Systems, methods and devices for producing, manufacturing and control of radiopharmaceuticals-full

Abstract

Systems, methods, and devices for generating radionuclides for use in production of radiopharmaceuticals; synthesizing the radionuclides generated and removing any unwanted products; measuring the quantity and activity level of the synthesized radionuclides; distributively delivering the radionuclides in appropriate quantities to modular cassette synthesis units in a modular cassette subsystem for contemporaneous/parallel production of radiopharmaceutical output and that allow reuse and/or quick, safe, and disposable replacement of portions of the subsystem; delivering non-radionuclide components to the modular cassette synthesis units as part of production of radiopharmaceutical output; measuring the quantity and activity level of each stream of radiopharmaceutical output; purifying the radiopharmaceutical output; dispensing individual doses in sterile vial(s); automatically producing labeling and dose related information; performing automated quality control on extracted samples of produced radiopharmaceutical output; and providing software and hardware controls for overall and sub-portion operation for optional remote data collection, communication, and/or control.

What is claimed is: 
     
         1 . A radiopharmaceutical production system comprising:
 a synthesis unit comprising a plurality of separate synthesis components; and   a connection receiving active product from a radionuclide generator,   wherein each of the synthesis components is configured to individually produce at least one radiopharmaceutical product comprising the received active product.   
     
     
         2 . The system according to  claim 1 , further comprising:
 a splitter positioned between the connection and the synthesis unit, wherein the splitter comprises:
 a vessel for receiving the active product; and 
 a synthesis unit selector that directs a predetermined amount of the received active product to at least one of the synthesis components. 
   
     
     
         3 . The system according to  claim 2 , wherein the splitter further comprises:
 a pump positioned between the vessel and the synthesis unit selector, wherein the pump pumps the predetermined amount of active material from the vessel to the synthesis unit selector.   
     
     
         4 . The system according to  claim 3 , wherein the splitter further comprises:
 a prime loop connected between the vessel and the pump;   a line between the pump and synthesis unit selector;   a rinse fluid line comprising a connection to the pump that enables a rinse fluid to be pumped through at least a portion of the prime loop; and   a gas supply line, wherein the fluid line and the gas line comprise a connection to the pump that enables a gas to be pumped through at least the line between the pump and the synthesis unit selector.   
     
     
         5 . The system according to  claim 4 , wherein the pump comprises a two position pump, wherein at a first position, the pump:
 connects a first portion and a second portion of the prime loop; and   connects the gas line to the line between the pump and the synthesis unit selector, and   wherein in a second position, the pump:
 disconnects the prime loop, 
 connects the vessel to the line between the pump and the synthesis unit selector, and 
 connects the rinse fluid line to the second portion of the prime loop. 
   
     
     
         6 . The system according to  claim 1 , wherein each of the plurality of synthesis components comprise a module and a cassette that connect to form a synthesis element, wherein the synthesis element comprises a reaction vessel and at least one of a QMA cartridge, heating provisions, a mixing chamber, a neutralizing chamber, a final production collection chamber, and a solid phase exchange cartridge. 
     
     
         7 . The system according to  claim 6 , wherein each of the plurality of synthesis components comprise at least one valveless pressure pump. 
     
     
         8 . The system according to  claim 7 , wherein the valveless pressure pump comprises at least one of a cascade pump and a membrane pump. 
     
     
         9 . The system according to  claim 7 , wherein the synthesis component further comprises a reagent component comprising a reagent material used to produce the radiopharmaceutical product from the active product. 
     
     
         10 . The system according to  claim 9 , wherein the reagent component is removable from the synthesis component. 
     
     
         11 . The system according to  claim 6 , wherein each of the synthesis components comprises a modular synthesis component that is configured to be interchangeable with any of the other synthesis components. 
     
     
         12 . The system according to  claim 11 , wherein the synthesis unit comprises six modular synthesis components. 
     
     
         13 . The system according to  claim 1 , further comprising:
 a high performance liquid chromatography (HPLC) unit that performs purification during production of the radiopharmaceutical product from the active product.   
     
     
         14 . The system according to  claim 13 , wherein the HPLC unit comprises a modular HPLC unit having a plurality of columns and a column selector device. 
     
     
         15 . The system according to  claim 14 , wherein the columns are disposable. 
     
     
         16 . The system according to  claim 14 , wherein the HPLC unit connects to at least one of the synthesis components. 
     
     
         17 . The system according to  claim 1 , further comprising:
 a splitter;   a purifying component;   an output component;   a vial filler;   a quality control component; and   a sensor that measures at least one of an activity level of a sample and a volume of the sample, wherein the sensor is comprised in at least one of the splitter, the synthesis unit, the purifying component, the output component, the vial filler, and the quality control component.   
     
     
         18 . The system according to  claim 17 , wherein the sensor comprises a cadmium zinc telluride (CZT) element. 
     
     
         20 . The system according to  claim 18 , wherein the sensor comprises a CZT rod that inserted into the sample. 
     
     
         21 . The system according to  claim 18 , wherein the sensor comprises a first CZT element provided at a first column end of a sample column and a second CZT element provided at an opposite column end of the sample column. 
     
     
         22 . The system according to  claim 17 , further comprising:
 an analog to digital (A/D) converter that separates pulses according to a height of each pulse measured at the sensor; and   a processing component comprised in a field programmable gate array that converts a signal received from the A/D converter into an activity measurement for the sample.   
     
     
         23 . The system according to  claim 17 , further comprising:
 a sample vessel;   a shield surrounding the sample vessel;   a probe placed at a side of the sample having the shield interposed between the probe and the sample; and   a strain gauge positioned below the shield, wherein the shield comprises an opening that enables a portion of the sample vessel to make contact with the strain gauge, wherein the strain gauge determines a volume of the sample based on a strain measurement.   
     
     
         24 . The system according to  claim 1 , further comprising an automated, closed path vial filler, the vial filler comprising:
 a bulk product vial containing a bulk product;   a peristaltic pump coupled with the bulk product vial;   a dispensing manifold assembly coupled with the peristaltic pump; and   at least one final product vial coupled to the dispensing manifold assembly, wherein the peristaltic pump is configured to transfer a predetermined amount of bulk product from the bulk product vial to the at least one final product vial via the dispensing manifold assembly.   
     
     
         25 . The system according to  claim 24 , the vial filler further comprising:
 a stepper motor operably coupled with the peristaltic pump.   
     
     
         26 . The system according to  claim 25 , the vial filler further comprising:
 a dilution container having a dilution solution, wherein the dilution container is in fluid communication with the bulk product vial and disposed between the peristaltic pump and the dispensing manifold assembly.   
     
     
         27 . The system according to  claim 1 , further comprising:
 An automated quality control apparatus for testing of radio-synthesized tracers for at least one selected from a group consisting of particle and color content, filter membrane integrity, pH value, residual solvent volume, Kryptofix concentration, bacterial endotoxins concentration, radionuclidic identify, radionuclidic purity, radiochemical identity, radiochemical purity, and sterility.   
     
     
         28 . The system according to  claim 27 , wherein the quality control apparatus further stores records of testing results. 
     
     
         29 . The system according to  claim 27 , wherein the quality control apparatus performs self calibration 
     
     
         30 . The system according to  claim 27 , wherein the quality control apparatus performs a plurality of tests in parallel. 
     
     
         31 . The system according to  claim 1 , further comprising:
 an active product generator.   
     
     
         32 . The system according to  claim 31 , wherein the active product generator comprises a continuous output active product generator that generates a selected amount of active product on-demand. 
     
     
         33 . The system according to  claim 32 , wherein the continuous output active product generator comprises:
 a metering pump and a first check valve to control delivery of a metered amount of a fluid containing O-18 atoms to a target cell irradiated by a proton beam, wherein the proton beam converts O-18 to radioactive F-18;   a second check valve coupled to the target cell to control on-demand removal of a portion of the fluid enriched with F-18; and   a gas pressurized switching valve to chase the portion of the fluid enriched with F-18 from the system.   
     
     
         34 . The system according to  claim 33 , wherein the continuous output active product generator further comprises:
 a reprocessing line that returns unused material for reuse; and   an electrochemical component for separating and cleaning the unused material prior to reuse.   
     
     
         35 . The system according to  claim 1 , further comprising an automated labeling component that labels the radiopharmaceutical product. 
     
     
         36 . The system according to  claim 1 , further comprising a communication connection to a dispensing pharmacy. 
     
     
         37 . The system according to  claim 36 , wherein the dispensing pharmacy is remote from the synthesis unit. 
     
     
         38 . The system according to  claim 1 , further comprising a control component that interfaces with the synthesis unit to manage the production of the radiopharmaceutical product. 
     
     
         39 . The system according to  claim 38 , wherein the system further comprises a splitter, and wherein the control component further comprises an interface for controlling the splitter to manage the production of the radiopharmaceutical product. 
     
     
         40 . The system according to  claim 39 , wherein the system further comprises a vial filler, and wherein the control component further comprises an interface for controlling the vial filler to manage the production of the radiopharmaceutical product. 
     
     
         41 . The system according to  claim 40 , wherein the system further comprises a quality control apparatus, and wherein the control component further comprises an interface for controlling the quality control apparatus to manage the production of the radiopharmaceutical product. 
     
     
         42 . The system according to  claim 41 , wherein the system further comprises a an active product generator, wherein the control component further comprises an interface for controlling the active product generator to manage the production of the radiopharmaceutical product. 
     
     
         43 . The system according to  claim 42 , wherein the system further comprises a labeling component and a connection to a dispensing pharmacy, wherein the control component further comprises an interface for controlling the labeling component and the dispensing pharmacy in order to manage the production and distribution of the radiopharmaceutical product. 
     
     
         44 . The system according to  claim 43 , wherein the control component receives input from a logistics component regarding parameters for the production and distribution of radiopharmaceutical to a patient within a required amount of time and manages the workload of the system based on the received input. 
     
     
         45 . The system according to  claim 43 , wherein the control component generates a report regarding the production of radiopharmaceutical product via the system. 
     
     
         46 . The system according to  claim 43 , wherein the control component tracks pharmaceuticals from a production stage to a patient dosage stage. 
     
     
         47 . The system according to  claim 38 , wherein the control component comprises:
 a user interface that receives a selection of a synthesis unit component and receives at least one of a type and an amount of radiopharmaceutical product to be produced,   wherein the control component operates the system in order to produce the amount of radiopharmaceutical received via the user interface and using the indicated synthesis unit component.   
     
     
         48 . The system according to  claim 47 , wherein the user interface further comprises:
 a graphic representation of a connection between subcomponents of the system used for production of the indicated radiopharmaceutical product.   
     
     
         49 . A method of producing radiopharmaceuticals, comprising:
 generating radionuclides for use in production of a radiopharmaceutical product;   receiving instructions via a user interface to produce the radiopharmaceutical product; and   automatically synthesizing the radiopharmaceutical product using the radionuclides.   
     
     
         50 . The method of  claim 49 , further comprising:
 removing unwanted products included with at least one selected from a group consisting of the generated radionuclides, the radiopharmaceutical, and an intermediate compound in the synthesis.   
     
     
         51 . The method of  claim 49 , further comprising:
 measuring at least one selected from a group consisting of a quantity and an activity level of a sample during the radiopharmaceutical production process.   
     
     
         52 . The method of  claim 49 , further comprising:
 distributively delivering the radionuclides in an appropriate quantity to one of a plurality of modular cassette synthesis units in a modular cassette subsystem for production of radiopharmaceutical output.   
     
     
         53 . The method of  claim 49 , further comprising:
 distributively delivering the radionuclides in appropriate quantities to a plurality of modular cassette synthesis units in a modular cassette subsystem for parallel production of radiopharmaceutical output.   
     
     
         54 . The method of  claim 49 , wherein each modular cassette synthesis is configured to allow disposable replacement of portions of the subsystem. 
     
     
         55 . The method of  claim 52 , further comprising:
 delivering appropriate quantities of non-radionuclide components to the plurality of modular cassette synthesis units as part of the production of radiopharmaceutical output.   
     
     
         56 . The method of  claim 55  further comprising:
 upon production of the radiopharmaceutical output from the plurality of modular cassette synthesis units, measuring at least one selected from a group consisting of the quantity and activity level of a stream of radiopharmaceutical output. 
 
     
     
         57 . The method of  claim 56 , wherein the measuring is performed via at least one selected from a group consisting of a radioactivity sensor and a dose calibrator. 
     
     
         58 . The method of  claim 55 , further comprising
 upon production of the radiopharmaceutical output from the plurality of modular cassette synthesis units, measuring at least one selected from a group consisting of the quantity and activity level of each of a plurality of streams of radiopharmaceutical output.   
     
     
         59 . The method of  claim 49 , further comprising:
 purifying the radiopharmaceutical output.   
     
     
         60 . The method of  claim 49 , wherein purifying the radiopharmaceutical output comprises removing any unwanted products included with the generated radionuclides including drying or deprotecting at least one selected from a group consisting of the generated radionuclides, the radiopharmaceutical, and an intermediate compound. 
     
     
         61 . The method of  claim 60 , wherein the purifying is at least partially performed in at least one disposable column. 
     
     
         62 . The method of  claim 49 , further comprising:
 distributively dispensing bulk product in one or more sterile vials or manufactured dose containers.   
     
     
         63 . The method of  claim 62 , further comprising:
 automatically labeling a container of the radiopharmaceutical product.   
     
     
         64 . The method of  claim 49 , further comprising:
 automatically producing dose related information for use with the doses.   
     
     
         65 . The method of  claim 49 , further comprising:
 performing automated quality control on one or more extracted samples from the produced radiopharmaceutical output.   
     
     
         66 . The method of  claim 49 , further comprising:
 providing dose information to a remote dispensing pharmacy.   
     
     
         67 . The method of  claim 66 , wherein a dose is determined prior to generating radionuclides, and wherein the amount of radionuclide is generated based on the determined dose, and wherein the dose information provided to the remove dispensing pharmacy comprises the previously determined dose. 
     
     
         68 . The method of  claim 49 , further comprising:
 providing at least one selected from a group consisting of software and hardware controls for a plurality of sub-portion operation that enables remote at least one selected from a group consisting of data collection, troubleshooting, communication, and control.   
     
     
         69 . The method of  claim 49 , further comprising:
 replacing components for a single run product within an internal shielded opening with multiple subsystems that each enable an individual production run.   
     
     
         70 . The method of  claim 69 , wherein the multiple subsystems are configured to allow parallel production operations. 
     
     
         71 . The method of  claim 49 , comprising running a plurality of steps in a quality control process in an automated manner contemporaneously with a dispensing operation of the method. 
     
     
         72 . The method of  claim 49 , further comprising:
 running an automated purification process comprising at least one selected from a group consisting of high performance liquid chromatography (HPLC), low pressure chromatography, flash chromatography, and Sep-Pak purification and isolation processes.   
     
     
         73 . The method of  claim 72 , wherein the automated purification process is run using a disposable column.