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WO2016130458A1 - Système automatisé de contrôle de qualité pour produits radiopharmaceutiques - Google Patents

Système automatisé de contrôle de qualité pour produits radiopharmaceutiques Download PDF

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Publication number
WO2016130458A1
WO2016130458A1 PCT/US2016/016952 US2016016952W WO2016130458A1 WO 2016130458 A1 WO2016130458 A1 WO 2016130458A1 US 2016016952 W US2016016952 W US 2016016952W WO 2016130458 A1 WO2016130458 A1 WO 2016130458A1
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WIPO (PCT)
Prior art keywords
radiopharmaceutical
radiopharmaceutical solution
quality control
solution
sample
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PCT/US2016/016952
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English (en)
Inventor
Atilio Anzellotti
Aaron Mcfarland
Clive Brown-Proctor
Daniel Hillesheim
Mark Khachaturian
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ABT Molecular Imaging Inc
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ABT Molecular Imaging Inc
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Priority claimed from US14/618,772 external-priority patent/US20150160171A1/en
Application filed by ABT Molecular Imaging Inc filed Critical ABT Molecular Imaging Inc
Publication of WO2016130458A1 publication Critical patent/WO2016130458A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/0093—Radioactive materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N2030/77—Detectors specially adapted therefor detecting radioactive properties
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8804—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 automated systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8868—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample elemental analysis, e.g. isotope dilution analysis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/74—Optical detectors

Definitions

  • This invention relates to conducting quality control tests on
  • radiopharmaceuticals for use in positron emission tomography PET
  • the present invention relates to systems for analyzing a liquid sample of PET biomarker.
  • a biomarker is used to interrogate a biological system and can be created by
  • PET positron-emission tomography
  • PET positron-emission tomography
  • MRI magnetic resonance imaging
  • CT computed tomography
  • ultrasonography which image the patient's anatomy rather than physiological images.
  • Physiological activity provides a much earlier detection measure for certain forms of disease, cancer in particular, than do anatomical changes over time.
  • a positron-emitting radioisotope undergoes radioactive decay, whereby its nucleus emits positrons.
  • a positron inevitably travels less than a few millimeters before interacting with an electron, converting the total mass of the positron and the electron into two photons of energy.
  • the photons are displaced at approximately 180 degrees from each other, and can be detected simultaneously as "coincident" photons on opposite sides of the human body.
  • the modern PET scanner detects one or both photons, and computer reconstruction of acquired data permits a visual depiction of the distribution of the isotope, and therefore the tagged molecule, within the organ being imaged.
  • Radioisotopes are produced in a cyclotron.
  • Cyclotrons operate by accelerating electrically-charged particles along outward, quasi-spherical orbits to a predetermined extraction energy generally on the order of millions of electron volts.
  • the high-energy electrically-charged particles form a continuous beam that travels along a predetermined path and bombards a target.
  • a nuclear reaction occurs at a sub-atomic level, resulting in the production of a radioisotope.
  • the radioisotope is then combined chemically with other materials to synthesize a radiochemical or radiopharmaceutical (hereinafter
  • radiopharmaceutical suitable for introduction into a human body.
  • the cyclotrons traditionally used to produce radioisotopes for use in PET have been large machines requiring great commitments of physical space and radiation shielding. These requirements, along with considerations of cost, made it unfeasible for individual hospitals and imaging centers to have facilities on site for the production of radiopharmaceuticals for use in PET.
  • radiopharmaceuticals for use in PET are synthesized at centralized production facilities. The radiopharmaceuticals then must be transported to hospitals and imaging centers up to 200 miles away. Due to the relatively short half-lives of the handful of clinically important positron-emitting radioisotopes, it is expected that a large portion of the radioisotopes in a given shipment will decay and cease to be useful during the transport phase. To ensure that a sufficiently large sample of active radiopharmaceutical is present at the time of the application to a patient in a PET procedure, a much larger amount of radiopharmaceutical must be synthesized before transport. This involves the production of radioisotopes and synthesis of radiopharmaceuticals in quantities much larger than one (1) unit dose, with the expectation that many of the active atoms will decay during transport.
  • the need to transport the radiopharmaceuticals from the production facility to the hospital or imaging center also dictates the identity of the isotopes selected for PET procedures.
  • site of treatment also dictates the identity of the isotopes selected for PET procedures.
  • fluorine isotopes, and especially fluorine-18 (or F-18) enjoy the most widespread use.
  • the F-18 radioisotope is commonly synthesized into [ 18 F]fluorodeoxyglucose, or [ 18 F]FDG, for use in PET.
  • F-18 is widely used mainly because its half-life, which is approximately 110 minutes, allows for sufficient time to transport a useful amount.
  • the current system of centralized production and distribution largely prohibits the use of other potential radioisotopes.
  • radiopharmaceutical For example, for the synthesis of [ 18 F]FDG from mannose triflate, a number of quality control tests exist.
  • the final [ 18 F]FDG product should be a clear, transparent solution, free of particulate impurities; therefore, it is important to test the color and clarity of the final radiopharmaceutical solution.
  • the final radiopharmaceutical solution is normally filtered through a sterile filter before administration, and it is advisable to test the integrity of that filter after the synthesized radiopharmaceutical solution has passed through it.
  • the acidity of the final radiopharmaceutical solution must be within acceptable limits (broadly a pH between 4.5 and 7.5 for [ F]FDG, although this range may be different depending upon the application and the radiopharmaceutical tracer involved).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. This high performance liquid
  • chromatography column separates chemical species within the sample radiopharmaceutical solution into a number of separated chemical species.
  • a refractive index detector measures the amount of each separated chemical species from said high performance liquid
  • a radiation detector measures the radioactivity of each separated chemical species from said high performance liquid chromatography column.
  • a high performance liquid chromatography column to receive the second part of the sample radiopharmaceutical solution, said high performance liquid chromatography column to separate chemical species within the second part of the sample radiopharmaceutical solution into a number of separated chemical species; a refractive index detector to measure the amount of each separated chemical species from said high performance liquid chromatography column; and a radiation detector to measure the radioactivity of each separated chemical species from said high performance liquid chromatography column.
  • some embodiments include a high performance liquid chromatography pump to direct a mobile phase solvent to the valve and the HPLC column.
  • an HPLC-based quality control testing system also comprises an ultraviolet-light detector or UV/VIS detector to measure the optical qualities of the second part of the sample radiopharmaceutical solution.
  • the ultraviolet-light detector or UV/VIS detector measures the optical qualities of the second part of the sample radiopharmaceutical solution before the second part of the sample radiopharmaceutical solution enters the high performance liquid
  • many embodiments of the present general inventive concept include a pH detector to measure the pH of the sample radiopharmaceutical solution.
  • 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.
  • 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 chemical 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 chemical species within the third aliquot of the clarified radiopharmaceutical solution into a number of separated chemical species;
  • the measurement of the radioactivity of each separated chemical species from said high performance liquid chromatography column is performed by means of a radiation detector, said radiation detector including at least two radiation probes, said at least two radiation probes including: a first radiation probe to measure the radioactivity of the first aliquot of the sample radiopharmaceutical solution held in said first sample collection vessel; and a second radiation probe to measure the radioactivity of each separated chemical species from said high performance liquid chromatography column.
  • some embodiments of the method described above include a step of measuring the pH of the clarified radiopharmaceutical solution.
  • the radioisotope is selected from the group consisting of carbon-11, nitrogen-13, oxygen-15, and fluorine-18.
  • the radiopharmaceutical is [ 18 F]-2-fluoro-2-deoxy-D- glucose (hereinafter [ 18 F]FDG).
  • a method for conducting quality control tests on a radiopharmaceutical using an automated quality control system encompasses conveying a first portion of a radiopharmaceutical solution to a radiopharmaceutical solution pumping mechanism; conveying a second portion of said radiopharmetutical solution to a series of collection vials for additional quality control testing; pumping said first portion of a radiopharmaceutical solution to an injection valve, said inj ection 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 endotoxicity testing directing a second aliquot of the clarified radiopharmaceutical solution into at least one high performance liquid
  • said high performance liquid chromatography column to separate chemical species within the second aliquot of the clarified radiopharmaceutical solution into a number of separated chemical species; measuring the optical qualities of the second 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 chemical species from said high performance liquid chromatography column; and measuring the radioactivity of each separated chemical species from said high performance liquid chromatography column.
  • measuring the radioactivity of each separated chemical species from said high performance liquid chromatography column is performed by means of a radiation detector, said radiation detector including at least two radiation probes, said at least two radiation probes including a first radiation probe to measure the radioactivity of the first aliquot of the sample radiopharmaceutical solution and a second radiation probe to measure the radioactivity of each separated chemical species from said high performance liquid chromatography column.
  • the radioisotope is selected from the group consisting of carbon-11 , nitrogen-13, oxygen-15, and fluorine-18, iodine-124, gallium-68.
  • the radiopharmaceutical selected from the group consisting of [18F]-2-fluoro-2-deoxy-D-glucose, [ 18F] Sodium Floride, [18F] 3'-deoxy- 3'fluorothymidine, [18F]fluoromisonidazole, [18F]Florbetaben, [18F]Florbetapir, [18F]- fluoro-ethyl-tyrosine, [18F]flutemetamol, [18F]flurocholine, [18F]Fallypride, [18F]FDOPA, [l lC]Choline, [l lC]methionine, [HC]acetate, [HC]N-Methylspiperone, [l lC]Carfentanil and [HCJRaclopride.
  • the system used is capable of performing automated self-cleaning after completion of tests.
  • the second aliquot in said high performance liquid chromatography column is measure for C1DG concentration.
  • the second aliquot is measured by radiation detector for radionucleic identity, radionucleic purity, radiochemical identity, or radiochemical purity.
  • the second aliquot is measured by a multichannel analyzer for radionucleic purity.
  • the second aliquot is measured by a colormetric detector for color and clarity.
  • the first aliquot in collection vial is contained in
  • the high performance liquid chromatography column is in series with at least one other high performance liquid chromatography column.
  • the high performance liquid chromatography column is in parallel with at least one other high performance liquid chromatography column.
  • the automated quality control system is configured for a specific radiopharmaceutical.
  • the automated quality control system further includes a system for detecting the presence of a phase transfer catalyst in a radiopharmaceutical solution, encompassing a reagent that will react with the catalyst when added to the radiopharmaceutical solution, said reagent to be mixed with the radiopharmaceutical solution, said reagent including iodine.
  • the phase transfer catalyst is selected from the group consisting of Kryptofix 2.2.2, 18-Crown-6, and Quaternary amine-derivatives.
  • Radiopharmaceuticals supports a method for determining the concentration of a phase transfer catalyst in a radiopharmaceutical solution, including mixing a reagent including iodine with a radiopharmaceutical solution to form a mixture; and measuring the absorbance of the mixture.
  • Radiopharmaceuticals supports a method for determining the concentration of a selected phase transfer catalyst in a radiopharmaceutical solution, including: mixing a reagent including iodine with a radiopharmaceutical solution to form a mixture, said reagent to react with the selected catalyst; measuring the visible light absorbance properties of the mixture; and comparing the visible light absorbance of the mixture to previously established visible light absorbance properties for selected known concentrations of the selected catalyst.
  • the means for measuring the concentration of said chemical species in said radiopharmaceutical solution include a gas chromatograph or electronic mems "nose" device.
  • the quality control module includes means for detecting the concentration of potassium and crown ethers in said radiopharmaceutical solution.
  • the means for detecting the concentration of potassium and crown ethers are adapted to detect the concentration of l,10-diaza-4,7, 13, 16,21,24- hexaoxabicyclo[8.8.8]hexacosane.
  • the means for detecting the concentration of potassium and crown ethers in said radiopharmaceutical solution include a silica gel with iodoplatinate and a color recognition sensor.
  • the means for method for detecting the chemical purity of said radiopharmaceutical includes measurement using the electrical conductivity.
  • 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.
  • FIG 1 is an schematic illustration of one example embodiment of the present general inventive concept, showing an overview of a PET biomarker production system, including the accelerator, the chemical production module (CPM), the dose synthesis module (DSM), and the quality control module (QCM);
  • CPM chemical production module
  • DSM dose synthesis module
  • QCM quality control module
  • Figure 2 is a flow diagram illustration of an example embodiment of a DSM according to the present general inventive concept
  • Figure 3 is a schematic illustration of one example embodiment of the dose synthesis card
  • Figure 4 is a flow diagram illustration of an example embodiment of an HPLC-based QCM according to the present general inventive concept, showing among other items an injection valve for an HPLC-based QCM, showing the injection valve in a first state;
  • Figure 5 is a second flow diagram illustration of the example embodiment of an HPLC-based QCM shown in Figure 4, showing the injection valve in a second state;
  • Figure 6A is a third 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 6B 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
  • a chemical production module, dose synthesis module, and HPLC-based quality control module for a PET biomarker radiopharmaceutical production system are described more fully hereinafter.
  • This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided to ensure that this disclosure is thorough and complete, and to ensure that it fully conveys the scope of the invention to those skilled in the art.
  • the system comprises an injection valve to direct the flow of a sample radiopharmaceutical solution within the system; a sample radiopharmaceutical solution syringe-pump to direct the sample radiopharmaceutical solution to said injection valve; a high performance liquid chromatography pump to direct a mobile phase solvent to said injection valve; a pH detector to measure the pH of the sample radiopharmaceutical solution; a first sample collection vessel to receive a first aliquot of the sample radiopharmaceutical solution from said injection valve, said first sample collection vessel to hold the first aliquot of the sample radiopharmaceutical solution for measurement of the radioactivity of the sample radiopharmaceutical solution; a second sample collection vessel to receive a second aliquot of the sample radiopharmaceutical solution from said injection valve, said second sample collection vessel to hold the second aliquot of the sample radiopharmaceutical solution for endotoxicity testing; an endotoxin detector to perform endotoxicity
  • a chemical production module, dose synthesis module, and HPLC-based quality control module operate in conjunction with a complete PET biomarker production system.
  • a PET biomarker production system comprises an accelerator 10, which produces the radioisotopes; a chemical production module (or CPM) 20; a dose synthesis module (or DSM) 30; and an HPLC-based quality control module (or QCM) 50.
  • CPM chemical production module
  • DSM dose synthesis module
  • QCM HPLC-based quality control module
  • the radiopharmaceutical solution is synthesized from the radioisotope and then purified for testing and administration. Following synthesis and purification, a portion (the “sample portion") of the resultant
  • radiopharmaceutical solution is transported by way of a quality-control transfer line 1600 to the QCM 50, and another portion flows into a dose vessel 200.
  • a number of diagnostic instruments perform automated quality control tests on the sample portion.
  • FIG. 2 shows a flow diagram of one example embodiment of a dose synthesis module according to the present general inventive concept.
  • the radioisotope involved is flourine-18 (F-18), produced from the bombardment in a cyclotron of heavy water containing the oxygen- 18 isotope.
  • F-18 flourine-18
  • the present general inventive concept also embraces radiopharmaceutical synthesis systems generating and using other radioisotopes, including carbon-1 1, nitrogen-13, and oxygen-15.
  • the radioisotope enters a reaction chamber or reaction vessel 110 from the radioisotope delivery tube 112.
  • the radioisotope F-18 is still mixed with quantities of heavy water from the biomarker generator.
  • a number of other reagents and substances are introduced into the reaction vessel 110 by way of several inputs, including, in some embodiments, some or all of the following: a first organic reagent input 120, a second organic reagent input 122, an aqueous input 130, and a gas input.
  • a first organic ingredient is introduced to the reaction vessel 110 from the first organic reagent input 120.
  • the first organic ingredient includes a solution of potassium complexed to l, 10-diaza-4,7, 13, 16,21 ,24- hexaoxabicyclo[8.8.8]hexacosane (commonly called Kryptofix 222TM, hereinafter
  • the potassium-kryptofix complex or similar organometallic complex is carried by acetonitrile as solvent.
  • the potassium activates the F-18 fluoride radioisotope, while the kryptofix binds the potassium atoms and inhibits the formation of a potassium-fluoride complex.
  • the gas input 140 fills the reaction vessel 110 with an inert gas such as dry nitrogen.
  • the mixture in the reaction vessel 110 is heated by to remove residual heavy water by evaporating the azeotropic water/acetonitrile mixture.
  • a vacuum helps to remove the vaporized water.
  • the second organic input 122 adds a second organic ingredient to the mixture in the reaction vessel 110.
  • the second organic ingredient is mannose triflate in dry acetonitrile.
  • the solution is then 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, commonly 18F-fluorodeoxy glucose tetraacetate (FTAG).
  • FTAG 18F-fluorodeoxy glucose tetraacetate
  • aqueous acid in many embodiments, aqueous hydrochloric acid— is introduced through the aqueous input 130.
  • the hydrochloric acid removes the protective acetyl groups on the 18 F-FTAG, leaving 18 F-fludeoxyglucose (i.e. [ 18 F]FDG) in what may now be called the synthesized, pre-purified radiopharmaceutical solution.
  • the [ 18 F]FDG in solution passes from the reaction vessel 110 through a solid phase extraction column 160.
  • the solid phase extraction column 160 comprises a length filled with an ion exchange resin, a length filled with alumina, and a length filled with carbon- 18.
  • the radiopharmaceutical solution is collected in a product collection vial 210.
  • the product collection vial 210 includes a vent 285 to allow air or gas to escape the product collection vial 210 as the product collection vial 210 fills with radiopharmaceutical solution.
  • the production collection vial 210 collects all of the purified radiopharmaceutical solution as a single bolus before portions of the purified
  • radiopharmaceutical solution are distributed to other destinations as described infra. From the product collection vial 210, a first portion of the purified radiopharmaceutical solution is directed through a quality-control transfer line 400 to a QCM 50. From the product collection vial 210, a second portion of the purified radiopharmaceutical solution is directed through a sterile filter 170 and through a first post-sterile-filter pathway 262 into a sterility sample vial 230.
  • a first part of the second portion of the purified radiopharmaceutical solution in the sterility sample vial 230 remains in the sterility sample vial 220, and a second part of the second portion of the purified radiopharmaceutical solution in the sterility sample vial 230 travels by way of a second post-sterile-filter pathway 264 into a product injection vial 250.
  • the second part of the second portion of the purified radiopharmaceutical solution collected in the product injection vial 250 is generally the radiopharmaceutical solution that will be administered to one or more patients.
  • second part of the second portion of the purified radiopharmaceutical solution collected in the product injection vial 250 constitutes a majority of the radiopharmaceutical solution produced in the synthesis process.
  • a second portion of the purified radiopharmaceutical solution is directed through a sterile filter 170 before passing through a first post-sterile-filter pathway 262 into a sterility sample vial 230.
  • the integrity of the filter 170 is tested by passing inert gas through the filter 170 at increasing pressure.
  • a pressure sensor measures the pressure of the inert gas upon the filter 170 and detects whether the filter 170 is still intact.
  • the filter 170 is expected in to be capable of maintaining integrity under pressures of at least 50 pounds per square inch (psi).
  • FIG. 3 displays a schematic view of one example embodiment of a dose synthesis module (DSM) card 30'.
  • the DSM card 30' includes a reaction vessel 110a where the radiopharmaceutical solution is synthesized.
  • a radioisotope input 112a introduces the radioisotope F-18 into the reaction vessel 110a through a radioisotope input channel 1121.
  • the radioisotope is still mixed with quantities of heavy water from the biomarker generator.
  • 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 1 10 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 at least one extraction component 1601a, where some undesirable substances are removed from the solution, thereby clarifying the radiopharmaceutical solution.
  • the DSM card 30' includes multiple purification components 1601a, 1601b (which, in some cases, are solid phase extraction components or trap and release
  • the extraction component 1601a comprises a solid phase extraction (SPE) column, having a length with an ion exchange resin, a length filled with alumina, and a length filled with carbon-18.
  • the radiopharmaceutical passes through the extraction component 1601a with a mobile phase that in many embodiments includes acetonitrile from the organic input 124a.
  • a mobile phase that in many embodiments includes acetonitrile from the organic input 124a.
  • the mobile phase and impurities emerge from the SPE column 1601a, 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.
  • 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 200a, which in the illustrated embodiment is incorporated into a syringe 202.
  • the dose administration vessel is filled beforehand with a mixture of phosphate buffer and saline. As the clarified radiopharmaceutical solution fills the sterile dose administration vessel 200a, a sample portion of the clarified
  • radiopharmaceutical solution is diverted through an extraction channel 1600 to the quality- control module.
  • any excess solution remaining in the dose administration vessel 200a 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 20 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 20 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 20, it is easier than under previous systems to keep the reagents and solvents sterile and
  • a sterile environment is supported and
  • the DSM 30 is adapted to be disposable.
  • the filter integrity test, the color and clarity test, the acidity test, the volatile organics test, the chemical purity test, and the radiochemical purity test are performed for every dose.
  • some quality control tests need be performed only once or twice per batch, such as the radionuclide purity test (using a radiation probe to measure the half-life of the F-18 in the [ 18 F]FDG), the bacterial endotoxin test, and the sterility test. These tests are performed generally on the first and last doses of each batch. Because these per-batch quality control tests are conducted less frequently, they may not be included in the QCM, but rather may be conducted by technicians using separate laboratory equipment.
  • Figure 4 shows a flow chart illustrating one example embodiment of an
  • HPLC-based QCM 50 according to the present general inventive concept.
  • the example embodiment of an HPLC-based QCM 50 illustrated in Figure 4 is to test a first portion of purified radiopharmaceutical solution (hereinafter "the sample radiopharmaceutical solution” or simply “sample”) from a DSM.
  • an HPLC- based QCM 50 includes an HPLC pump 503, which draws mobile phase solvent from a mobile phase solvent reservoir 509 and through a degasser 504; a syringe-pump assembly 520 to load into the HPLC-based QCM 50 the sample radiopharmaceutical solution from a quality-control transfer line 1600; an HPLC column 515; an injection valve 516; and fixed volume fluid loop 517.
  • the HPLC-based QCM 50 according to the present general inventive concept includes a radiation detector 522 with one or more radiation probes; in the illustrated example embodiment shown in Figure 4, the radiation detector 522 includes two radiation probes, 542a and 542b.
  • the HPLC-based QCM 50 includes an UV/VIS detector 502 to test the optical qualities of the sample. In some embodiments, the HPLC-based QCM 50 includes an RI detector 505 to test the radionuclidic identity of the sample.
  • a sample radiopharmaceutical solution enters the syringe-pump assembly 520 from the quality-control transfer line 1600.
  • the sample radiopharmaceutical solution is stored within a syringe 525. Then, a portion of the sample radiopharmaceutical solution is propelled by the syringe 525 or a similar mechanism and thereby is loaded, in a steady, even, and substantially reproducible manner, into a first QCM pathway 527.
  • the syringe- pump assembly 520 draws water or other solvent, such as LAL reagent water, from a reagent water reservoir 501.
  • the sample radiopharmaceutical solution moves through the first QCM pathway 527 and passes through a first injection valve line 561 to enter the injection valve 516.
  • Another portion of the sample radiopharmaceutical solution within the syringe 525 is directed within the syringe-pump assembly 520 to enter a second QCM pathway 523; this second portion of the sample radiopharmaceutical solution passes through the second QCM pathway 523 into an endotoxin testing sample vessel 521.
  • Any remainder third portion of the sample radiopharmaceutical solution within the syringe 525 is directed within the syringe-pump assembly 520 to enter a third QCM pathway 529, which conveys the remainder third portion of the sample radiopharmaceutical solution to a waste vessel 507.
  • radiopharmaceutical solution is tested for endotoxicity.
  • sample aliquot collected in the test vial 521 is tested for endotoxicity by diluting the sample aliquot and subjecting the diluted sample aliquot to an endotoxicity test.
  • the endotoxicity test is conducted by an automated endotoxin detector.
  • the endotoxicity test is conducted by an automated endotoxin spectrophotometer.
  • the endotoxicity test comprises the use of a kinetic hemocyte lysate-based assay for the detection and quantification of microbial contaminants. In some embodiments, other forms of endotoxicity tests are used.
  • the first injection valve line 561 conveys the sample radiopharmaceutical solution from the syringe-pump assembly 520 into the injection valve 516.
  • the second injection valve line 562 conveys solution from the injection valve
  • the pH detector 513 includes a solid state detector. In some embodiments, the pH detector 513 includes an in-line solid state pH detector. After the solution passes through the pH detector 513, the solution is directed to the waste vessel 507. [0065]
  • the third injection valve line 563 conveys to the injection valve 516 mobile phase solvent drawn by the HPLC pump 503 from the mobile phase solvent reservoir 509 through the degasser 504.
  • the fourth injection valve line 564 conveys fluid from the injection valve 516 to the HPLC column 515.
  • the fifth injection valve line 565 conveys fluid from the injection valve 516 into the fixed-volume fluid loop 517
  • the sixth valve line 565 conveys fluid from the fixed-volume fluid loop 517 into the injection valve 516.
  • three of the injection valve lines 561, 563, and 565 are input lines
  • three of the injection valve lines 562, 564, and 566 are output lines.
  • the injection valve 516 directs incoming fluid
  • FIGS 4 and 5 show the injection valve 516 in two different states.
  • the injection valve 516 In the first state (also called State A), shown in Figure 4, the injection valve 516 is positioned such that a channel within the injection valve 516 directs fluid from the first injection valve line 561 to the second injection valve line 562; that is, in State A, sample radiopharmaceutical solution passes from thefirst QCM pathway 527, through the first injection valve line 561, through the injection valve 516, and then through the second injection valve line 562 to the pH detector 513.
  • mobile phase solvent from the HPLC pump 503 passes through the third injection valve line 563 into the injection valve
  • the mobile phase solvent within the fixed-volume fluid loop 517 continues through the sixth injection valve line 566 back into the injection valve 516, where the mobile phase solvent is directed into the fourth injection valve line 564 and thereafter conveyed to the HPLC column 515.
  • the injection valve 516 is rotated 60 degrees into the second state (or State B), shown in Figure 5.
  • State B the sample radiopharmaceutical solution passes from the first injection valve line 561, through the injection valve 516, and then into the fifth injection valve line 565; from the fifth injection valve line 565, the sample radiopharmaceutical solution enters the fixed-volume fluid loop 517.
  • sample radiopharmaceutical solution flowing through the fixed-volume fluid loop 517 exits the fixed-volume fluid loop 517 and re-enters the injection valve 516 through the sixth injection valve line 566; the sample radiopharmaceutical solution is then directed into the second injection valve line 562, and the sample radiopharmaceutical solution passes through the second injection valve line 562 to the pH detector 513 and the waste vessel 507.
  • the sample radiopharmaceutical solution from the fixed- volume fluid loop 517 is directed into the fourth injection 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 UV/VIS detector 502 comprises a ultra-violet and visible light spectrometer. In some embodiments, the UV/VIS detector 502 comprises a UV spectrophotometer. In some embodiments, the UV/VIS detector 502 comprises a UV spectrophotometer with a deuterium light source. In some embodiments, the UV/VIS detector 502 comprises a UV spectrophotometer with a tungsten-halogen light source. In some embodiments, the UV/VIS detector 502 comprises a UV spectrophotometer like the Smartline UV Detector 2500, manufactured by KNAUER. In some embodiments, the HPLC-based QCM 50 includes a detector comprises a
  • 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, as shown in Figure 4. 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 radiopharmaceutical compound) to other radioactive products (such as free F-18 ion and [ 18 F]FTAG).
  • 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.
  • [ 18 F]FDG has a slightly shorter retention time compared to FDG that lacks a radioisotope.
  • [ 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.
  • the RI detector 505 also measures the residual concentration in the sample radiopharmaceutical solution of solvents such as acetonitrile and ethanol. Generally, a purified radiopharmaceutical solution will be considered to pass quality control testing if the residual concentration of acetonitrile in the sample radiopharmaceutical solution is less than or equal to 400 ppm.
  • 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 6A 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 601, a dose calibrator for radioactivity level measurements 602, a endotoxin measurement device 603 (which in some embodiments can be a Charles River Sample tester), a color metric device 604 for color and clarity testing, a sample card system for additional QC testing 650, 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 601, a dose calibrator for radioactivity level measurements 602, a endotoxin measurement device 603 (which in some embodiments can be a Charles River
  • Figure 6B illustrates an 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.
  • a 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 measurements 602; a endotoxin measurement device 603 (which in some embodiments can be a Charles River Sample tester); a color metric device 604 for color and clarity testing; and an electronic eye device the measure the electronic conductivity of said radiopharmaceutical 605.
  • the 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 present general inventive concept comprises an HPLC-based quality control system for conducting a number of automated tests on a radiopharmaceutical solution, and in particular on a synthesized and purified radiopharmaceutical solution for use in positron emission tomography.
  • An HPLC-based quality control system according to the present general inventive concept provides a quality control testing system that makes efficient use of sample volume.
  • the present general inventive concept 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; 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.

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Abstract

La présente invention concerne un système automatisé de contrôle de qualité basé sur la HPLC permettant d'effectuer un essai de contrôle de qualité sur une solution radiopharmaceutique peu de temps après sa synthèse. Un système automatisé de contrôle de qualité basé sur la HPLC permet une utilisation efficace du volume d'échantillon et est compatible avec une pluralité de radio-isotopes et de composés radiopharmaceutiques. Selon plusieurs modes de réalisation, la nature automatisée d'un système automatisé de contrôle de qualité basé sur la HPLC permet de réaliser rapidement des essais de contrôle de qualité avec un impact minimal sur le flux de travaux d'utilisateur. Lorsqu'il est utilisé comme faisant partie d'un système de production radiopharmaceutique de biomarqueur de PET intégré, le concept général selon la présente invention permet à un fabricant de produire un produit et d'effectuer des essais de contrôle de qualité avec des coûts par dose inférieurs et des durées d'essai plus courtes.
PCT/US2016/016952 2015-02-10 2016-02-08 Système automatisé de contrôle de qualité pour produits radiopharmaceutiques Ceased WO2016130458A1 (fr)

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