaction system 100 , according to various aspects of the current invention.
- the system 100 may include a reagent pack 110 , a gasket 120 between the reagent pack 110 and a reaction cassette 130 .
- both the reagent pack 110 and the reaction cassette 130 may be connected to a control interface plate 150 located, e.g., at a back portion of the system 100 .
- a membrane 140 is provided between the control interface plate 150 and the reaction cassette 130
- the gasket 120 is provided between the reagent pack 110 and the reaction cassette 130 .
- the gasket 120 and the membrane 140 may provide, e.g., fluid insulation such as water tightness of the connection between the reagent pack 110 and the reaction cassette 130 , and between the reaction cassette 130 and the interface plate 150 , respectively. Additionally, the gasket 120 and membrane 140 may be individually used to bond two neighboring cassettes or modules together. The gasket 120 may alternately be comprised of a collection of o-rings instead of a continuous sheet.
- the system 100 may be used for the synthesis of chemical compounds such as, for example, radiopharmaceutical products, that are typically used in small quantities and that utilize reagents having a short shelf life.
- a reagent cover 102 may be provided to cover and protect the reagent pack 110 from outside environmental factors such as heat, humidity and/or impact.
- the cassette 130 may include one or ore chambers 180 in which a reaction such as, for example, a synthesis reaction, can take place.
- the reaction may take place in one or more chamber 180 after reagents included in the reagent pack 110 have been transferred into the chamber 180 to start the reaction.
- the reagent pack 110 can be removed independently of the remaining parts or units of the system 100 such as, e.g., the cassette 130 , and can be replaced with either another reagent pack having a larger quantity of reagent and/or a different reagent.
- the reagent pack 110 may contain, for example, specific reagents needed for the processing or synthesis of a specific product.
- the reagent pack 110 may be connected to the cassette 130 via one or more supply channels (see, e.g., 320 in FIG. 6 ) that are constituted by corresponding channels etched or otherwise formed within either or both the cassette 130 and the reagent pack 110 and that are connected to each other via corresponding holes in the gasket 120 . Accordingly, a reagent can be transferred from the reagent pack 110 to the cassette 130 through the gasket 120 without having to use a transfer line or other outside transfer device or valve.
- supply channels see, e.g., 320 in FIG. 6
- FIG. 8 A more detailed discussion of the connection between the reagent pack 110 and the cassette 130 is provided below in connection with FIG. 8 below.
- the gasket 120 may be snugly placed between the reagent pack 110 and the cassette 130 to provide insulation and, for example, avoid reagent leakage from the reagent pack 110 and/or from the cassette 130 while allowing an efficient communication between the reagent pack 110 and the cassette 130 to provide for complete, fast, and efficient fluid and/or reagent transfer.
- the reagent pack 110 may be stored separately, and inserted into the system 100 in fluid communication with the cassette 130 immediately or a short time prior to use, as needed.
- the cassette 130 may be coupled to the planar-shaped interface plate 150 via the membrane 140 provided therebetween.
- the interface plate 150 may be connected to the cassette 130 via one or more supply channels (not shown) that are constituted by corresponding channels etched or otherwise formed within either or both the cassette 130 and the interface plate 150 and that connect to each other via corresponding holes in the gasket 140 .
- the gasket 140 may be snugly placed between the interface plate 150 and the cassette 130 to provide insulation and, for example, avoid reagent leakage from the interface plate 150 and/or from the cassette 130 while allowing communication between the interface plate 150 and the cassette 130 to provide for complete, fast, and efficient fluid and/or reagent transfer.
- the interface plate 150 may also be in direct fluid communication with the reagent pack 110 via one or more channels that may be formed through the interface plate 150 , the gaskets 140 and 120 , and/or the cassette 130 , but where the channels do not communicate with any chamber 180 of the reaction cassette 130 . Accordingly, the reagent in the reagent pack 110 may be directly controlled via the interface plate 150 .
- the interface plate 150 may include a plurality of ports 160 , located on an opposite surface of the interface plate 150 to the surface that is in contact with the gasket 140 , the plurality of ports 160 being used for gas, vacuum and/or fluid to be pumped in, or out of, one or more chambers 180 of the cassette 130 and/or the reagent pack 110 .
- the ports 160 may be used to flow gas such as, for example, pressurized gas, into one or more of the supply channels of the reagent pack 110 , or of the cassette 130 , or of both the reagent pack 110 and the cassette 130 , also in order to induce or prevent the transfer of fluid between the various units of the system 100 .
- the interface plate 150 may have ports 170 connected to supply or drain lines to allow, for example, supply or drainage of reagent, catalyst, or other needed ingredient.
- any reagent or combination of reagents and ingredients present in the reagent pack 110 may be completely and rapidly transferred to a chamber 180 of the cassette 130 via one or more of the supply channels connecting the reagent pack 110 and the cassette 130 , or between one chamber 180 and another chamber 180 , via channels connecting the chambers 180 within the cassette 130 .
- Manipulating the pneumatics between the reagent pack 110 and the cassette 130 via the ports 160 may include, for example, creating a vacuum in a supply channel connecting the reagent pack 110 and the cassette 130 to create a suction effect and transfer a reagent present in the reagent pack 110 into a given chamber 180 of the cassette 130 as a result of that suction effect.
- the reagent pack 110 and one or more chambers 180 of the cassette 130 may be connected to a module such as the module 250 illustrated in FIG. 5 via the ports 160 and one or more channels formed in the cassette 130 , in the reagent pack 110 , in the interface plate 150 and in the gaskets 120 and 140 in order to allow the flow of gas, such as pressurized gas, and/or vacuum, to the reagent pack 110 or to/from a chamber 180 .
- gas such as pressurized gas, and/or vacuum
- a vacuum may be applied to the chamber 180 through a supply channel connecting the chamber 180 to a vacuum/gas source via one or more of the ports 160 to create a pressure gradient between the chamber 180 and the reagent pack 110 , while a flow of pressurized gas may be provided in the reagent pack 110 through a channel connecting the reagent pack 110 to a source of pressurized gas at one or more of the ports 160 of the interface plate 150 .
- the combined action of pressurized gas urging the reagent in an outward direction from the reagent pack 110 via a channel formed in the reagent pack 110 , and the action of the pressure gradient or vacuum created inside the chamber 180 and pulling the reagent into the chamber 180 via a suction effect, may ensure a rapid and complete reagent transfer from the reagent pack 110 to the chamber 180 .
- the fluid passages may be pinched off by pneumatic action on the membrane 140 , past which the fluid channels are routed.
- a gas may be provided from the chamber 180 into the reagent pack 110 to keep the reagent in the reagent pack 110 and to prevent the reagent from accidentally discharging outside the reagent pack 110 before an appropriate time.
- the flow of gas from the chamber 180 may be discontinued and a pressure gradient, such as a vacuum, may be created as explained below in greater detail in reference to FIG. 8 below.
- a vacuum is created in the module by opening a vacuum valve coupled to a port 160 of the interface plate 150 .
- a pressure gradient is created in the chamber 180 .
- pressurized air may be provided to the reagent pack 110 via a port 160 so as to enter the reagent pack 110 from above the fluid level in the reagent pack 110 and to urge the reagent through a channel connecting the reagent pack 110 to the chamber 180 until all the reagent has been transferred from the reagent pack 110 to the chamber 180 .
- such a transfer is made possible by the combined action of the pressure gradient created in the chamber 180 and the pressurized gas in the reagent pack 110 .
- the reagent being transferred from the reagent pack 110 into one or more chambers 180 of the modular cassette 130 may be a radioactive input, and the synthesis of a product, such as a radioactive product, may take place in a chamber 180 of the cassette 130 .
- the radioactive input may be a radioactive isotope typically produced in a cyclotron.
- both the cassette 130 and the reagent pack 110 may be disposable.
- FIG. 5 is a perspective view of a synthesis module in operation, according to various aspects of the current invention.
- the disposable reaction cassette 230 and the reagent pack 210 are clamped together and held attached to the non-disposable module 250 via the clamping mechanism 270 during use of the system 200 .
- the clamping mechanism 270 also provides the pressure and cohesive strength necessary to create a leak-free fluid connection between the reagent pack 210 and the cassette 230 by aligning respective channels formed in each of the reagent pack 210 and the cassette 230 , as well as provide enough pressure and cohesive strength between the reagent pack 210 and the reaction cassette 230 to allow the gaskets 220 and 240 , respectively provided between the reagent pack 210 and the reaction cassette 230 , and between the reaction cassette 230 and the module 250 , to fulfill their function of providing insulation and preventing leakage of reagent or other ingredients.
- the respective channels in the reagent pack 210 and in the cassette 230 , as well as the open channels formed in the gaskets 220 and 240 , are all aligned so as to create fluid connections between the cassette 230 and the reagent pack 210 , as well as between a cover 202 , the module 250 and each of the reagent pack 210 and the cassette 230 .
- the removable reagent pack 210 may be covered by a protective cover (not shown) on the surface that is in contact with the gasket 220 , the protective cover covering one or more cavities or pockets within the reagent pack where an amount and/or a number of reagents may be stored, as illustrated in FIGS. 6-7 and described below. Accordingly, if the protective cover is punctured, the reagent present in the cavities or pockets is able to be transferred out of the reagent pack 210 .
- the clamping mechanism 270 in one aspect of the system 200 also provides activation of the connections between the various modules by, for example, puncturing the protective cover that may cover the cavities or pockets in the reagent pack 210 in order to allow reagent located inside the cavities or pockets to be delivered to a chamber (not shown) of the cassette 230 .
- the clamping mechanism 270 may also provide sufficient pressure to enable the sealing gaskets to seal the various modules and prevent leakage or outside impurities from penetrating the modular reaction system 200 .
- the clamping mechanism 270 may also provide a mechanism to allow for the ejection of the cassette 230 and/or of the reagent pack 210 after use.
- the reagent pack 210 in operation, is removeably inserted in the system 200 .
- the reagent pack 210 may have a protective membrane covering the surface of the reagent pack 210 and keeping the reagent inside the reagent pack 210 .
- the reagent pack 210 may include a plurality of cavities or pockets in which one or more reagents or ingredients may be stored, where each cavity may have two exits, a fluid exit and a vent.
- the module 250 may urge the clamping mechanism 270 to clamp the various modules of the system 200 , such as the reagent pack 210 and the reaction cassette 230 , and to allow tubes to pneumatically puncture portions of the membrane covering one or more pockets in the reagent pack 210 in order to allow the transfer of reagent stored in the one or ore of the pockets from the reagent pack 210 to the cassette 230 .
- transfer of reagent from the reagent pack 210 to the cassette 230 may be performed by manipulating pneumatics as discussed above with respect to FIG. 4 .
- FIGS. 6-7 are perspective views of components of a modular cassette system, according to various aspects of the current invention.
- the interface plate 305 includes a plurality of perforating appendages such as, for example, tubes, 320 , that may perforate capsules present in a reagent pack and that may include reagent.
- the interface plate 305 may be made blunt and taller than the sharp tubes 320 . These blunt features may allow light manual assembly of the reagent pack against the cassette without breaking the seals into any of the sensitive reagent volumes.
- the module clamps the reagent pack and cassette tightly to the front of the module, in the process, breaking through all of the foil barriers.
- the reagent pack 310 may include individual phials, vials, pods, or capsules 315 in which an amount of reagent may be stored. Accordingly, on the surface of the reagent pack 310 that is to be in contact with the cassette 330 , the individual capsules 315 in the reagent pack 310 store one or more reagents.
- the tubes 320 present on a surface of interface plate 305 directly facing the surface of the reagent pack 310 may become actuated by the action of the clamping system, or by an actuation mechanism, and may puncture one or more of the individual capsules 315 in order to allow the transfer of reagent stored in the capsules 315 of the reagent pack 310 to one or more chambers 380 of the cassette 330 .
- the transfer of reagent from the reagent pack 310 to the cassette 330 may be performed pneumatically as discussed above with respect to FIG. 2 .
- FIG. 6 also illustrates the cassette 330 having a plurality of chambers 380 , where the chambers 380 are connected to each other via channels formed within the cassette 330 , and where any individual chamber 380 may be independently used as a reaction vessel.
- the channels connecting any two chambers 380 may connect the bottom of the first chamber 380 to the top of the second chamber 380 in order to permit the pneumatically activated reagent transfer from the first chamber 380 to the second chamber 380 .
- the phials or capsules 315 may be configured to be individual removable units that can be placed at various locations of the reagent pack 310 .
- a reagent pack 310 may have one or more reagent capsules 315 that contain reagent and that can be placed at different locations of the reagent pack 310 , according to a given need.
- specific locations of the capsules 315 may correspond to a configuration where the reagent present in the capsule 315 is transferred only to specific chambers 380 of the cassette 330 .
- the system 300 allows for an exhaustive control of the reaction sites within the cassette 330 , and may also allow for several reactions to take place independently during a same time period within the same cassette 330 .
- FIG. 8 illustrates a principle of fluid transfer according to various aspects of the current invention.
- FIG. 8 is a schematic illustration of a plurality of mixing chambers 410 , 450 and 490 , wherein the cavity in each chamber may be large enough to allow a two-phase mixture of liquid and vapor, and to establish a fluid level with the vapor located above the fluid.
- the chambers 410 , 450 and 490 may be reaction chambers of the reaction cassette 130 and/or of the reagent pack 110 discussed above with respect to FIG. 4 , and the fluid transfer between the chambers of the reaction cassette 130 and/or of the reagent pack 110 may be controlled according to the above-discussed vacuum and pressure as described below.
- each chamber may have one or more entry and exit passages.
- the chamber 410 may be a reaction chamber having input lines 412 and 414 to input fluids, reagents and/or other solid, liquid, or gaseous ingredients, to be mixed or reacted together.
- the line 422 may be used to provide the chamber 410 with a pressurized gas such as, for example, N 2 or any combination of gas or gases other than N 2 , such one or more inert gas, oxygen or air as long as the gas that does not interact with the fluid composition or ingredients present in the chamber 410 to create an unwanted chemical reaction, by opening a valve at the line 422 .
- a gas referred to as “inert” in this disclosure may be inert with respect to the fluid, ingredients or reagents present in the chamber 410 , even without being inert with respect to other compositions or other compounds.
- An exemplary purpose of the pressurized gas provided via the line 422 to the chamber 410 is to apply a downward pressure to the fluid present in the chamber 410 and urge the fluid out of the chamber 410 to chamber 450 via the transfer line 430 .
- the chambers 410 , 450 and 490 may be configured so as to have an amount of space, or distance, between the vacuum lines 424 , 464 and 484 and the free surface of the fluid in order to prevent splashing or splattering from causing fluid to be ingested by the vacuum lines and thus to be lost from the process.
- baffles may be used to prevent the fluid from being ingested in a vacuum line. The additional amount of space above the free surface of the fluid may also be useful when sparging the fluid to remove any gases dissolved in the fluid.
- the line 422 may be opened to allow a pressurized inert gas to flow into the chamber 410 and to create a pressure urging the fluid downward in the chamber 410 and ultimately out of the chamber 410 via the transfer line 430 .
- the gas line 462 in the second chamber 450 may be closed, and the vacuum line 464 in the chamber 450 may be opened by opening a vacuum valve located at the line 464 .
- a vacuum is created in chamber 450 , a suction action of the fluid present in the first chamber 410 may be produced through the transfer line 430 .
- the combined action of the pushing action of the pressurized gas flowing in the chamber 410 via the line 422 and of the suction action of the vacuum created in the transfer line 430 and provided via the chamber 450 results in the entirety of the fluid present in the chamber 410 to be transferred rapidly to the chamber 450 .
- accidental subsequent fluid transfer to chamber 490 from chamber 450 may also be prevented by maintaining a positive pressure inside the chamber 490 and the transfer line 470 by, for example, flowing gas via the gas line 482 into the chamber 490 and possibly in the transfer line 470 .
- no fluid that has been transferred from chamber 410 to chamber 450 can accidentally be further transferred to chamber 490 .
- the pressurized gas line 462 of the chamber 450 may remain closed, and no pressurized gas is provided to the chamber 450 .
- a pressurized gas may be provided to the chamber 450 via the gas line 462 before any fluid transfer from the chamber 410 to the chamber 450 in order to keep the fluid in the chamber 410 and avoid accidental transfer of fluid via the line 430 before such time when fluid transfer is desired.
- the pressurized gas is flowed inside chamber 450 via the gas line 462 while the vacuum line 464 is closed. Because the only other opening in the chamber 450 is the transfer line 430 , the pressurized gas flows through the transfer line 430 into the fluid present in the chamber 410 .
- gas sparging or bubbling of the fluid may occur at the end of the transfer line 430 located at the bottom of the chamber 410 , which may prevent any amount of fluid from accidentally being transferred from the chamber 410 to the chamber 450 . Accordingly, accidental fluid transfer may be avoided, and no fluid is transferred before fluid transfer from chamber 410 to chamber 450 is desired.
- the chamber 450 may also have one or more input lines such as input lines 452 and 454 , through which additional reagents, or ingredients, may be provided, for example during a second stage of a manufacturing or reaction process, after or before the fluid has been transferred from chamber 410 into chamber 450 . Accordingly, mixing of various additional ingredients with the fluid transferred from the chamber 410 to the chamber 450 may take place inside the chamber 450 . According to various aspects of the current invention, a subsequent transfer of the fluid now present in chamber 450 to chamber 490 can be accomplished in a similar process to the process described above with respect to the transfer of fluid between chambers 410 and 450 .
- gas line 462 is opened to allow flow of a pressurized inert gas into chamber 450 while vacuum line 484 of the chamber 490 is opened to create a suction action.
- the fluid present in chamber 450 is entirely transferred to the chamber 490 via transfer line 470 .
- additional ingredients or reactants may be added to the fluid via input lines 492 and 494 .
- an additional mixture or reaction of various fluids and chemicals may be performed in the successive chambers 410 , 450 and 490 during separate successive stages of an overall chemical process, and various effluents or fluids may be transferred to one or more of the chambers by manipulating the vacuum lines and pressure lines of the various chambers as discussed above, and without having to use wet valves or pumps in the transfer lines.
- chemical synthesis may be performed in the various chambers 410 , 450 and 490 illustrated in FIG. 8 . It should be noted that although only three chambers are illustrated in FIG. 8 , there may be as many chambers as needed to effectuate any required number of reaction steps.
- the three chambers 410 , 450 and 490 may be reaction chambers of the reaction cassette 130 and/or of the reagent pack 110 discussed with respect to FIG. 4 , and the fluid transfer between the chambers of the reaction cassette 130 and/or of the reagent pack 110 may be controlled according to the vacuum and pressure control mechanisms described with respect to FIG. 8 .
- the above system and operation can be controlled and operated via hardware and software, as discussed in greater detail below,
- FIG. 9 presents an example system diagram of various hardware components and other features, for use in accordance with an aspect of the present invention.
- the present invention may be implemented using hardware, software, or a combination thereof and may be implemented in one or more computer systems or other processing systems.
- the invention is directed toward one or more computer systems capable of carrying out the functionality described herein.
- An example of such a computer system 500 is shown in FIG. 9 .
- the computer system 500 may be configured to communicate with the multi-synthesis backplane/bus system discussed above in FIG. 2A .
- Computer system 500 includes one or more processors, such as processor 504 .
- the processor 504 is connected to a communication infrastructure 506 (e.g., a communications bus, cross-over bar, or network).
- a communication infrastructure 506 e.g., a communications bus, cross-over bar, or network.
- Computer system 500 can include a display interface 502 that forwards graphics, text, and other data from the communication infrastructure 506 (or from a frame buffer not shown) for display on a display unit 530 .
- Computer system 500 also includes a main memory 508 , preferably random access memory (RAM), and may also include a secondary memory 510 .
- the secondary memory 510 may include, for example, a hard disk drive 512 and/or a removable storage drive 514 , representing a floppy disk drive, a magnetic tape drive, an optical disk drive, etc.
- the removable storage drive 514 reads from and/or writes to a removable storage unit 518 in a well-known manner.
- Removable storage unit 518 represents a floppy disk, magnetic tape, optical disk, etc., which is read by and written to removable storage drive 514 .
- the removable storage unit 518 includes a computer usable storage medium having stored therein computer software and/or data.
- secondary memory 510 may include other similar devices for allowing computer programs or other instructions to be loaded into computer system 500 .
- Such devices may include, for example, a removable storage unit 522 and an interface 520 .
- Examples of such may include a program cartridge and cartridge interface (such as that found in video game devices), a removable memory chip (such as an erasable programmable read only memory (EPROM), or programmable read only memory (PROM)) and associated socket, and other removable storage units 522 and interfaces 520 , which allow software and data to be transferred from the removable storage unit 522 to computer system 500 .
- EPROM erasable programmable read only memory
- PROM programmable read only memory
- Computer system 500 may also include a communications interface 524 .
- Communications interface 524 allows software and data to be transferred between computer system 500 and external devices.
- Examples of communications interface 524 may include a modem, a network interface (such as an Ethernet card), a communications port, a Personal Computer Memory Card International Association (PCMCIA) slot and card, etc.
- Software and data transmitted from, e.g., the multi-synthesis backplane/bus system discussed above in FIG. 2A and transferred via communications interface 524 are in the form of signals 528 , which may be electronic, electromagnetic, optical or other signals capable of being received by communications interface 524 .
- These signals 528 are provided to communications interface 524 via a communications path (e.g., channel) 526 .
- This path 526 carries signals 528 and may be implemented using wire or cable, fiber optics, a telephone line, a cellular link, a radio frequency (RF) link and/or other communications channels.
- RF radio frequency
- the terms “computer program medium” and “computer usable medium” are used to refer generally to media such as a removable storage drive 580 , a hard disk installed in hard disk drive 570 , and signals 528 .
- These computer program products provide software to the computer system 500 . The invention is directed to such computer program products.
- Computer programs are stored in main memory 508 and/or secondary memory 510 . Computer programs may also be received via communications interface 524 . Such computer programs, when executed, enable the computer system 500 to perform the features of the present invention, as discussed herein. In particular, the computer programs, when executed, enable the processor 510 to perform the features of the present invention. Accordingly, such computer programs represent controllers of the computer system 500 .
- the software may be stored in a computer program product and loaded into computer system 500 using removable storage drive 514 , hard drive 512 , or communications interface 520 .
- the control logic when executed by the processor 504 , causes the processor 504 to perform the functions of the invention as described herein.
- the invention is implemented primarily in hardware using, for example, hardware components, such as application specific integrated circuits (ASICs). Implementation of the hardware state machine so as to perform the functions described herein will be apparent to persons skilled in the relevant art(s).
- the invention is implemented using a combination of both hardware and software.
- FIG. 10 is a block diagram of various example system components, in accordance with an aspect of the present invention.
- FIG. 10 shows a communication system 600 usable in accordance with, e.g., the multi-synthesis backplane/bus system discussed above in FIG. 2A , according to an aspect of the present invention.
- the communication system 600 includes one or more accessors 660 , 662 (also referred to interchangeably herein as one or more “users”) and one or more terminals 642 , 666 .
- data for use in accordance with the present invention is, for example, input and/or accessed by accessors 660 , 664 via terminals 642 , 666 , such as personal computers (PCs), minicomputers, mainframe computers, microcomputers, telephonic devices, or wireless devices, such as personal digital assistants (“PDAs”) or a hand-held wireless devices coupled to a server 643 , such as a PC, minicomputer, mainframe computer, microcomputer, or other device having a processor and a repository for data and/or connection to a repository for data, via, for example, a network 644 , such as the Internet or an intranet, and couplings 645 , 646 , 664 .
- the couplings 645 , 646 , 664 include, for example, wired, wireless, or fiberoptic links.
- the method and system of the present invention operate in a stand-alone environment, such as on a single terminal.
- FIG. 11 illustrates a flow diagram for performing a synthesis method 1100 in a modular system, in accordance with an aspect of the present invention.
- the method includes, among other things, providing 1102 one or more reaction cassettes, and coupling 1104 one or more reagent packs to the one or more reaction cassettes via one or more couplings.
- the method further includes providing 1106 one or more gaskets between adjacent cassettes and/or reagent packs to prevent leakage between the adjacent cassettes and/or reagent packs, wherein the one or more couplings include channels formed in the one or more cassettes, the one or more reagent packs and the one or more gaskets, and the channels are in communication with one another.
Abstract
Description
- This application claims priority to U.S. Patent Application No. 61/508,373 filed on Jul. 15, 2011, titled “Modular Cassette Synthesis Unit”; U.S. Provisional Application No. 61/508,294 filed on Jul. 15, 2011, titled “Systems, Methods, and Devices for Producing, Manufacturing, and Control of Radiopharmaceuticals”; and U.S. Patent Application No. 61/508,359 and filed on Jul. 15, 2011, titled “Cassette Reaction Vessel Using a Cascade of Valveless Pressure Pumps.” Each of the above applications is incorporated by reference herein in its entirety.
- 1. Field of Invention
- Aspects of the present invention relate to methods and systems for reagent interaction in a modular context. More specifically, aspects of the present invention relate to methods and systems that effectuate and control reagent interaction through the remote action of pneumatic valves in a modular context
- 2. Background
- Nuclear medicine is a branch of medical imaging that uses small amounts of radioactive materials to diagnose or treat a variety of diseases, including many types of cancers, heart disease, and other abnormalities within the body. For example, positive emission tomography (PET) is a type of nuclear medicine imaging in which a radiopharmaceutical that includes a radionuclide tracer is introduced into the body where it eventually accumulates in an organ or area of the body being examined. The radionuclide gives off energy in the form of POSITRONS, which are detected by devices, including a PET scanner. In PET, radiopharmaceuticals that incorporate the radionuclide fluorine-18, such as fluorodeoxyglucose (FDG), 3′-deoxy-3′-[18F]-pluorothymidine (FLT), [18F]-fluoromisonidazol (F-MISO), (4-[18F]-fluorobenzoyl)norbiotinamide (FBB) and PET Perfusion Agents (PPA), are commonly used.
- Due to the radioactive nature of radiopharmaceuticals, special consideration must be taken in their preparation, handling, and delivery. Production of fluorine-18 for use in a radiopharmaceutical is often difficult and/or expensive, requiring specialized equipment, such as a cyclotron. The production of the radioisotope often occurs at a remote facility by a third party, from which the hospital or lab receives patient doses that are ready to inject. Even if the radioisotope happens to be produced on site, final production of the radiopharmaceuticals used in many diagnostic imaging procedures requires manual preparation in a special aseptic environment to ensure a safe injectable product that is free of environmental contaminants. In addition, precise accounting of the radioactive nature of the radionuclide to be used in the radiopharmaceutical for each procedure is required, while taking into account that the bulk radionuclide product continuously decays over time.
- Furthermore, during preparation of radiopharmaceuticals, technicians must be shielded from the ionizing radiation of the radionuclide, and the purity of the radiopharmaceutical must be ensured by filtering and/or avoiding contamination through contact with particles in the air, on a surface, and/or when mixing with a diluting liquid, for example. In addition, because of the short half-life of the radionuclide, the efficient scheduling of patients, for example, along with a safe and efficient preparation of the radiopharmaceutical by technicians is critical to avoid wasting the prepared bulk product of the radionuclide.
- Shielded containment systems for use in combining cyclotron-produced radionuclides with non-radionuclide components to produce radiopharmaceuticals have been developed. There are, however, many drawbacks of these systems. In particular, typically only one radiopharmaceutical may be produced in a production run. After a run, various radionuclide raw material components and physical system components must be replaced or decontaminated, which can greatly delay the production process and/or make the process much less efficient. Further, many aspects of production of radiopharmaceuticals in such related art systems are not automated and/or may require time-consuming and/or awkwardly controllable hand production steps. In addition, the radioactivity and/or quantities of the raw radionuclide and/or the produced radiopharmaceutical may be inaccurate and/or difficult to determine precisely. Necessary quality control to be performed on the output radiopharmaceutical products may be time-consuming, inaccurate, and/or require high levels of worker input/skill, further hampering production and/or timely delivery of the produced radiopharmaceuticals.
- In addition, to carry out a process in which chemical reactions between a variety of reagents are to take place, such as in the production of radiopharmaceuticals, a large and complex setup is sometimes needed to channel liquids, reagents and/or compounds towards a reactor vessel. Channeling various ingredients towards the reactor vessel generally involves the use of tubing, threaded connectors, valving and the like, which are often a source of fluid losses due to fluid being retained or trapped therein. The uncertainty and un-repeatability of such losses can create errors in determining the respective amounts of ingredients necessary to complete a desired reaction process with a desired specific yield. Moreover, some ingredients or reagents may have a short shelf life and may have to be used very quickly after manufacture or after exposure to the environment, which further increases the need for complex reaction vessels.
- Accordingly, there is a need in the art for systems and methods that provide for chemical and/or physical interactions between a plurality of reagents and ingredients, while reducing or eliminating the need for excessive connections, tubing, and the like, particularly for the synthesis of chemical compounds such as, for example, radiopharmaceutical products, that are typically used in small quantities and that utilize reagents having a short shelf life. For example, the radioactive input may be a radioactive isotope typically produced in a cyclotron. There is a further need in the art for methods and systems that provide for chemical and/or physical interactions between a plurality of reagents and ingredients, while ensuring that subsequent reactions are not contaminated by remnants from previous reactions by providing, for example, one or more disposable reaction modules. There is a further need in the art for methods and systems in which one or more reaction modules may be removably connected to one another, as such methods and systems may be useful in providing the ability to quickly and efficiently dispose a plurality of ingredients and/or reagents in contact with each other in a reaction vessel or chamber. There is a further need in the art for systems and methods that provide for chemical and/or physical interactions between a plurality of reagents and ingredients when the reagents have a relatively short lifetime and must be mixed within a short period of time after being manufactured or exposed to the environment.
- In light of the above-described problems and unmet needs, a compact modular cassette system for the synthesis of radiopharmaceutical products may be provided, the compact modular cassette system including a modular unit having valve plates, a reaction cassette, a reagent pack, and other seal and connector plates, to ensure that reagents can be mixed together inside one or more chambers of the reaction cassette in a timely and efficient manner. According to various aspects of the present invention, when it is preferable to use a new chamber for each new reaction or process, a modular system where both the reaction cassette and the reagent pack are removable may be helpful, where either the reagent container, the reaction cassette, or both, can be removed from the modular cassette system and discarded after a desired reaction or process has taken place and, for example, the product of the reaction has been collected or further treated in a subsequent process.
- According to various aspects, the physical connection between a reagent pack and the reaction cassette may be provided via one or more corresponding channels etched, molded or machined in at least one of the reagent pack and the reaction cassette. In addition, reagent transfer between a reagent pack and a chamber inside the reaction cassette may be controlled by a module located remotely from both the reagent pack and the reaction cassette, which remains part of the overall modular system. According to additional aspects of the current invention, a broad side or broad face of the reaction cassette may be coupled to a corresponding broad side of the reagent pack or any other module that is part of the overall modular cassette system in order to allow for fluidic connections at various locations between neighboring cassettes, packs and other modules. In addition, e.g., radiation sensors and/or other heating elements may also be coupled to neighboring modules, cassettes or reagent packs. For example, the modular unit may include a number of power and fluid supply devices that are to remain stationary, and accordingly, the removable reaction cassette may be placed at a front end of the overall modular unit to facilitate operator interaction and, for example, to facilitate removal of the cassette to a disposal container. Furthermore, the modular unit may be coupled to the cassette so as to be located behind the cassette, which increases convenience of use of the modular unit when the modular unit includes communication lines coupling the cassette to supply lines located at a back portion of the modular unit.
- The module/cassette structure may also allow for an automatic ejection of the cassette. This may be advantageous in reducing operator exposure to the cassette and the hazardous radioactivity within waste droplets remaining within the cassette. The mini cell shielding structure may allow for the ejected cassettes to be guided to a shielded waste collection container. Further, future systems, with further development, may automatically install a fresh replacement cassette.
- Additional advantages and novel features of these aspects of the invention will be set forth in part in the description that follows, and in part will become more apparent to those skilled in the art upon examination of the following or upon learning by practice of the invention.
- Various example aspects of the systems and methods will be described in detail, with reference to the following figures, wherein:
-
FIG. 1 shows a system for radiopharmaceutical preparation according to an aspect of the invention; -
FIGS. 2A-2C show perspective views of a multi-synthesis unit according to an aspect of the invention; -
FIGS. 3A-3C show perspective views of a synthesis module according to an aspect of the invention; -
FIG. 4 is a perspective view of a modular cassette system, according to various aspects of the current invention; -
FIG. 5 is a perspective view of a synthesis module, according to various aspects of the current invention; -
FIGS. 6-7 are perspective views of components of a modular cassette system, according to various aspects of the current invention; -
FIG. 8 illustrates a principle of fluid transfer according to various aspects of the current invention; -
FIG. 9 presents an example system diagram of various hardware components and other features, for use in accordance with an aspect of the present invention; -
FIG. 10 is a block diagram of various example system components, in accordance with an aspect of the present invention; and -
FIG. 11 illustrates a flow diagram for performing a synthesis method in accordance with an aspect of the present invention. - These and other features and advantages of this invention are described in, or are apparent from, the following detailed description of various example aspects.
-
FIG. 1 shows a system for radiopharmaceutical preparation according to an aspect of the invention. Thesystem 50 may include a shielded container, such as a mini-cell 52. The mini-cell 52 may includecompartments Compartments multi-synthesis units 60. For example, amulti-synthesis unit 60 may be about 26-30 inches wide, 18-22 inches tall, and 18-24 inches deep. Amulti-synthesis unit 60 may be placed on a sliding track, for example, within a compartment so that themulti-synthesis unit 60 can easily be accessed for service or replacement of the modules or their components. - Each
multi-synthesis unit 60 may hold any number of modules as can be accommodated, while maintaining the overall compactness of thesystem 50. In the example shown inFIG. 1 , themulti-synthesis units 60 may each incorporate up to six modules. For example, the modules may include, but are not limited to,accessory modules 62 andsynthesis modules 64. The components of themodules multi-synthesis unit 60. A radiopharmaceutical material may be prepared in asynthesis module 64 with reagents provided from the reagent pack. Anadditional compartment 58 may be used to store waste products of the radiopharmaceuticals synthesis process of thesystem 50, for example. -
FIG. 2A is a perspective view of a six-module multi-synthesis unit, similar to themulti-synthesis unit 60 discussed inFIG. 1 , according to an aspect of the invention. For example, theunit 60 may be sized to fit into a reduced mini-cell volume, and positioned on slides so that it may be pulled forward in, e.g., the mini-cell 52, for service. Further,individual modules multi-synthesis unit 60 for service or replacement. According to various aspects, quick disconnects and hands-free connections between the modules and a multi-synthesis backplane/bus system (not shown) may be implemented to facilitate rapid module replacement. For example, as shown inFIGS. 2B and 2C , the backplane/bus approach may allow individual modules to slide into the system and through “quick disconnects” tie into utilities to include power, gasses, solvents, control connections and the like. The overall electronics and control package may tie in to this bus and allow the control to be located remotely and shielded away from the sources of radioactivity, which traditionally has created reliability issues. This is due to the failure of electronic components exposed to high levels of radioactivity in traditionally packaged synthesis units combining electronics (controls) and electromechanical components. According to various aspects of the subject invention, package of controls and electronics may be mounted in separate electrical box outside the shielded cell, and the package may be shared among a group of synthesis units (e.g., 6-12 synthesis units). In addition, according to various aspects, a cable management scheme may permit theentire multi-synthesis unit 60 to be pulled forward in the mini-cell for service without disconnecting fluid, gas, and electrical lines from the mini-cell. -
FIGS. 3A-3C show a number of perspective views of a synthesis module, similar to thesynthesis module 64 inFIG. 1 , according to an aspect of the invention. More specifically, each of thesynthesis modules 64 may be configured to include, among other things, a group ofradiation detectors 66, fixed air/vacuum connections 68, and floating luer connections (not shown). -
FIG. 4 is a perspective view of a valvelessmodular reaction system 100, according to various aspects of the current invention. InFIG. 2 , thesystem 100 may include areagent pack 110, agasket 120 between thereagent pack 110 and areaction cassette 130. According to various aspects, both thereagent pack 110 and thereaction cassette 130 may be connected to acontrol interface plate 150 located, e.g., at a back portion of thesystem 100. InFIG. 4 , amembrane 140 is provided between thecontrol interface plate 150 and thereaction cassette 130, while thegasket 120 is provided between thereagent pack 110 and thereaction cassette 130. According to various aspects, thegasket 120 and themembrane 140 may provide, e.g., fluid insulation such as water tightness of the connection between thereagent pack 110 and thereaction cassette 130, and between thereaction cassette 130 and theinterface plate 150, respectively. Additionally, thegasket 120 andmembrane 140 may be individually used to bond two neighboring cassettes or modules together. Thegasket 120 may alternately be comprised of a collection of o-rings instead of a continuous sheet. According to various aspects, thesystem 100 may be used for the synthesis of chemical compounds such as, for example, radiopharmaceutical products, that are typically used in small quantities and that utilize reagents having a short shelf life. According to various aspects, areagent cover 102 may be provided to cover and protect thereagent pack 110 from outside environmental factors such as heat, humidity and/or impact. - According to various aspects of the current invention, the
cassette 130 may include one orore chambers 180 in which a reaction such as, for example, a synthesis reaction, can take place. The reaction may take place in one ormore chamber 180 after reagents included in thereagent pack 110 have been transferred into thechamber 180 to start the reaction. Because theoverall system 100 is modular and thereagent pack 110 is a single unit of the overallmodular system 100, thereagent pack 110 can be removed independently of the remaining parts or units of thesystem 100 such as, e.g., thecassette 130, and can be replaced with either another reagent pack having a larger quantity of reagent and/or a different reagent. Thereagent pack 110 may contain, for example, specific reagents needed for the processing or synthesis of a specific product. - According to various aspects of the current invention, the
reagent pack 110 may be connected to thecassette 130 via one or more supply channels (see, e.g., 320 inFIG. 6 ) that are constituted by corresponding channels etched or otherwise formed within either or both thecassette 130 and thereagent pack 110 and that are connected to each other via corresponding holes in thegasket 120. Accordingly, a reagent can be transferred from thereagent pack 110 to thecassette 130 through thegasket 120 without having to use a transfer line or other outside transfer device or valve. A more detailed discussion of the connection between thereagent pack 110 and thecassette 130 is provided below in connection withFIG. 8 below. Thegasket 120 may be snugly placed between thereagent pack 110 and thecassette 130 to provide insulation and, for example, avoid reagent leakage from thereagent pack 110 and/or from thecassette 130 while allowing an efficient communication between thereagent pack 110 and thecassette 130 to provide for complete, fast, and efficient fluid and/or reagent transfer. For example, when reagents have a short shelf life and must be used within a short period of time after being manufactured or after being exposed to the environment, thereagent pack 110 may be stored separately, and inserted into thesystem 100 in fluid communication with thecassette 130 immediately or a short time prior to use, as needed. - According to various aspects of the current invention, the
cassette 130 may be coupled to the planar-shapedinterface plate 150 via themembrane 140 provided therebetween. According to various aspects of the current invention, theinterface plate 150 may be connected to thecassette 130 via one or more supply channels (not shown) that are constituted by corresponding channels etched or otherwise formed within either or both thecassette 130 and theinterface plate 150 and that connect to each other via corresponding holes in thegasket 140. Thegasket 140 may be snugly placed between theinterface plate 150 and thecassette 130 to provide insulation and, for example, avoid reagent leakage from theinterface plate 150 and/or from thecassette 130 while allowing communication between theinterface plate 150 and thecassette 130 to provide for complete, fast, and efficient fluid and/or reagent transfer. According to various aspects, theinterface plate 150 may also be in direct fluid communication with thereagent pack 110 via one or more channels that may be formed through theinterface plate 150, thegaskets cassette 130, but where the channels do not communicate with anychamber 180 of thereaction cassette 130. Accordingly, the reagent in thereagent pack 110 may be directly controlled via theinterface plate 150. Theinterface plate 150 may include a plurality ofports 160, located on an opposite surface of theinterface plate 150 to the surface that is in contact with thegasket 140, the plurality ofports 160 being used for gas, vacuum and/or fluid to be pumped in, or out of, one ormore chambers 180 of thecassette 130 and/or thereagent pack 110. - According to various aspects, the
ports 160 may be used to flow gas such as, for example, pressurized gas, into one or more of the supply channels of thereagent pack 110, or of thecassette 130, or of both thereagent pack 110 and thecassette 130, also in order to induce or prevent the transfer of fluid between the various units of thesystem 100. According to various aspects, theinterface plate 150 may have ports 170 connected to supply or drain lines to allow, for example, supply or drainage of reagent, catalyst, or other needed ingredient. An experimental foundation for the operation of the units of thesystem 100 to manipulate vacuum and pressurized gas, or pneumatics, to ensure complete and fast transfer of liquid and/or reagents from one unit to the next such as, for example, from thereagent pack 110 to thecassette 130 and/or vice-versa, is described below with reference toFIG. 8 . - According to various aspects of the current invention, by manipulating pneumatics via the
ports 160, any reagent or combination of reagents and ingredients present in thereagent pack 110 may be completely and rapidly transferred to achamber 180 of thecassette 130 via one or more of the supply channels connecting thereagent pack 110 and thecassette 130, or between onechamber 180 and anotherchamber 180, via channels connecting thechambers 180 within thecassette 130. Manipulating the pneumatics between thereagent pack 110 and thecassette 130 via theports 160 may include, for example, creating a vacuum in a supply channel connecting thereagent pack 110 and thecassette 130 to create a suction effect and transfer a reagent present in thereagent pack 110 into a givenchamber 180 of thecassette 130 as a result of that suction effect. - According to various aspects of the current invention, the
reagent pack 110 and one ormore chambers 180 of thecassette 130 may be connected to a module such as themodule 250 illustrated inFIG. 5 via theports 160 and one or more channels formed in thecassette 130, in thereagent pack 110, in theinterface plate 150 and in thegaskets reagent pack 110 or to/from achamber 180. According to various aspects, in order to ensure a complete transfer of reagent from thereagent pack 110 to achamber 180, a vacuum may be applied to thechamber 180 through a supply channel connecting thechamber 180 to a vacuum/gas source via one or more of theports 160 to create a pressure gradient between thechamber 180 and thereagent pack 110, while a flow of pressurized gas may be provided in thereagent pack 110 through a channel connecting thereagent pack 110 to a source of pressurized gas at one or more of theports 160 of theinterface plate 150. - Accordingly, the combined action of pressurized gas urging the reagent in an outward direction from the
reagent pack 110 via a channel formed in thereagent pack 110, and the action of the pressure gradient or vacuum created inside thechamber 180 and pulling the reagent into thechamber 180 via a suction effect, may ensure a rapid and complete reagent transfer from thereagent pack 110 to thechamber 180. It should be noted that in order to prevent premature transfer of reagent between thereagent pack 110 and thechamber 180 from occurring, the fluid passages may be pinched off by pneumatic action on themembrane 140, past which the fluid channels are routed. Alternatively, a gas may be provided from thechamber 180 into thereagent pack 110 to keep the reagent in thereagent pack 110 and to prevent the reagent from accidentally discharging outside thereagent pack 110 before an appropriate time. When the transfer of reagent from thereagent pack 110 to thechamber 180 is desired, the flow of gas from thechamber 180 may be discontinued and a pressure gradient, such as a vacuum, may be created as explained below in greater detail in reference toFIG. 8 below. - According to various aspects, when forward flow from the
reagent pack 110 to thechamber 180 is desired, a vacuum is created in the module by opening a vacuum valve coupled to aport 160 of theinterface plate 150. As a result, a pressure gradient is created in thechamber 180. In addition, pressurized air may be provided to thereagent pack 110 via aport 160 so as to enter thereagent pack 110 from above the fluid level in thereagent pack 110 and to urge the reagent through a channel connecting thereagent pack 110 to thechamber 180 until all the reagent has been transferred from thereagent pack 110 to thechamber 180. According to various aspects, such a transfer is made possible by the combined action of the pressure gradient created in thechamber 180 and the pressurized gas in thereagent pack 110. - According to various aspects, the reagent being transferred from the
reagent pack 110 into one ormore chambers 180 of themodular cassette 130 may be a radioactive input, and the synthesis of a product, such as a radioactive product, may take place in achamber 180 of thecassette 130. For example, the radioactive input may be a radioactive isotope typically produced in a cyclotron. According to various aspects, both thecassette 130 and thereagent pack 110 may be disposable. An advantage of the valveless system illustrated inFIG. 4 is the elimination of problems related to losses created by fluid or reagent remaining in valves and other tubing typically used to connect a reactor with a source of reagents. -
FIG. 5 is a perspective view of a synthesis module in operation, according to various aspects of the current invention. InFIG. 5 , thedisposable reaction cassette 230 and thereagent pack 210 are clamped together and held attached to thenon-disposable module 250 via theclamping mechanism 270 during use of thesystem 200. According to various aspects, theclamping mechanism 270 also provides the pressure and cohesive strength necessary to create a leak-free fluid connection between thereagent pack 210 and thecassette 230 by aligning respective channels formed in each of thereagent pack 210 and thecassette 230, as well as provide enough pressure and cohesive strength between thereagent pack 210 and thereaction cassette 230 to allow thegaskets reagent pack 210 and thereaction cassette 230, and between thereaction cassette 230 and themodule 250, to fulfill their function of providing insulation and preventing leakage of reagent or other ingredients. Accordingly, when theclamping mechanism 270 is in action, the respective channels in thereagent pack 210 and in thecassette 230, as well as the open channels formed in thegaskets cassette 230 and thereagent pack 210, as well as between acover 202, themodule 250 and each of thereagent pack 210 and thecassette 230. - According to various aspects, the
removable reagent pack 210 may be covered by a protective cover (not shown) on the surface that is in contact with thegasket 220, the protective cover covering one or more cavities or pockets within the reagent pack where an amount and/or a number of reagents may be stored, as illustrated inFIGS. 6-7 and described below. Accordingly, if the protective cover is punctured, the reagent present in the cavities or pockets is able to be transferred out of thereagent pack 210. Accordingly, theclamping mechanism 270 in one aspect of thesystem 200 also provides activation of the connections between the various modules by, for example, puncturing the protective cover that may cover the cavities or pockets in thereagent pack 210 in order to allow reagent located inside the cavities or pockets to be delivered to a chamber (not shown) of thecassette 230. Theclamping mechanism 270 may also provide sufficient pressure to enable the sealing gaskets to seal the various modules and prevent leakage or outside impurities from penetrating themodular reaction system 200. According to various aspects, theclamping mechanism 270 may also provide a mechanism to allow for the ejection of thecassette 230 and/or of thereagent pack 210 after use. - According to various aspects of the current invention, in operation, the
reagent pack 210, which is initially covered on both surfaces by a protective layer, and which is illustrated inFIGS. 6-7 and described in more detail below, is removeably inserted in thesystem 200. As discussed above, on the surface that is to be in contact with thecassette 230, thereagent pack 210 may have a protective membrane covering the surface of thereagent pack 210 and keeping the reagent inside thereagent pack 210. According to various aspects, thereagent pack 210 may include a plurality of cavities or pockets in which one or more reagents or ingredients may be stored, where each cavity may have two exits, a fluid exit and a vent. After thereagent pack 210 is inserted in thesystem 200, themodule 250, actuated, may urge theclamping mechanism 270 to clamp the various modules of thesystem 200, such as thereagent pack 210 and thereaction cassette 230, and to allow tubes to pneumatically puncture portions of the membrane covering one or more pockets in thereagent pack 210 in order to allow the transfer of reagent stored in the one or ore of the pockets from thereagent pack 210 to thecassette 230. When thereagent pack 210 is punctured and the stored reagents or ingredients are exposed to the transfer channels connecting thereagent pack 210 and thecassette 230, then transfer of reagent from thereagent pack 210 to thecassette 230 may be performed by manipulating pneumatics as discussed above with respect toFIG. 4 . -
FIGS. 6-7 are perspective views of components of a modular cassette system, according to various aspects of the current invention. According toFIG. 6 , theinterface plate 305 includes a plurality of perforating appendages such as, for example, tubes, 320, that may perforate capsules present in a reagent pack and that may include reagent. In some implementations, theinterface plate 305 may be made blunt and taller than thesharp tubes 320. These blunt features may allow light manual assembly of the reagent pack against the cassette without breaking the seals into any of the sensitive reagent volumes. Once the system is ready for synthesis to begin, the module clamps the reagent pack and cassette tightly to the front of the module, in the process, breaking through all of the foil barriers. Once this occurs, one may not be allowed to replace the reagent pack, but need to go forward through the process or abort it and start over. According toFIG. 7 , thereagent pack 310 may include individual phials, vials, pods, orcapsules 315 in which an amount of reagent may be stored. Accordingly, on the surface of thereagent pack 310 that is to be in contact with thecassette 330, theindividual capsules 315 in thereagent pack 310 store one or more reagents. Once thereagent pack 310 is inserted in thesystem 300, thetubes 320 present on a surface ofinterface plate 305 directly facing the surface of thereagent pack 310, may become actuated by the action of the clamping system, or by an actuation mechanism, and may puncture one or more of theindividual capsules 315 in order to allow the transfer of reagent stored in thecapsules 315 of thereagent pack 310 to one ormore chambers 380 of thecassette 330. According to various aspects, once thereagent pack 310 is punctured and the stored reagents or ingredients are exposed to the transfer channels connecting thereagent pack 310 to thecassette 330, the transfer of reagent from thereagent pack 310 to thecassette 330 may be performed pneumatically as discussed above with respect toFIG. 2 . -
FIG. 6 also illustrates thecassette 330 having a plurality ofchambers 380, where thechambers 380 are connected to each other via channels formed within thecassette 330, and where anyindividual chamber 380 may be independently used as a reaction vessel. It should be noted that the channels connecting any twochambers 380 may connect the bottom of thefirst chamber 380 to the top of thesecond chamber 380 in order to permit the pneumatically activated reagent transfer from thefirst chamber 380 to thesecond chamber 380. With respect toFIG. 7 , and according to various aspects, the phials orcapsules 315 may be configured to be individual removable units that can be placed at various locations of thereagent pack 310. Accordingly, areagent pack 310 may have one ormore reagent capsules 315 that contain reagent and that can be placed at different locations of thereagent pack 310, according to a given need. For example, specific locations of thecapsules 315 may correspond to a configuration where the reagent present in thecapsule 315 is transferred only tospecific chambers 380 of thecassette 330. As such, thesystem 300 allows for an exhaustive control of the reaction sites within thecassette 330, and may also allow for several reactions to take place independently during a same time period within thesame cassette 330. -
FIG. 8 illustrates a principle of fluid transfer according to various aspects of the current invention.FIG. 8 is a schematic illustration of a plurality of mixingchambers chambers reaction cassette 130 and/or of thereagent pack 110 discussed above with respect toFIG. 4 , and the fluid transfer between the chambers of thereaction cassette 130 and/or of thereagent pack 110 may be controlled according to the above-discussed vacuum and pressure as described below. - According to various aspects, each chamber may have one or more entry and exit passages. For example, the
chamber 410 may be a reaction chamber havinginput lines line 422 may be used to provide thechamber 410 with a pressurized gas such as, for example, N2 or any combination of gas or gases other than N2, such one or more inert gas, oxygen or air as long as the gas that does not interact with the fluid composition or ingredients present in thechamber 410 to create an unwanted chemical reaction, by opening a valve at theline 422. A gas referred to as “inert” in this disclosure may be inert with respect to the fluid, ingredients or reagents present in thechamber 410, even without being inert with respect to other compositions or other compounds. - An exemplary purpose of the pressurized gas provided via the
line 422 to thechamber 410 is to apply a downward pressure to the fluid present in thechamber 410 and urge the fluid out of thechamber 410 tochamber 450 via thetransfer line 430. Thechambers vacuum lines - According to various aspects of the current invention, in order to transfer all of the fluid present in the
first chamber 410 to thesecond chamber 450, theline 422 may be opened to allow a pressurized inert gas to flow into thechamber 410 and to create a pressure urging the fluid downward in thechamber 410 and ultimately out of thechamber 410 via thetransfer line 430. In addition, thegas line 462 in thesecond chamber 450 may be closed, and thevacuum line 464 in thechamber 450 may be opened by opening a vacuum valve located at theline 464. As a result, a vacuum is created inchamber 450, a suction action of the fluid present in thefirst chamber 410 may be produced through thetransfer line 430. Accordingly, the combined action of the pushing action of the pressurized gas flowing in thechamber 410 via theline 422 and of the suction action of the vacuum created in thetransfer line 430 and provided via thechamber 450 results in the entirety of the fluid present in thechamber 410 to be transferred rapidly to thechamber 450. According to various aspects, accidental subsequent fluid transfer tochamber 490 fromchamber 450 may also be prevented by maintaining a positive pressure inside thechamber 490 and thetransfer line 470 by, for example, flowing gas via thegas line 482 into thechamber 490 and possibly in thetransfer line 470. As a result of the existence of the positive pressure inchamber 490, no fluid that has been transferred fromchamber 410 tochamber 450 can accidentally be further transferred tochamber 490. - It should be noted that during the transfer process, the
pressurized gas line 462 of thechamber 450 may remain closed, and no pressurized gas is provided to thechamber 450. However, a pressurized gas may be provided to thechamber 450 via thegas line 462 before any fluid transfer from thechamber 410 to thechamber 450 in order to keep the fluid in thechamber 410 and avoid accidental transfer of fluid via theline 430 before such time when fluid transfer is desired. Accordingly, the pressurized gas is flowed insidechamber 450 via thegas line 462 while thevacuum line 464 is closed. Because the only other opening in thechamber 450 is thetransfer line 430, the pressurized gas flows through thetransfer line 430 into the fluid present in thechamber 410. As a result, gas sparging or bubbling of the fluid may occur at the end of thetransfer line 430 located at the bottom of thechamber 410, which may prevent any amount of fluid from accidentally being transferred from thechamber 410 to thechamber 450. Accordingly, accidental fluid transfer may be avoided, and no fluid is transferred before fluid transfer fromchamber 410 tochamber 450 is desired. - According to various aspects of the current invention, the
chamber 450 may also have one or more input lines such asinput lines chamber 410 intochamber 450. Accordingly, mixing of various additional ingredients with the fluid transferred from thechamber 410 to thechamber 450 may take place inside thechamber 450. According to various aspects of the current invention, a subsequent transfer of the fluid now present inchamber 450 tochamber 490 can be accomplished in a similar process to the process described above with respect to the transfer of fluid betweenchambers chamber 450 tochamber 490,gas line 462 is opened to allow flow of a pressurized inert gas intochamber 450 whilevacuum line 484 of thechamber 490 is opened to create a suction action. As a result, the fluid present inchamber 450 is entirely transferred to thechamber 490 viatransfer line 470. Inchamber 490, additional ingredients or reactants may be added to the fluid viainput lines - Accordingly, an additional mixture or reaction of various fluids and chemicals may be performed in the
successive chambers various chambers FIG. 8 . It should be noted that although only three chambers are illustrated inFIG. 8 , there may be as many chambers as needed to effectuate any required number of reaction steps. According to various aspects, the threechambers reaction cassette 130 and/or of thereagent pack 110 discussed with respect toFIG. 4 , and the fluid transfer between the chambers of thereaction cassette 130 and/or of thereagent pack 110 may be controlled according to the vacuum and pressure control mechanisms described with respect toFIG. 8 . - According to various aspects of the current invention, the above system and operation can be controlled and operated via hardware and software, as discussed in greater detail below,
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FIG. 9 presents an example system diagram of various hardware components and other features, for use in accordance with an aspect of the present invention. The present invention may be implemented using hardware, software, or a combination thereof and may be implemented in one or more computer systems or other processing systems. In one aspect, the invention is directed toward one or more computer systems capable of carrying out the functionality described herein. An example of such acomputer system 500 is shown inFIG. 9 . In some aspects, thecomputer system 500 may be configured to communicate with the multi-synthesis backplane/bus system discussed above inFIG. 2A . -
Computer system 500 includes one or more processors, such asprocessor 504. Theprocessor 504 is connected to a communication infrastructure 506 (e.g., a communications bus, cross-over bar, or network). Various software aspects are described in terms of this example computer system. After reading this description, it will become apparent to a person skilled in the relevant art(s) how to implement the invention using other computer systems and/or architectures. -
Computer system 500 can include adisplay interface 502 that forwards graphics, text, and other data from the communication infrastructure 506 (or from a frame buffer not shown) for display on adisplay unit 530.Computer system 500 also includes amain memory 508, preferably random access memory (RAM), and may also include asecondary memory 510. Thesecondary memory 510 may include, for example, ahard disk drive 512 and/or aremovable storage drive 514, representing a floppy disk drive, a magnetic tape drive, an optical disk drive, etc. Theremovable storage drive 514 reads from and/or writes to aremovable storage unit 518 in a well-known manner.Removable storage unit 518, represents a floppy disk, magnetic tape, optical disk, etc., which is read by and written toremovable storage drive 514. As will be appreciated, theremovable storage unit 518 includes a computer usable storage medium having stored therein computer software and/or data. - In alternative aspects,
secondary memory 510 may include other similar devices for allowing computer programs or other instructions to be loaded intocomputer system 500. Such devices may include, for example, aremovable storage unit 522 and aninterface 520. Examples of such may include a program cartridge and cartridge interface (such as that found in video game devices), a removable memory chip (such as an erasable programmable read only memory (EPROM), or programmable read only memory (PROM)) and associated socket, and otherremovable storage units 522 andinterfaces 520, which allow software and data to be transferred from theremovable storage unit 522 tocomputer system 500. -
Computer system 500 may also include acommunications interface 524. Communications interface 524 allows software and data to be transferred betweencomputer system 500 and external devices. Examples ofcommunications interface 524 may include a modem, a network interface (such as an Ethernet card), a communications port, a Personal Computer Memory Card International Association (PCMCIA) slot and card, etc. Software and data transmitted from, e.g., the multi-synthesis backplane/bus system discussed above inFIG. 2A and transferred viacommunications interface 524 are in the form ofsignals 528, which may be electronic, electromagnetic, optical or other signals capable of being received bycommunications interface 524. Thesesignals 528 are provided tocommunications interface 524 via a communications path (e.g., channel) 526. Thispath 526 carriessignals 528 and may be implemented using wire or cable, fiber optics, a telephone line, a cellular link, a radio frequency (RF) link and/or other communications channels. In this document, the terms “computer program medium” and “computer usable medium” are used to refer generally to media such as a removable storage drive 580, a hard disk installed in hard disk drive 570, and signals 528. These computer program products provide software to thecomputer system 500. The invention is directed to such computer program products. - Computer programs (also referred to as computer control logic) are stored in
main memory 508 and/orsecondary memory 510. Computer programs may also be received viacommunications interface 524. Such computer programs, when executed, enable thecomputer system 500 to perform the features of the present invention, as discussed herein. In particular, the computer programs, when executed, enable theprocessor 510 to perform the features of the present invention. Accordingly, such computer programs represent controllers of thecomputer system 500. - In an aspect where the invention is implemented using software, the software may be stored in a computer program product and loaded into
computer system 500 usingremovable storage drive 514,hard drive 512, orcommunications interface 520. The control logic (software), when executed by theprocessor 504, causes theprocessor 504 to perform the functions of the invention as described herein. In another aspect, the invention is implemented primarily in hardware using, for example, hardware components, such as application specific integrated circuits (ASICs). Implementation of the hardware state machine so as to perform the functions described herein will be apparent to persons skilled in the relevant art(s). - In yet another aspect, the invention is implemented using a combination of both hardware and software.
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FIG. 10 is a block diagram of various example system components, in accordance with an aspect of the present invention.FIG. 10 shows acommunication system 600 usable in accordance with, e.g., the multi-synthesis backplane/bus system discussed above inFIG. 2A , according to an aspect of the present invention. Thecommunication system 600 includes one or more accessors 660, 662 (also referred to interchangeably herein as one or more “users”) and one ormore terminals accessors terminals server 643, such as a PC, minicomputer, mainframe computer, microcomputer, or other device having a processor and a repository for data and/or connection to a repository for data, via, for example, anetwork 644, such as the Internet or an intranet, andcouplings couplings -
FIG. 11 illustrates a flow diagram for performing asynthesis method 1100 in a modular system, in accordance with an aspect of the present invention. The method includes, among other things, providing 1102 one or more reaction cassettes, andcoupling 1104 one or more reagent packs to the one or more reaction cassettes via one or more couplings. The method further includes providing 1106 one or more gaskets between adjacent cassettes and/or reagent packs to prevent leakage between the adjacent cassettes and/or reagent packs, wherein the one or more couplings include channels formed in the one or more cassettes, the one or more reagent packs and the one or more gaskets, and the channels are in communication with one another. - While this invention has been described in conjunction with the example aspects outlined above, various alternatives, modifications, variations, improvements, and/or substantial equivalents, whether known or that are or may be presently unforeseen, may become apparent to those having at least ordinary skill in the art. Accordingly, the exemplary aspects of the invention, as set forth above, are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the invention. Therefore, the invention is intended to embrace all known or later-developed alternatives, modifications, variations, improvements, and/or substantial equivalents.
Claims (30)
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US14/871,287 US10906020B2 (en) | 2011-07-15 | 2015-09-30 | Systems, methods and devices for producing, manufacturing and control of radiopharmaceuticals |
US17/131,420 US11904289B2 (en) | 2011-07-15 | 2020-12-22 | Systems, methods and devices for producing, manufacturing and control of radiopharmaceuticals |
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Owner name: BATTELLE MEMORIAL INSTITUTE, OHIO Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ZAMBANINI, JOSEPH EDWARD;REEL/FRAME:039184/0221 Effective date: 20160629 Owner name: BATTELLE MEMORIAL INSTITUTE, OHIO Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:HOLLEY, DAVID ARTHUR;REEL/FRAME:039184/0085 Effective date: 20160621 Owner name: BATTELLE MEMORIAL INSTITUTE, OHIO Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:STROUP, JEFFREY TAYLOR;REEL/FRAME:039184/0369 Effective date: 20160617 |