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WO2016130463A1 - Système automatique de production et de contrôle qualité de produits radiopharmaceutiques - Google Patents

Système automatique de production et de contrôle qualité de produits radiopharmaceutiques Download PDF

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Publication number
WO2016130463A1
WO2016130463A1 PCT/US2016/016964 US2016016964W WO2016130463A1 WO 2016130463 A1 WO2016130463 A1 WO 2016130463A1 US 2016016964 W US2016016964 W US 2016016964W WO 2016130463 A1 WO2016130463 A1 WO 2016130463A1
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Prior art keywords
radiopharmaceutical
approximately
radioisotope
mci
mev
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Inventor
Mark Khachaturian
Doug Ferguson
Aaron Mcfarland
Atilio Anzellotti
Clive Brown-Proctor
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ABT Molecular Imaging Inc
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ABT Molecular Imaging Inc
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Priority claimed from US14/618,795 external-priority patent/US11135321B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se

Definitions

  • This invention relates to a method and apparatus for automatically producing of radiopharmaceuticals and the automatic quality control testing of said radipharmaceuticals.
  • Cyclotrons are used to generate high energy charged particle beams for purposes such as nuclear physics research and medical treatments.
  • One area where cyclotrons have found particular utility is in the generation of radiopharmaceuticals, also known as biomarkers, for medical diagnosis by such techniques as positron emission tomography (PET).
  • PET positron emission tomography
  • a conventional cyclotron involves a substantial investment, both in monetary and building resources.
  • An example of one of the more compact conventional cyclotrons used for radiopharmaceutical production is the Eclipse RD developed by the company founded by the present inventor and now produced by Siemens. The self-shi elded version of the Eclipse RD can be installed in a facility without a shielded vault.
  • the minimum room size for housing the Eclipse RD is 7.31 m x 7.01 m x 3 m (24 ft x 23 ft x 10 ft).
  • the cyclotron room includes a concrete pad with a minimum thickness of 36 cm (14 in).
  • the power requirements often involve a dedicated and substantial electrical power system.
  • the minimum electrical service required for the Eclipse RD is a 208 ( ⁇ 5 %) VAC, 150 A, 3-phase service.
  • [ 18 F]FDG requires up to 45 min using one of the larger conventional radiochemical synthesis systems, such as the Explora FDG4 radiochemistry module, originally developed by a company founded by the present inventor and now produced by Siemens.
  • the processing time is significant with respect to the half-life of the radioisotope. Accordingly, the production yield fraction of a biomarker of a conventional radiopharmaceutical synthesis system is far from ideal, often limited to a range of approximately 50 % to 60 % of the component substances.
  • the processing time fraction is approximately 40 % of the half-life of the [ 18 F]F ⁇ radioisotope. Corrected to the end of bombardment, the Explora FDG 4 has an yield fraction of approximately 65 %.
  • the production of approximately 90 GBq (2400 mCi) of [ 18 F]F ⁇ requires a bombardment time of approximately 120 min using the Eclipse RD cyclotron.
  • the short half-lives and low yields require production of a significantly greater amount of the biomarker than is actually needed for the intended use.
  • the radioactivity of a unit dose of a biomarker administered to a particular class of patient or subject for medical imaging is considerable smaller, generally ranging from 0.185 GBq to 0.555 GBq (5 mCi to 15 mCi) for human children and adults and from
  • the final radiopharmaceutical solution should be tested for the presence and levels of volatile organics, such as ethanol or methyl cyanide, that may remain from synthesis process. Likewise, the solution should be tested for the presence of crown ethers or other reagents used in the synthesis process, as the presence of these reagents in the final dose is problematic. Further, the radiochemical purity of the final solution should be tested to ensure that it is sufficiently high for the solution to be useful. Other tests, such as tests of radionuclide purity, tests for the presence of bacterial endotoxins, and tests of the sterility of the synthesis system, are known in the art.
  • a conventional cyclotron for radiopharmaceutical production generates a beam of charged particles having an average energy in the range of 11 MeV to 18 MeV, a beam power in the range of 1.40 kW and 2.16 kW, and a beam current of approximately 120 ⁇ A.
  • the weight of an electromagnet of such a conventional cyclotron for radiopharmaceutical production typically ranges between 10 tons and 20 tons.
  • the Eclipse RD is an 11 MeV negative-ion cyclotron producing up to two particle beams each with a 40 ⁇ beam current.
  • the major power consuming components of a cyclotron are typically the magnet system power supply, the RF system amplifier, the ion source transformer, the vacuum system cryopump compressor, and the water system.
  • the magnet system power supply and the RF system amplifier are the most significant.
  • the operating power consumption of the Eclipse RD is specified at 35 kW.
  • the standby power consumption of the Eclipse RD is specified at less than 7 kW.
  • the magnet system of the Eclipse RD produces a mean field of 1.2 T using 3 kW of power.
  • the RF system of the Eclipse RD has a maximum amplifier power of 10 kW.
  • the ion source system of the Eclipse RD is specified for a maximum FT current of 2 niA.
  • Figure 1 is a representative illustration of an array of dees in a conventional cyclotron. For simplicity, only two dees 12 are illustrated. However, there are typically four or more dees used. Cyclotrons having fewer dees require more turns in the ion acceleration path, a higher acceleration voltage, or both to energize the ions to the desired level.
  • the dees 12 are positioned in the valley of a large electromagnet and enclosed in a vacuum tank.
  • an ion source 81 continuously generates ions 19 through the addition or subtraction of electrons from a source substance.
  • ions 19 are introduced into the cyclotron at the center of the array of dees 12, they are exposed a strong magnetic field generated by opposing magnet poles 11 situated above and below the array of dees 12.
  • a radio frequency (RF) oscillator applies a high frequency, high voltage signal to each of the dees 12 causing the charge of the electric potential developed across each of the dees 12 to alternate at a high frequency.
  • Neighboring dees are given opposite charges such that ions 19 entering the gap between neighboring dees 12 see a like charge on the dee behind them and an opposite charge on the dee ahead of them, which results in acceleration (i.e., increasing the energy) of the ions 19. With each energy gain, the orbital radius of the ions 19 increases. The result is a stream of ions 19 following an outwardly spiraling path.
  • the ions 19 ultimately exit the cyclotron as a particle beam 40 directed at a target 89.
  • Figure 2 illustrates an exploded view of selected components of a
  • the cyclotron includes upper and lower yokes 54 that cooperatively engage when assembled to define an acceleration chamber and opposing upper and lower magnet poles 11.
  • Each magnet pole 11 includes two wedge-shaped pole tips 32, commonly referred to as "hills” where the magnetic flux 58 is mostly concentrated.
  • the recesses between the hills 32 are commonly referred to as “valleys” 34 where the gap between the magnet poles 11 is wider.
  • a dee 12 is located in each open space defined by the corresponding upper and lower valleys 34.
  • the nuclear reaction that occurs as the particle beam 40 irradiates the target substance 100 contained therein to produce the desired radioisotope generates prompt high-energy gamma radiation and neutron radiation. Additionally, residual radiation is indirectly generated by the nuclear reaction that yields the radioisotope. During the nuclear reaction, neutrons are ejected from the target substance and when they strike an interior surface of the cyclotron, gamma radiation is generated. Finally, direct bombardment of components such as the
  • a cyclotron must be housed in a shielded vault or be self- shielded. Although commonly composed of layers of exotic and costly materials, shielding systems only can attenuate radiation; they cannot absorb all of the gamma radiation or other ionizing radiation.
  • the target substance is commonly transferred to a radioisotope processing system.
  • radioisotope processing systems are numerous and varied and are well known in the prior art.
  • the radioisotope processing system prepares the radioisotope for the tagging or labeling of molecules of interest to enhance the efficiency and yield of the radiopharmaceutical synthesis processes.
  • the radioisotope processing system may extract undesirable molecules, such as excess water or metals to concentrate or purify the target substance.
  • the automated radiopharmaceutical production and quality control system includes a particle accelerator, a radiopharmaceutical micro-synthesis system, and an automated quality control system.
  • the micro-accelerator of the improved biomarker generator is optimized for producing radioisotopes useful in synthesizing
  • radiopharmaceutical in quantities on the order of one unit dose allowing for significant reductions in the quantity of radioisotope required and the processing time when compared to conventional radiopharmaceutical processing systems.
  • the automated quality control system simplifies radiopharmaceutical production by automatically performing the required quality control tests and generating a dose record to be used as a quality control record.
  • the system is also self shielded such that the the radiation field outside the shield is acceptable for radiation workers ( ⁇ 1 mrem/hr).
  • the improved biomarker generator includes a small, low-power particle accelerator (hereinafter "micro-accelerator”) for producing approximately multiple unit doses of a radioisotope that is chemically bonded (e.g. , covalently bonded or ionically bonded) to a specific molecule.
  • the micro-accelerator produces per run a maximum quantity of radioisotope that is approximately equal to the quantity of radioisotope required by the radiopharmaceutical micro-synthesis system to synthesize a unit dose of biomarker.
  • the micro-accelerator takes advantage of various novel features, either independently or in combination to reduce size, weight, and power requirements and consumption.
  • the features of the micro-accelerator described allow production of a radioisotope with a maximum radioactivity of approximately 2.59 GBq (70 mCi) using a particle beam with an average energy in the range of 5 MeV to 18 MeV or in various sub-ranges thereof and a maximum beam power in the range of 50 W to 200 W.
  • One feature of the micro-accelerator is the use of permanent magnets to contain the ions during acceleration and eliminate the electromagnetic coils of the common to conventional radiopharmaceutical cyclotrons.
  • Each of the permanent magnets and the dees are wedge-shaped and arranged into a substantially circular array.
  • a series of collimator channels in selected dees initially direct the path of the ions introduced at the center of the array. After exiting the series of collimator channels, the ions travel through the main channels of the dees until the desired energy level is achieved.
  • the permanent magnet cyclotron provides substantial improvements with respect to cost, reliability, size, weight, infrastructure requirements, and power requirements compared to conventional
  • radiopharmaceutical cyclotrons
  • Another feature of the micro-accelerator is the use of an improved radio frequency (RF) system powered by a rectified RF power supply.
  • a rectified input supplies a high voltage transformer to supply power to the RF oscillator.
  • the RF signal produced by the RF system is high peak-to-peak voltage at the resonant frequency of the RF oscillator enveloped by the line voltage frequency. The charged particles are only accelerated during a portion of the line voltage cycle. The resulting RF power supply compensates for reduced activity by increasing the current.
  • a still further feature of the micro-accelerator is the use of an internal target cyclotron where the target is located within the magnetic field and the particle beam irradiates the internal target while still within the magnetic field.
  • This allows the magnet system to assist in containing harmful radiation related to the nuclear reaction that converts the target substance into a radioisotope and eliminates a major source of radiation inherent in a conventional positive-ion cyclotron.
  • the micro-accelerator can take advantage of the benefits without a significant disadvantage normally associated with a positive particle beam. Beams of positively-charged particles generally are more stable than beams of negatively-charged particle because the reduced likelihood of losing an electron at the high velocities that charged particles experience in a cyclotron.
  • Losing an electron usually causes the charged particle to strike an interior surface of the cyclotron and generate additional radiation. Minimizing the production of excess radiation reduces the amount of shielding required. Additionally, a positive ion cyclotron requires significantly less vacuum pumping equipment. Reducing the amount of shielding and vacuum pumping equipment reduces the size, weight, cost, complexity, power requirements, and power consumption of the cyclotron.
  • the radiopharmaceutical micro-synthesis system provides a significant reduction in processing time that directly reduces the quantity of the radioisotope required to synthesize the desired biomarker.
  • the method for producing a radiopharmaceutical using the improved biomarker generator calls for providing a micro-accelerator, producing charged particles, accelerating the charged particles, and forming a particle beam to irradiate a target substance and produce a radioisotope.
  • the improved biomarker generator allows operation using a volume of the target substance that is unusually small in the area of radiopharmaceutical production.
  • the radioisotope and at least one reagent are transferred to the radiopharmaceutical micro-synthesis system.
  • the radioisotope undergoes processing as necessary.
  • the radiopharmaceutical micro-synthesis system combines the radioisotope with the reagent or reagents to synthesize the biomarker.
  • the system includes a radiopharmaceutical micro-synthesis system having at least one microreactor and/or microfluidic chip. Using the unit or precursory unit dose of the radioisotope and at least one reagent, the radiopharmaceutical micro-synthesis system synthesizes on the order of a unit dose of a biomarker. Chemical synthesis using
  • microreactors or microfluidic chips is significantly more efficient than chemical synthesis using conventional macroscale chemical synthesis technology. Yields are higher and reaction times are shorter, thereby significantly reducing the quantity of radioisotope required in synthesizing a unit dose of biomarker. Accordingly, because the micro- accelerator only produces relatively small quantities of radioisotope per production run, the maximum beam power of the micro-accelerator is approximately two to three orders of magnitude less than the beam power of a conventional particle accelerator. As a direct result of this dramatic reduction in maximum beam power, the micro-accelerator is significantly smaller and lighter than a conventional particle accelerator, has less stringent infrastructure requirements, and requires far less electricity. Additionally, many of the components of the small, low-power accelerator are less costly and less sophisticated, such as the magnet, magnet coil, vacuum pumps, and power supply, including the RF oscillator.
  • the synergy that results from combining the micro-accelerator and the radiopharmaceutical micro-synthesis system having at least one microreactor and/or microfluidic chip cannot be overstated.
  • This combination which is the essence of the improved biomarker generator, provides for the production of approximately one unit dose of radioisotope in conjunction with the nearly on-demand synthesis of one unit dose of a biomarker.
  • the improved biomarker generator is an economical alternative that makes in- house biomarker generation at the imaging site a viable option even for small regional hospitals.
  • the present general inventive concept comprises quality control systems incorporating high performance liquid chromatography (HPLC) to perform quality control testing on a radiopharmaceutical solution shortly after synthesis.
  • HPLC high performance liquid chromatography
  • an HPLC-based quality control system according to the present general inventive concept makes efficient use of sample volume and is compatible with and able to test a variety of radioisotopes and radiopharmaceutical compounds.
  • the automated nature of an HPLC-based quality control system according to the present general inventive concept allows for quality control tests to be conducted quickly and with minimal impact on user workflow. Overall, and especially when used as part of an integrated PET biomarker radiopharmaceutical production system as described herein, the present general inventive concept permits a radiopharmaceutical manufacturer to produce product and conduct quality control tests on the product with lower per dose costs.
  • An accelerator produces per run a maximum quantity of radioisotope that is approximately equal to the quantity of radioisotope required by the microfluidic chemical production module to synthesize a unit dose of biomarker.
  • Chemical synthesis using microreactors or microfluidic chips (or both) is significantly more efficient than chemical synthesis using conventional (macroscale) technology. Percent yields are higher and reaction times are shorter, thereby significantly reducing the quantity of radioisotope required in synthesizing a unit dose of radiopharmaceutical. Accordingly, because the accelerator is for producing per run only such relatively small quantities of radioisotope, the maximum power of the beam generated by the accelerator is approximately two to three orders of magnitude less than that of a conventional particle accelerator.
  • the accelerator is significantly smaller and lighter than a conventional particle accelerator, has less stringent infrastructure requirements, and requires far less electricity. Additionally, many of the components of the small, low-power accelerator are less expensive than the comparable components of conventional accelerators. Therefore, it is feasible to use the low-power accelerator and accompanying CPM within the grounds of the site of treatment. Because radiopharmaceuticals need not be synthesized at a central location and then transported to distant sites of treatment, less radiopharmaceutical need be produced, and different isotopes, such as carbon-11, may be used if desired.
  • radiopharmaceuticals for PET can be administered to patients almost immediately after synthesis.
  • eliminating or significantly reducing the transportation phase does not eliminate the need to perform quality control tests on the CPM and the resultant radiopharmaceutical solution itself.
  • the traditional 45 to 60 minutes required for quality control tests on radiopharmaceuticals produced in macro scale is clearly inadequate.
  • the accelerator and the CPM are producing a radiopharmaceutical solution that is approximately just one (1) unit dose, it is important that the quality control tests not use too much of the radiopharmaceutical solution; after some solution has been sequestered for testing, enough radiopharmaceutical solution must remain to make up an effective unit dose.
  • a high- performance-liquid-chromatography -based quality control testing system to test a sample radiopharmaceutical solution comprises a high performance liquid chromatography column to receive a sample radiopharmaceutical solution.
  • a refractive index detector measures the amount of each separated molecularly distinct species from said high performance liquid chromatography column
  • a radiation detector measures the radioactivity of each separated molecularly distinct species from said high performance liquid chromatography column.
  • the system also includes an automated endotoxin detector to perform endotoxicity testing on the first part of the sample radiopharmaceutical solution held in the first sample collection vessel.
  • an automated endotoxin detector to perform endotoxicity testing on the first part of the sample radiopharmaceutical solution held in the first sample collection vessel.
  • the automated endotoxin detector includes a kinetic hemocyte lysate-based assay.
  • an HPLC-based quality control testing system includes a radiation detector that comprises at least two radiation probes, with a first radiation probe to measure the radioactivity of a part of the sample radiopharmaceutical solution that has not passed through said high performance liquid chromatography column and a second radiation probe to measure the radioactivity of each separated molecularly distinct species from said high performance liquid chromatography column.
  • a method for conducting quality control tests in real time on a radiopharmaceutical comprises: introducing into a reaction vessel a radioisotope and at least one reagent for synthesis of a preselected radiopharmaceutical; reacting said radioisotope and said at least one reagent to produce said preselected radiopharmaceutical in a raw state radiopharmaceutical solution containing undesirable chemical entities; conveying said raw state radiopharmaceutical solution through at least one cleansing step wherein at least one undesirable chemical entity is removed from said radiopharmaceutical solution, whereby said radiopharmaceutical solution is clarified; conveying a portion of said clarified radiopharmaceutical solution to a radiopharmaceutical solution pumping mechanism; pumping said clarified
  • radiopharmaceutical solution to an injection valve, said injection valve to direct the flow of said clarified radiopharmaceutical solution; directing a first aliquot of the clarified radiopharmaceutical solution into a first sample collection vessel, said first sample collection vessel to hold the first aliquot of the clarified radiopharmaceutical solution for measurement of the radioactivity of the clarified radiopharmaceutical solution; directing a second aliquot of the clarified radiopharmaceutical solution into a second sample collection vessel, said second sample collection vessel to hold the second aliquot of the sample radiopharmaceutical solution for endotoxicity testing; directing a third aliquot of the clarified radiopharmaceutical solution into a high performance liquid chromatography column, said high performance liquid chromatography column to separate molecularly distinct species within the third aliquot of the clarified radiopharmaceutical solution into a number of separated molecularly distinct species; measuring the optical qualities of the third aliquot of the sample
  • radiopharmaceutical solution by means of an ultraviolet-light detector; using a refractive index detector to measure the amount of each separated molecularly distinct species from said high performance liquid chromatography column; and measuring the radioactivity of each separated molecularly distinct species from said high performance liquid
  • said cyclotron has a maximum beam power selected from the group consisting of 50 W, 75 W, 100 W, 125 W, 150 W, 175, and 200 W.
  • said average energy of said charged particles is in the range of 5 MeV to 10 MeV.
  • said computer prints out a dose record summarizing the results of the quality control test.
  • said system simultaneously manages manufacture of said radioisotopes and said radiopharmaceutical production and said quality control.
  • said system activates an ion source which generates a beam of charged particles accelerated through a magnetic and electric field to an energy greater than or equal to the nuclear binding energy of the target substance.
  • said system selects a target substance for said radioisotope of said radiopharmaceutical. [0044] In some embodiments, said charged particles hitting said target substance produces a selected radioisotope.
  • said system generating a particle beam of charged particles with a maximum beam power of 200 W, said charged particles selected from the group consisting of protons and deuterons, said charged particles accelerated to an average energy at least equal to the nuclear binding energy of said target substance.
  • said system receives said radioisotope from manual injection into said disposable microfluidic radiopharmaceutical synthesis card system.
  • said system has a vacuum pump attached to the vent line of said disposable microfluidic radiopharmaceutical synthesis card system to remove vapor formation.
  • said system has the capability to read an RF ID chip or bar code to identify said radiopharmaceutical associated with said dose synthesis card.
  • said system has a shield around the cyclotron reducing the radiation field to acceptable levels ( ⁇ 1 mrem/hr).
  • an HPLC-based quality control system allows for quality control tests to be conducted quickly and with minimal impact on user workflow; the automated system relieves a technician from having to perform a number of the quality control tests.
  • the present general inventive concept permits a radiopharmaceutical manufacturer to produce product and conduct quality control tests on the product with lower per dose costs.
  • Figure 1 is a perspective view of the ionization and acceleration components disposed within a conventional cyclotron
  • Figure 2 is an exploded illustration of certain components of a prior art cyclotron
  • Figure 3 is a perspective view one embodiment of a micro-accelerator suitable for use in the improved biomarker generator described herein, in the form of a cyclotron using permanent magnets, showing the micro-accelerator in an open configuration;
  • Figure 4 is a perspective view of the lower platform of the micro-accelerator of Figure
  • Figure 5 is an elevation view, in cross-section taken along line 5-5 of Figure 6, illustrating the micro-accelerator of Figure 3 in a closed configuration;
  • Figure 6 is a plan view of the lower platform shown in Figure 4 with the dees shown in cross-section to illustrate the flight path of the ions during acceleration;
  • Figure 8 is an exploded illustration of one embodiment of a micro-accelerator incorporating an internal target, suitable for use in the improved biomarker generator described herein;
  • Figure 9 is a block diagram of the improved biomarker generator described herein for producing a unit dose of a biomarker
  • Figure 10 is a flow diagram of one embodiment of the method for producing approximately one unit dose of a biomarker using the improved biomarker generator described herein;
  • Figure 11 is a schematic of the automated system which includes a computer which controls the cyclotron, synthesis system, and quality control system;
  • Figure 12 is a schematic illustration of an embodiment of the dose synthesis card which only has a connection line to QC system and no sample card;
  • Figure 13 is a schematic illustration of a automated radiopharmaceutical production system with automated QC which does not require a sample card;
  • Figure 14A is a flow diagram showing a fully automated QC system which tests for all pharmacopeia (e.g. regulatory requirements) using a multi-port switching valve to distribute the sample to a number of additional pieces of equipment; and
  • pharmacopeia e.g. regulatory requirements
  • Figure 14B is a fourth flow diagram showing a fully automated QC system which tests for all pharmacopeia (e.g. regulatory requirements) using a series of load loops or ports to draw samples for a number of additional pieces of equipment from a sample line.
  • pharmacopeia e.g. regulatory requirements
  • the improved biomarker generator includes a particle accelerator and a radiopharmaceutical micro- synthesis system.
  • the micro-accelerator of the improved biomarker generator is optimized for producing radioisotopes useful in synthesizing radiopharmaceuticals in quantities on the order of one unit dose allowing for significant reductions in size, power requirements, and weight when compared to conventional radiopharmaceutical cyclotrons.
  • radiopharmaceutical micro-synthesis system of the improved biomarker generator is a small volume chemical synthesis system comprising a microreactor and/or a microfluidic chip and optimized for synthesizing the radiopharmaceutical in quantities on the order of one unit dose allowing for significant reductions in the quantity of radioisotope required and the processing time when compared to conventional radiopharmaceutical processing systems.
  • Such probes are also referred to in the art as radiotracers and radioligands and, more generically, as radiochemicals.
  • patient and “subject” refer to any human or animal subject, particularly including all mammals.
  • a “unit dose” refers to the quantity of radioactivity that is administered for medical imaging to a particular class of patient or subject.
  • a unit dose of the radiopharmaceutical necessarily comprises a unit dose of a radioisotope.
  • the improved biomarker generator of the present invention departs significantly from the established practice in that it is engineered to produce a per run maximum amount of radioisotope on the order of tens of millicuries.
  • the micro-accelerator produces a maximum of approximately 2.59 GBq (70 mCi) of the desired radioisotope per production run.
  • a particle accelerator producing a radioisotope on this scale requires significantly less beam power than conventional particle accelerators used for radiopharmaceutical production.
  • the micro-accelerator generates a particle beam having a maximum beam power of 200 W. In various embodiments, the micro-accelerator generates a particle beam having a maximum beam power of
  • the micro-accelerator is significantly smaller and lighter than a conventional cyclotrons used in radiopharmaceutical production and requires less electricity. Many of the components of the micro-accelerator are less costly and less sophisticated compared to conventional cyclotrons used in radiopharmaceutical production.
  • Figures 3 illustrates one embodiment of a selected portion of a micro- accelerator in the form of a cyclotron using permanent magnets 10a (hereinafter a
  • the valleys between the respective pairs of permanent magnets 20 are occupied by a plurality of dees 45, with one dee being disposed in each valley.
  • a centrally located ion injection opening 33 is defined through the upper and lower platforms 29 allowing the ion source 82 to generate ions at the center of the circular array of dees 45 and permanent magnets 20.
  • the micro-accelerator includes an RF system 44 in electrical communication with each of the dees 45 via a plurality of through-openings defined by the lower platform.
  • a dee support 46 attached to each dee 45 extends through a corresponding through-opening and electrically connects the attached dee to the RF system 44.
  • Each of the permanent magnets 20 and the dees 45 are wedge-shaped. Each permanent magnet 20 has a first end positioned proximate to the center of the array and a second positioned proximate to the periphery of the array. Likewise, each dee 45 has a first end positioned proximate to the center of the array and an second end positioned proximate to the periphery of the array. Each of the dees 45 defines a main channel 14 through which ions travel as they are accelerated. When the dees 45 are disposed with the valleys, the faces of the permanent magnet pole tips are disposed in substantially the same plane as the side of the of the corresponding horizontal member of the dees that define the main channel 14.
  • the horizontal inner surfaces of the dees are substantially co- planar with the corresponding pole faces of the magnet pairs.
  • a magnet gap is defined between corresponding permanent magnets 20 of the upper and lower platforms 29. Accordingly, the entire channel has a substantially homogeneous height, which provides an unobstructed flight path for the ions being accelerated therein.
  • the upper and lower platforms 29 are supported by a plurality of legs 37.
  • each leg 37 is defined by the body of a pneumatic or hydraulic cylinder 38.
  • the lower platform defines a plurality of through openings 35 for slidably receiving a piston rod 39 of each of the cylinders 38.
  • the distal end 42 of each piston rod 39 is connected to the upper platform.
  • engagement of the upper and lower platforms 29 is accomplished by retraction of the piston rods 39 into the respective cylinders 38.
  • Separation of the upper and lower platforms 29 is accomplished by extending the piston rods 39 from within the cylinders 38. While this construction is disclosed, it will be understood that other configurations are contemplated as well.
  • ions exiting the second collimator channel 13b travel across the interposed hill and enter the third collimator channel 13c.
  • the first, second and third collimator channels 13a, 13b, 13c are configured to define the first revolution of the ions during acceleration. Ions that lack the desired initial energy level are rejected by not allowing such ions to enter the first collimator channel 13a. After exiting the third collimator channel 13c, the ions travel through the main channels 14 defined by each of the dees 45 until the desired energy level is achieved.
  • the permanent magnet cyclotron 10a provides substantial improvements with respect to cost and reliability when compared to conventional cyclotrons producing particle beams with energies of 10 MeV or less using electromagnets or superconducting magnets. Because the permanent magnet cyclotron 10a allows for the exclusion of the electromagnetic coils of the common to conventional radiopharmaceutical cyclotrons, the volume and weight are significantly reduced. In one embodiment, the volume and weight of the micro- accelerator are 40 % of the volume and weight of conventional radiopharmaceutical cyclotrons, with a corresponding minimum equipment cost savings of approximately 25 % of the equipment cost of conventional radiopharmaceutical cyclotrons.
  • FIG. 7 is a block diagram of an improved RF system used in one embodiment of the micro-accelerator (hereinafter the "improved RF cyclotron").
  • the improved RF system includes a rectifier circuit 220 that accepts line voltage and produces a rectified voltage signal.
  • the rectifier circuit 220 is a full wave rectifier incorporating two or more diodes, such as a dual diode rectifier.
  • the rectified voltage signal is the positive portion of the line voltage.
  • the rectified voltage signal supplies the input of a high voltage step-up transformer 222 capable of supplying a high voltage and high current RF supply signal.
  • the resonance frequency of the RF oscillator is 72 MHz producing an RF signal having a frequency of 72 MHz with a maximum peak-to-peak voltage of 30 kV enveloped in the 60 Hz line voltage frequency.
  • the ion source of one embodiment of the micro-accelerator is optimized for positive ion production.
  • Beams of positively-charged particles generally are more stable than beams of negatively-charged particle because the reduced likelihood of losing an electron at the high velocities that charged particles experience in a cyclotron. Losing an electron usually causes the charged particle to strike an interior surface of the cyclotron and generate additional radiation. Minimizing the production of excess radiation reduces the amount of shielding required.
  • a positive ion cyclotron requires significantly less vacuum pumping equipment. Reducing the amount of shielding and vacuum pumping equipment reduces the size, weight, cost, complexity, power requirements, and power consumption of the cyclotron.
  • Figure 8 illustrates one embodiment of the micro-accelerator 10b in the form of a positive ion cyclotron (hereinafter "internal target cyclotron") where the target 183 (hereinafter “internal target”) is located within the magnetic field.
  • the positive ion particle beam 184 irradiates the internal target 183 while still within the magnetic field 182 produced by the opposing magnet poles 186, 188. Consequently, the magnet system assists in containing harmful radiation related to the nuclear reaction that converts the target substance into a radioisotope.
  • the internal target 183 eliminates a major source of radiation inherent in a conventional positive-ion cyclotron by eliminating the need for the conventional extraction blocks. In their absence, much less harmful radiation is generated. Thus, the internal target 183 eliminates a considerable disadvantage for positive-ion cyclotrons. A reduction in harmful radiation generation translates into a reduction in the amount of shielding and the associated benefits discussed above.
  • the internal target 183 includes a stainless steel tube 192 that conducts the target substance.
  • the stainless steel tube 192 has a target section centered in the path that the particle beam 184 travels following the final increment of acceleration.
  • the longitudinal axis of the target section is substantially parallel to the magnetic field 182 generated by the magnet system and substantially perpendicular to the electric field generated by the RF system.
  • the remainder of the stainless steel tube 192 is selectively shaped and positioned such that it does not otherwise obstruct the path followed by the particle beam 184 during or following its acceleration.
  • the internal target 183 defines an opening 196 that is positioned in a path of the particle beam 184.
  • the charged particles have an average energy in the range of 8 MeV to 10 MeV. In yet another embodiment of the micro-accelerator 112, the charged particles have an average energy in the range of 7 MeV to 18 MeV. In more specific embodiments of the micro-accelerator 112, the charged particles are protons, deuterons, or alpha particles with an average energy in the range of 5 MeV to 18 MeV, 5 MeV to 10 MeV, 7 MeV to 10 MeV, 8 MeV to 10 MeV, or 7 MeV to 18 MeV.
  • the micro-accelerator 112 generates a particle beam with a beam current of approximately 1 ⁇ consisting essentially of protons having an energy of approximately 7 MeV, the particle beam having beam power of approximately 7 W and being collimated to a diameter of approximately 1 mm.
  • the micro-accelerator produces a maximum of approximately 0.666 GBq (18 mCi) of fiuorine-18 per production run. In another embodiment, the micro-accelerator produces a maximum of approximately 0.185 GBq (5 mCi) of fluorine- 18 per production run. In yet another embodiment, the micro- accelerator produces a maximum of approximately 1.11 GBq (30 mCi) of carbon- 11 per production run. In further embodiment, the micro-accelerator produces a maximum of approximately 1.48 GBq (40 mCi) of nitrogen-13 per production run.
  • the improved biomarker generator of the present invention may be embodied in many different forms.
  • the permanent magnet cyclotron 10a, the improved RF cyclotron, and the internal target cyclotron 10b are examples of suitable components for use in a particle accelerator optimized as a micro-accelerator.
  • the various features of the permanent magnet cyclotron 10a, the improved RF cyclotron, and the internal target cyclotron 10b can be mixed and matched in a single micro-accelerator.
  • one embodiment of the micro-accelerator is a combination of the permanent magnet
  • micro- accelerator a combination of the internal target cyclotron 10b with the improved RF system.
  • a still further embodiment is the combination of the permanent magnet
  • Figure 9 illustrates one embodiment of the improved biomarker generator including a micro-accelerator 912 and a radiopharmaceutical micro-synthesis system 914, which as previous indicated incorporates at least one of a microreactor and microfluidic chip.
  • the radiopharmaceutical micro- synthesis system 914 will necessarily be configured to process the quantity of the
  • microreactors and microfluidic chips typically perform their respective functions in less than 15 min, some in less than 2 min. This significant reduction in processing time directly allows a reduction in the quantity of the radioisotope required to synthesis the desired biomarker.
  • a microfluidic chip exercises digital control over variables such as the duration of the various stages of a chemical process, which leads to a well-defined and narrow distribution of residence times. Such control also enables extremely precise control over flow patterns within the microfluidic chip.
  • the use of a microfluidic chip facilitates the automation of multiple, parallel, and/or sequential chemical processes.
  • FIG 10 is a flow diagram of one embodiment of the method for producing a radiopharmaceutical using the improved biomarker generator.
  • the method calls for providing a micro-accelerator, producing charged particles, accelerating the charged particles, and forming a particle beam to irradiate a target substance and produce a radioisotope.
  • a particle beam of protons bombards the target substance of [ 18 0]water.
  • the protons in the particle beam interact with the oxygen-18 isotope in the [ OJwater molecules .
  • the improved biomarker generator allows operation using a volume of the target substance that is unusually small in the area of radiopharmaceutical production.
  • a sufficient quantity of a fluorine- 18 can be produced using a [ 18 0]water target substance with a volume of approximately 1 mL because the maximum mass of the radioisotope required to produce a unit dose of a radiopharmaceutical is on the order of nanograms.
  • the internal target 183 discussed above is particularly well-suited for handling target substance volumes on this scale. While this example contemplates the use of a liquid target substance, one skilled in the art will recognize that certain methods of producing a radioisotope or radiolabeled precursor require an internal target that can accommodate a gaseous or solid target substance. Further, while the example given contemplates the production of fluorine- 18, the internal target may be modified to enable the production of other radioisotopes or radiolabeled precursors, including [ n C]C0 2 and
  • radiopharmaceutical is reacted with a radioisotope, typically by nucleophilic substitution, electrophilic substitution, or ion exchange.
  • a radioisotope typically by nucleophilic substitution, electrophilic substitution, or ion exchange.
  • the chemical nature of the reactive precursor varies and depends on the physiological process that has been selected for imaging.
  • Exemplary organic reactive precursors include sugars, amino acids, proteins, nucleosides, nucleotides, small molecule pharmaceuticals, and derivatives thereof.
  • Synthesis refers to the production of the biomarker by the union of chemical elements, groups, or simpler compounds, or by the degradation of a complex compound, or both. Synthesis, therefore, includes any tagging or labeling reactions involving the radioisotope and any processes (e.g., concentration, evaporation, distillation, enrichment, neutralization, and purification) used in producing the biomarker or in processing the target substance for use in synthesizing the biomarker.
  • processes e.g., concentration, evaporation, distillation, enrichment, neutralization, and purification
  • the volume of the target substance is too great to be manipulated efficiently within some of the internal structures of the radiopharmaceutical micro-synthesis system and/or (2) the concentration of the radioisotope in the target substance is lower than is necessary to optimize the synthesis reaction(s) that yield the biomarker. Accordingly, one embodiment of the
  • radiopharmaceutical micro-synthesis system incorporates integrated separation components providing the ability to concentrate the radioisotope.
  • suitable separation components include ion-exchange resins, semi-permeable membranes, or nanofibers. Such separations via semi-permeable membranes usually are driven by a chemical gradient or electrochemical gradient.
  • Another example of processing the target substance includes solvent exchange. Continuing the example from above, the concentration of fluorine- 18 obtained from a proton bombardment of [ 18 0]water is usually below 1 ppm. This dilute solution needs to be concentrated to approximately 100 ppm in order to optimize the kinetics of the biomarker synthesis reactions. This processing occurs in the radiopharmaceutical micro-synthesis system 114.
  • the precursory unit dose of the radioisotope may be used to compensate for a radiopharmaceutical micro-synthesis system having a yield fraction that is significantly less than 100 % of the radioactivity supplied. Further, the precursory unit dose may be used to compensate for radioactive decay during the time required in administering the biomarker to the patient or subject.
  • the synthesis of a biomarker comprising a positron-emitting radioisotope should be completed within approximately the two half-lives of the radioisotope immediately following the production of the unit or precursory unit dose to avoid the significant increase in inefficiency that would otherwise result.
  • the chemical production module, the dose synthesis card and the sample card operate in conjunction with a complete PET biomarker production system.
  • this PET biomarker production system comprises an accelerator 1110, which produces the radioisotopes; a chemical production module (or CPM) 1120; a dose synthesis card 1130; a sample line 1640; and a quality control module (or QCM) 1150.
  • the accelerator 1110 has produced a radioisotope
  • the radioisotope travels via a radioisotope delivery tube 1112 to the dose synthesis card 1130 attached to the CPM 1120.
  • the CPM 1120 holds reagents and solvents that are required during the radiopharmaceutical synthesis process.
  • the radiopharmaceutical solution is synthesized from the radioisotope and then purified for testing and administration. Following synthesis and purification, a small percentage of the resultant radiopharmaceutical solution is the automated quality control system 1150, while the remainder flows into a dose administration vessel 1200.
  • the quality control system can be a card based system and the syringe can be replaced by a vial.
  • a computer 1209 controls all three systems and ensures that the system is capable of operating all three systems; cyclotron, synthesis system and quality control system simultaneously to ensure the most efficient workflow.
  • the system can be also configured to accept manual injection, input, or introduction 1207 of a radioisotope from a separate cyclotron.
  • the computer 1209 can also control multiple targets in the cyclotron and move them into the beam of the cyclotron independently to produce different radioisotopes.
  • the system can be configured with a vacuum pump to optimize the synthesis process and yield of the radiopharmaceutical.
  • the system will have a shield around the cyclotron which is some embodiments is less than 11 feet in diameter and reduces the radiation field around the cyclotron to such a level that it is safe for a radiation worker to be present (typically ⁇ 1 mrem/hr) to be present in the workspace 1210 around the accelerator 1110.
  • a dose synthesis card 30' includes a reaction vessel 110a where the radiopharmaceutical solution is synthesized, a QC draw line 1600 for automatic extraction of QC sample, and a RF ID chip or barcode for radiopharmaceutical identification, 1602.
  • the purpose of the RF ID chip or barcode is to uniquely identify the type of radiopharmaceutical that is being produced so that a user does not mistakenly produce a radiopharmaceutical which is incompatible with the card.
  • a radioisotope input 112a introduces the radioisotope F-18 into the reaction vessel 110a through a radioisotope input channel 1121.
  • an organic input 124a introduces a solution of potassium-kryptofix complex in acetonitrile into the reaction vessel 110a through an organic input channel 1241.
  • a combination nitrogen-input and vacuum 154 pumps nitrogen gas into the reaction vessel 110a through a gas channel 1540a and a valve 1541, which valve is at that time in an open position.
  • the mixture A in the reaction vessel 110a is heated in nitrogen atmosphere to azeotropically remove water from the mixture A, the vaporized water being evacuated through the gas channel 1540a and the vacuum 154.
  • the organic input 124a introduces mannose triflate in dry acetonitrile into the reaction vessel 110a through the organic input channel 1241.
  • the solution is heated at approximately 110 degrees Celsius for approximately two minutes.
  • the F-18 has bonded to the mannose to form the immediate precursor for [ 18 F]FDG, FTAG.
  • aqueous hydrochloric acid is introduced into the reaction vessel 110a through an aqueous input 132a and an aqueous channel 1321.
  • the hydrochloric acid removes the protective acetyl groups on the intermediate 18 F-FTAG, leaving 18 F-fludeoxyglucose (i.e. [ 18 F]FDG).
  • the [ 18 F]FDG in solution passes from the reaction vessel 110a through a post-reaction channel 1101 into a solid phase extraction column 160a, where some undesirable substances are removed from the solution, thereby clarifying the radiopharmaceutical solution.
  • the solid phase extraction (SPE) column 160a comprises a length with an ion exchange resin, a length filled with alumina, and a length filled with carbon-18.
  • the radiopharmaceutical passes through the purification component column 160a and in some embodiments passes through a second purification component 1601 with a mobile phase that in many embodiments includes acetonitrile from the organic input 124a.
  • the purification components 160a 1601 can be single phase extraction components or trap and release purification components depending on the radiopharmaceutical. As some of the mobile phase and impurities emerge from the SPE column 160a, they pass through a second post-reaction channel 1542 and through a three-way valve 175 and waste channel 1104 into a waste receptacle 210. As the clarified
  • the radiopharmaceutical solution emerges from the SPE column 160a, the radiopharmaceutical solution next passes through the second post-reaction channel 1542 and through the three- way valve 175 into a filter channel 1103 and then through a filter 170a.
  • the filter 170a removes other impurities (including particulate impurities), thereby further clarifying the radiopharmaceutical solution.
  • the filter 170a includes a Millipore filter with pores approximately 0.22 micrometers in diameter.
  • the clarified radiopharmaceutical solution travels via the post-clarification channel 1105 into the sterile dose administration vessel 1200, which in the illustrated embodiment is incorporated into a syringe 1202 or a collection vial.
  • the dose administration vessel is filled beforehand with a mixture of phosphate buffer and saline.
  • Figure 13 displays a schematic view of one embodiment of the dose synthesis card 30' together with the attached sample card 40'. As the clarified radiopharmaceutical solution fills the sterile dose administration vessel 1200, some of the solution B is diverted through an extraction channel 1401, an open valve 1403, and a transfer channel 1402 into the sample card 40'.
  • the sample card 40' contains a number of sample loops 404a-h, which hold separated aliquots of solution for imminent testing, and a number of valves 408a-h, which at this stage are closed. Once the test-sample aliquots of radiopharmaceutical solution are collected, the sample card 40' is separated from the dose synthesis card 30' and inserted into the QCM. The aliquots then travel through the now-open valves 408a-h into the sample egress ports 406a-h, from which the aliquots pass into the test vessels, as was shown in Figure 4. In the some embodiments, each of the sample loops 404a-h holds approximately 10 microliters of sample solution.
  • any excess solution remaining in the dose administration vessel 1200 is extracted by a vent 156 through a first venting channel 1560b and thence conveyed through an open valve 1561 and through a second venting channel 1560a into the waste receptacle 210.
  • the vacuum 154 evacuates residual solution from the transfer channel 1402 through a now-open valve 1403 and a solution evacuation channel 1540b
  • the CPM holds sufficient amounts of reagents and solvents that are required during the radiopharmaceutical synthesis process to carry out multiple runs without reloading. Indeed, in some embodiments the CPM is loaded with reagents and solvents approximately once per month, with that month's supply of reagents and solvents sufficient to produce several dozen or even several hundred doses of radiopharmaceutical. As the reagents and solvents are stored in the CPM, it is easier than under previous systems to keep the reagents and solvents sterile and uncontaminated.
  • FIG. 14A is a flow diagram showing a fully automated QC system which tests for all pharmacopeia (e.g. regulatory requirements) using a multi-port switching valve to distribute the sample to a number of additional pieces of equipment.
  • pharmacopeia e.g. regulatory requirements
  • the injection valve 516 is rotated 60 degrees into the second state (or State B), shown in Figure 14.
  • the sample radiopharmaceutical solution from the fixed- volume fluid loop 517 is directed into the fourth inj ection valve line 564.
  • the fixed-volume loop 517 has a volume of approximately 20 microliters. However, those of skill in the art will recognize that other volumes the fixed-volume loop 517 are possible and are contemplated by the present invention.
  • the radiopharmaceutical solution from the fixed-volume fluid loop 517 passes by at least one radiation probe 542, which is part of or connected to a radiation detector 522.
  • the sample radiopharmaceutical solution passes by or through a UV/VIS detector 502 to test the optical clarity of the sample radiopharmaceutical solution.
  • the UV/VIS detector 502 comprises a ultra-violet and visible light spectrometer.
  • the UV/VIS detector 502 comprises a UV spectrophotometer.
  • the UV/VIS detector 502 comprises a UV spectrophotometer with a deuterium light source.
  • the UV/VIS detector 502 comprises a UV/VIS detector 502
  • the UV/VIS detector 502 comprises a UV spectrophotometer like the Smartline UV Detector 2500, manufactured by KNAUER.
  • the HPLC-based QCM 50 includes a detector comprises a spectrophotometer that detects a range of the electromagnetic spectrum that includes infrared light.
  • the HPLC-based QCM 50 includes multiple detectors, including, in some embodiments, multiple UV/VIS detectors or, in some embodiments, multiple spectrophotometers or spectrometers.
  • the UV/VIS detector 502 tests the sample
  • radiopharmaceutical solution for the presence of residual Krypotofix.
  • a purified radiopharmaceutical solution will be considered to pass quality control testing for Kryptofix if the residual concentration of Kryptofix in the final product is less than or equal to 50 micrograms per milliliter solution.
  • the radiopharmaceutical solution from the fixed- volume fluid loop 517 passes by or through the UV/VIS detector 502 before entering the HPLC column 515. In some embodiments, the radiopharmaceutical solution from the fixed-volume fluid loop 517 passes by or through a UV/VIS detector after entering and passing though the HPLC column 515.
  • the sample radiopharmaceutical solution passes into the HPLC column 515.
  • the HPLC column 515 separates [ 18 F]FDG within the sample radiopharmaceutical solution from any other radioactive products or other organic impurities. In this way, the HPLC column 515 assists testing the radiochemical identity of the sample radiopharmaceutical solution—that is, the HPLC column 515 helps to identify the ratio of [ 18 F]FDG (or other desired).
  • the HPLC column 515 separates the [ 18 F]FDG from other compounds based on their different retention time, making possible the identification of the [ 18 F]FDG based on retention time and allowing other instruments to analyze the [ 18 F]FDG separately from other compounds.
  • the sample radiopharmaceutical solution passes through a refractive index detector (RI detector) 505.
  • the RI detector 505 detects, measures and quantifies the presence of compounds as they are eluted from the HPLC column 515.
  • [ 18 F]FDG is identified based on its retention time, as are other compounds present in the sample radiopharmaceutical solution. In general, [ 18 F]FDG has a slightly shorter retention time compared to FDG that lacks a radioisotope. In some embodiments, the radiochemical purity of the separated [ 18 F]FDG within the sample radiopharmaceutical solution is also measured after the elution of the separated [ 18 F]FDG within the sample radiopharmaceutical solution from the HPLC column 515.
  • an HPLC-based QCM 50 includes a radiation detector 522 with at least one radiation probe 542.
  • multiple HPLC-based QCM pumps and columns can be used as shown in Figure 6 503, 504, 607.
  • the radiation probe 542 measures the radioactivity of the separated [ 18 F]FDG within the sample radiopharmaceutical solution eluted from the HPLC column 515.
  • the radiation probe 542 also measures the radioactivity of other radioactive products (such as free F-18 ion and [ 18 F]FTAG) eluted from the HPLC column 515.
  • HPLC column 515 and tested for radiochemical identity, radiochemical purity, and the presence of residual impurities, the sample radiopharmaceutical solution is conveyed to the waste vessel 507.
  • HPLC-based QCM 50 according to the present general inventive concept also includes, on the line carrying the sample radiopharmaceutical solution from the HPLC column 515 to the waste vessel 507, a backpressure valve 506.
  • Figure 14A illustrates an embodiment of the automated quality control system which has a multiport valve 608 to distribute said radiopharmaceutical sample to additional QC equipment for quality control testing including; a phase transfer catalyst device 600, a multi channel analyzer for radionucleic purity and identity 600, a dose calibrator for radioactivity level measurements 608, a endotoxin measurement device 602 which in some embodiments can be a Charles River Sample tester, a color metric device 603, for color and clarity testing, a sample card system for additional QC testing 604, an electronic eye device the measure the electronic conductivity of said radiopharmaceutical 605, a gas chromatraphy system for residual solvent identification 606, and parallel HPLC pumps and columns 503, 504, 607 which is some embodiments can be in series.
  • a phase transfer catalyst device 600 a multi channel analyzer for radionucleic purity and identity 600
  • a dose calibrator for radioactivity level measurements 608 a endotoxin measurement device 602 which in some embodiments can be a Charles River Sample tester, a color
  • Figure 14B illustrates another embodiment of the automated quality control system which has a sample line 598 with a number of load loops or ports 611a-f arranged in series, with each load loop or port diverting a portion of radiopharmaceutical solution from the sample line 598 to a testing device; each testing device thus draws a small sample volume of radiopharmaceutical solution from the total amount of radiopharmaceutical solution passing through the sample line 598.
  • the testing devices include: a phase transfer catalyst device 600; a multi-channel analyzer for radionucleic purity and identity 601; a dose calibrator for radioactivity level
  • sample line 598 terminates in sample card system for additional QC testing 650; but those of skill in the art will recognized that other arrangements are also possible and are encompassed by the present general inventive concept.
  • additional testing devices "feed off of (i.e., received sample radiopharmaceutical solution from) the sample line 598; in some embodiments, these testing devices may include, for example, a gas chromatraphy system for residual solvent identification.
  • an iodine reagent is mixed with a sample solution containing the phase transfer catalyst Kryptofix 2.2.2; this mixture causes a red suspension to form, which can be observed visually.
  • concentration of Kryptofix 2.2.2 in the solution is proportional to the color intensity of the suspension, and visual differences were observed for solutions having a Kryptofix 2.2.2 concentration in the range of 0 to 100 ppm.
  • Kryptofix 2.2.2 are mixed together before the mixture is passed through the detector chamber or the iodine reagent and the sample solution containing Kryptofix 2.2.2 are mixed together inside the detector chamber. Next, the mixture enters the detector chamber. The presence or absence of suspension is determined visually, and the absorbance is measured with a detector. The concentration of Kryptofix 2.2.2 in the mixture is determined by comparing the absorbance results with a calibration curve obtained from test solutions having known Kryptofix 2.2.2 concentrations.
  • the subsystem used to determine the concentration of the phase transfer catalyst comprises reservoirs for the sample and iodine solutions connected to a metering device and a UV-Vis cell or microfluidic chip with a clear window for detection.
  • the phase transfer catalyst is Kryptofix 2.2.2.
  • the present general inventive concept permits concentration determination having the following characteristics: simplicity, specificity, low toxicity, and high throughput, which are desirable for [18F]-labeled radiotracers owing to the relatively short half-life of the [18F] isotope (109 min).
  • the iodine reagent is mixed with a sample solution containing Kryptofix 2.2.2, which causes a red suspension to form.
  • the concentration of Kryptofix 2.2.2 in the solution is proportional to the color of the suspension.
  • the iodine reagent and the sample solution containing Kryptofix 2.2.2 are mixed together before the mixture is passed through the detector chamber. Next, the mixture enters the detector chamber. The presence or absence of suspension is determined visually, and the absorbance is measured with a detector. The concentration of Kryptofix 2.2.2 in the mixture is determined by comparing the absorbance results with a calibration curve obtained from test solutions having known Kryptofix 2.2.2 concentrations.
  • the radiopharmaceutical micro-synthesis system is flexible and may be used to synthesize biomarkers labeled with other radioisotopes, such as carbon-1 1, nitrogen-13, or oxygen-15.
  • the improved biomarker generator discussed herein is flexible enough to produce quantities on the order of a unit dose of biomarkers that are labeled with radioisotopes that do not emit positrons or for producing small doses of radiopharmaceuticals other than biomarkers.
  • the radiopharmaceutical micro-synthesis system may comprise parallel circuits, enabling simultaneous production of unit doses of a variety of biomarkers.
  • the improved biomarker generator may be engineered to produce unit doses of biomarker on a frequent basis.
  • biomarker generator allows for the nearly on-demand production of a biomarker in a quantity on the order of one unit dose. Because the half-lives of the radioisotopes most suitable for safe molecular imaging of a living organism are very short, nearly on-demand production of unit doses of biomarkers presents a significant advancement for both clinical medicine and biomedical research.
  • the reduced size, weight, and cost, the reduced infrastructure (power and structural) requirements, and the improved reliability of the micro-accelerator coupled with the speed and overall efficiency of the radiopharmaceutical micro-synthesis system make in-house biomarker generation a viable option even for small regional hospitals.
  • the various embodiments of the micro-accelerator generate the magnetic field using permanent magnets, move the target into the magnetic field allowing the magnet system to help contain radiation generated during radioisotope production, incorporate the improved RF system described herein, and use combinations of these features to provide the aforementioned improvements over conventional cyclotrons used in radiopharmaceutical production.
  • a system allows for automated sampling and analysis of a radiopharmaceutical solution in real time.
  • a cyclotron, chemical production module, and quality control module are all controlled by the same computer, and all three component subsystems (cyclotron, chemical production module, and quality control module) run simultaneously, in series or in parallel.
  • the QCM is analyzing dose N-7 (said dose N-7 having just emerged from the CPM), and the cyclotron is simultaneously producing the radioisotopes to go into dose N+7.
  • Such a setup helps to streamline the process of generating radiopharmaceutical doses.
  • Some embodiments include automating the entire workflow.
  • Various embodiments of systems according to the present general inventive concept also facilitate the use of small target volumes for radioisotope precursor target materials.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Un système automatique de production et de contrôle qualité de produits radiopharmaceutiques comprend un accélérateur de particules, un sous-système de micro-synthèse de produits radiopharmaceutiques et un sous-système de contrôle qualité. Le micro-accélérateur de ce générateur amélioré de biomarqueurs est optimisé en vue de la production de radioisotopes utiles pour la synthèse de quantités de produits radiopharmaceutiques de l'ordre de doses unitaires multiples, et permet des réductions significatives en termes de taille, de consommation d'énergie et de poids, comparativement aux cyclotrons à produits radiopharmaceutiques classiques. Le sous-système de micro-synthèse de produits radiopharmaceutiques comprend un système de synthèse chimique de petit volume comprenant un micro-réacteur et/ou une puce microfluidique et est optimisé pour la synthèse du produit radiopharmaceutique en petites quantités, ce qui permet des réductions significatives en termes de durée de traitement et de quantité de radioisotope nécessaire. Le sous-système automatique de contrôle qualité est utilisé pour tester la composition et les caractéristiques du produit radiopharmaceutique et s'assurer que son injection ne présente aucun danger.
PCT/US2016/016964 2015-02-10 2016-02-08 Système automatique de production et de contrôle qualité de produits radiopharmaceutiques Ceased WO2016130463A1 (fr)

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CN108573321A (zh) * 2017-03-10 2018-09-25 美国西门子医疗解决公司 放射性药物的生产
CN112888137A (zh) * 2021-03-31 2021-06-01 山东第一医科大学附属肿瘤医院(山东省肿瘤防治研究院、山东省肿瘤医院) 用于回旋加速器液体靶的靶水定量分配装置

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CN108573321A (zh) * 2017-03-10 2018-09-25 美国西门子医疗解决公司 放射性药物的生产
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CN112888137A (zh) * 2021-03-31 2021-06-01 山东第一医科大学附属肿瘤医院(山东省肿瘤防治研究院、山东省肿瘤医院) 用于回旋加速器液体靶的靶水定量分配装置

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