Systems and methods for resin-retained transport of radionuclides and radiopharmaceutical production

Abstract

The present disclosure provides a method of preparing a plurality of metal radionuclides for transport including applying a solution comprising a plurality of metal radionuclides in a solvent to a device comprising a solid-phase exchange column comprising a resin, retaining at least a portion of the plurality of metal radionuclides on the resin; flowing a gas through the device to remove at least a portion of the solvent from the solid-phase exchange column; and disposing the device in a radiation shielding container for transport.

Description

Atty. Dkt. No.: 642631-0113 (MDA24-078)SYSTEMS AND METHODS FOR RESIN-RETAINED TRANSPORT OF RADIONUCLIDES AND RADIOPHARMACEUTICAL PRODUCTION CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 761,671, filed February 21, 2025, the entire contents of which are incorporated herein by reference.TECHNICAL FIELD

[0002] The present technology relates generally to systems and methods for distribution of radionuclides and radiopharmaceutical production, and more specifically relates to systems and methods for transporting radionuclides for radiopharmaceutical production.BACKGROUND

[0003] The following description of the background of the present technology is provided simply as an aid in understanding the present technology and is not admitted to describe or constitute prior art to the present technology.

[0004] Conventionally, radionuclides are synthesized at manufacturing facilities, and shipped in liquid phase in sealed vials to clinical or research facilities for use. However there is a risk of chemical spill during shipping and loss of material during fluid transfer. Furthermore, radionuclide concentration can be harder to control because larger solution volumes may be needed for effective fluid transfer.SUMMARY OF THE PRESENT TECHNOLOGY

[0005] In an aspect, the present disclosure provides a method of preparing a plurality of metal radionuclides fortransport including applying a solution comprising a plurality of metal radionuclides in a solvent to a device comprising a solid-phase exchange column comprising a resin, retaining at least a portion of the plurality of metal radionuclides on the resin; flowing a gas through the device to remove at least a portion of the solvent from the solid-phase exchange column; and disposing the device in a radiation shielding container for transport.

[0006] Preparing the plurality of metal radionuclides for transport may include receiving the plurality of metal radionuclides from a cyclotron or nuclear reactor; and forming the-1- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)solution comprising the plurality of metal radionuclides and the solvent. The solvent may include about 0.1 M to about 12 M hydrochloric acid.

[0007] Preparing the plurality of metal radionuclides for transport may include forming the device. Forming the device may include 3D printing the device. Forming the device may include molding the device.

[0008] Applying the solution to the device may include coupling a liquid transfer module to an inlet of the device coupled to the solid-phase exchange column. Coupling the liquid transfer module to the device may include coupling a screw fitting of the liquid transfer module to the inlet of the device.

[0009] Preparing the plurality of metal radionuclides for transport may include loading the resin into the solid-phase exchange column between two porous frit filters. The resin may include N,N,N’,N’-tetra-n-octyldi glycolamide (DGA).

[0010] Preparing the plurality of metal radionuclides for transport may include transporting the portion of the plurality of metal radionuclides on the resin in the device disposed in the radiation shielding container. Transporting may include transporting the portion of the plurality of metal radionuclides on the resin in the device disposed in the radiation shielding container from a facility forming the plurality of metal radionuclides to an end-use location.

[0011] In an aspect, the present disclosure provides a method of receiving at a second location transported from a first location a device comprising a solid-phase exchange column, the solid-phase exchange column comprising a plurality of metal radionuclides retained on a resin therein, the device disposed in a radiation shielding container.

[0012] The method of receiving the device may include eluting at least a portion of the metal radionuclides from the resin. Eluting the portion of the metal radionuclides may include applying an elution solution of about 0.01 M to about 0.1 M hydrochloric acid to the solidphase exchange column. Eluting the portion of the metal radionuclides may include coupling a liquid transfer module to an inlet of the device coupled to the solid-phase exchange column to apply the elution solution and collecting the at least the portion of the metal radionuclides from an outlet of the device. Coupling the liquid transfer module to the device may include coupling a screw fitting from the liquid transfer module to the inlet of the device. The method of receiving the device may include forming the at least the portion of the metal radionuclides-2- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)into a radiopharmaceutical product. The first location may be a facility forming the plurality of metal radionuclides and the second location may be an end-use location.

[0013] In an aspect, the present disclosure provides a system for transporting a radionuclide. The system includes a device comprising a solid-phase exchange column, an inlet of the solid-phase exchange column, an outlet of the solid-phase exchange column, and a first side of the device, wherein the inlet and the outlet are disposed on the first side of the device; the solid-phase exchange column comprising a resin to retain a plurality of metal radionuclides; and a radiation shielding container configured to receive the device.

[0014] The system may include the plurality of metal radionuclides retained on the resin. The resin may include N,N,N’,N’-tetra-n-octyldi glycolamide (DGA). The inlet may include a screw fitting and the outlet may include a slip tip fitting. The system may include a liquid transfer module to couple to the inlet of the solid-phase exchange column to apply a solution to the solid-phase exchange column. The solid-phase exchange column may include two porous frit filters with the resin disposed therebetween.

[0015] In any embodiment, the plurality of metal radionuclides may include64Cu,67Cu,89Zr,86Y,90Y,153Sm,161Tb,225Ac,177Lu, or a combination of any two or more thereof. In any embodiment, the device may include an inlet coupled to the solid-phase exchange column, an outlet coupled to the solid-phase exchange column, and a first side of the device, wherein the inlet and the outlet are on the first side of the device.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 is a schematic of a system for transporting a radionuclide.

[0017] FIGS. 2A-2C illustrates a device for transporting a radionuclide. FIG. 2A is a perspective view of the device. FIG. 2B is a cross-sectional view of the device. FIG. 2C is a view of the inlet side of the device.

[0018] FIG. 3 is an illustrated flow chart showing a general scheme for transporting a radionuclide.

[0019] FIG. 4 is a block diagram of a system for receiving a transported radionuclide and forming a radiopharmaceutical product using the transported radionuclide.-3- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0020] FIG. 5 is a flow chart showing the general scheme for preparing a radionuclide for transport.

[0021] FIG. 6 is a flow chart showing the general scheme for receiving a transported radionuclide and forming a radiopharmaceutical product.

[0022] FIG. 7 is a graph illustrating chelation of177LuCh with DOTA, where the77LuCh was eluted from a device for transporting the77LuCh.DETAILED DESCRIPTION

[0023] It is to be appreciated that certain aspects, modes, embodiments, variations, and features of the present methods are described below in various levels of detail in order to provide a substantial understanding of the present technology. It is to be understood that the present disclosure is not limited to particular uses, methods, reagents, compounds, compositions, or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0024] Definitions

[0025] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs. As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. For example, reference to “a cell” includes a combination of two or more cells, and the like. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, analytical chemistry and nucleic acid chemistry and hybridization described below are those well-known and commonly employed in the art.

[0026] As used herein, the term “about” in reference to a number is generally taken to include numbers that fall within a range of 1%, 5%, or 10% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value).

[0027] As used herein, the “administration” of an agent or drug to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function.-4- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)Administration can be carried out by any suitable route, including but not limited to, orally, intranasally, intrathecally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), rectally, intrathecally, intraocularly, intradermally, transmucosally, iontophoretically, or topically. Administration includes self-administration and the administration by another.

[0028] As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to mean a polymer comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, / .< ., peptide isosteres. Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides, or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well known in the art.

[0029] As used herein, a “sample” or “biological sample” refers to a body fluid or a tissue sample isolated from a subject. In some cases, a biological sample may consist of or comprise whole blood, platelets, red blood cells, white blood cells, plasma, sera, urine, feces, epidermal sample, vaginal sample, skin sample, cheek swab, sperm, amniotic fluid, cultured cells, bone marrow sample, tumor biopsies, aspirate and / or chorionic villi, cultured cells, endothelial cells, synovial fluid, lymphatic fluid, ascites fluid, interstitial or extracellular fluid and the like. The term "sample" may also encompass the fluid in spaces between cells, including gingival crevicular fluid, bone marrow, cerebrospinal fluid (CSF), saliva, mucus, sputum, semen, sweat, urine, or any other bodily fluids. Samples can be obtained from a subject by any means including, but not limited to, venipuncture, excretion, ejaculation, massage, biopsy, needle aspirate, lavage, scraping, surgical incision, or intervention or other means known in the art. A blood sample can be whole blood or any fraction thereof, including blood cells (red blood cells, white blood cells or leukocytes, and platelets), serum and plasma.

[0030] As used herein, the terms “subject”, “patient”, or “individual” can be an individual organism, a vertebrate, a mammal, or a human. In some embodiments, the subject, patient, or individual is a human.-5- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0031] “Substantially” or “essentially” means nearly totally or completely, for instance, 95% or greater of some given quantity. In some embodiments, “substantially” or “essentially” means 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%.

[0032] As used herein, the term “therapeutic agent” is intended to mean a compound that, when present in an effective amount, produces a desired therapeutic effect on a subject in need thereof.

[0033] “Treating” or “treatment” as used herein covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, z.e., arresting its development; (ii) relieving a disease or disorder, z.e., causing regression of the disorder; (iii) slowing progression of the disorder; and / or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder. Therapeutic effects of treatment include, without limitation, inhibiting recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastases, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. By “treating a cancer” is meant that the symptoms associated with the cancer are, e.g., alleviated, reduced, cured, or placed in a state of remission.

[0034] It is also to be appreciated that the various modes of treatment of disorders as described herein are intended to mean “substantial,” which includes total but also less than total treatment, and wherein some biologically or medically relevant result is achieved. The treatment may be a continuous prolonged treatment for a chronic disease or a single, or few time administrations for the treatment of an acute condition.

[0035] Pharmaceutically acceptable salts of compounds described herein are within the scope of the present technology and include acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, allergenic, or irritating, and is bioavailable). When the compound of the present technology has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalene sulfonic-6- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the present technology has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia or organic amines (e.g., di cyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine). Such salts can be prepared in situ during isolation and purification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed.

[0036] Those of skill in the art will appreciate that compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or stereoisomerism. As the formula drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, stereochemical or geometric isomeric forms, it should be understood that the present technology encompasses any tautomeric, conformational isomeric, stereochemical and / or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms.Transporting Radionuclides

[0037] In conventional methods, radionuclides are generated at specialized production facilities and subsequently transported in a liquid phase within securely sealed vials to clinical or research destinations where they are used for various applications, including as radiopharmaceutical products. These methods, while widespread, present several risks and challenges.

[0038] The transportation of liquid phase radionuclides introduces a significant hazard of chemical spills. Any breach or leak of the vial containing the radionuclide during the shipping process can result in contamination and potential exposure to hazardous materials, posing a threat to people and the environment.

[0039] Furthermore, there is a risk of material loss during fluid transfer processes at the radionuclide generation facilities and the receiving facilities. For example, transferring radionuclides from their shipping vials to radiopharmaceutical synthesizers can lead to-7- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)unintentional spillage or adherence of the material to the transfer apparatus, resulting in a loss of radioactive material.

[0040] Additionally, maintaining precise control over radionuclide concentration can be challenging using conventional transport methods. To provide effective fluid transfer, larger volumes of the liquid phase radionuclide may be used, which can complicate the task of achieving a predetermined radionuclide concentration. This can impact the efficacy and accuracy of both clinical procedures and research experiments, where precise dosages are often used.

[0041] Disclosed herein are systems and methods for processing and storing radionuclides for transport, including for shipping from generation facilities to end-use locations. Methods disclosed herein include methods for preparing a radioisotope for transport in a dry solid-phase exchange column, methods for eluting a radioisotope from a dry solid-phase exchange column into a fixed volume of liquid, and a combination thereof. Systems disclosed herein include radionuclide transportation systems including a device with a solid-phase exchange column, and inlet and outlet on the same side of the microfluidic device, and a radiation shielding container configured to receive the device.

[0042] The systems and methods address the problems of radionuclide generation, storage, and transportation by providing a device including a solid-phase exchange column for processing and storing radionuclides. The solid-phase exchange column may include a resin to retain a plurality of metal radionuclides, and the device may be used for storing or distributing radionuclides to manufacturing facilities; where the solid-phase exchange column itself may serve as the vehicle in which to ship radionuclides. The system may include a radiation shielding container configured to receive the device for shielding radiation during transport or storage. This reduces or eliminates the possibility of spills during transportation, reduces or removes the possibility of loss due to liquid handling (e.g., loading a module from a vial of liquid) and allows users to achieve higher molar radionuclidic purity and volume control at the point of elution. The microfluidic system may also be stacked to a companion device that may contain components needed for radiosynthesis and may be used to synthesize tracers such as DOTATATE and MUC13 antibody -based radiotracers and others.

[0043] The radionuclides used in the systems and methods disclosed herein may be metal radionuclides. The metal radionuclides may be any that are suitable for research or clinical-8- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)settings. Nonlimiting examples of the metal radionuclides include64Cu,67Cu,89Zr,86Y,90Y,153Sm,161Tb,225Ac,177LU, or a combination of any two or more thereof.

[0044] The radionuclides may be used to form radiopharmaceutical products. Radiopharmaceutical products may include diagnostic radiopharmaceutical products and therapeutic radiopharmaceutical products. Diagnostic radiopharmaceutical products may include those used to research or diagnose medical conditions in a subject by emitting radiation that can be detected by imaging equipment. Therapeutic radiopharmaceutical products may be used to research or treat diseases (e.g., certain types of cancer) by delivering targeted radiation to diseased cells.Systems for Transporting Radionuclides

[0045] In an aspect, the present disclosure provides a system for transporting one or more radionuclides. FIG. 1 is a schematic of a system 100 for transporting one or more radionuclides. The system 100 may include a device 110, a radiation shielding container 130, a liquid transfer module 120, or a combination of any two or more thereof. The device 110 may include a solid-phase exchange column 116 in which one or more radionuclides may be retained. The radiation shielding container 130 may house the device 110 during transportation, and the device 110 may be disposed in the radiation shielding container 130. The liquid transfer module 120 may transfer liquid to and / or from the device 110.

[0046] The device 110 may include a solid-phase exchange column 116, an inlet 112 of the solid-phase exchange column, and an outlet 114 of the solid-phase exchange column. The inlet 112 and the outlet 114 may be disposed on the same side of the device 110. For example, the device 110 may include a first side 118 of the device 110, and the inlet 112 and the outlet 114 may be disposed on the first side 118 of the device 110. Disposing the inlet 112 and the outlet 114 on the same side of the device 110 may ease liquid transfer to and / or from the device 110, for example where system 100 includes automated liquid transfer. Disposing the inlet 112 and the outlet 114 on the same side of the device 110 may provide compatibility with the liquid transfer module 120. The device 110 may include one or more channels connecting the solidphase exchange column 116 to the inlet 112 and / or the outlet 114.

[0047] The inlet 112 and the outlet 114 of the device 110 may include fittings to provide removable coupling with the liquid transfer module 120. Nonlimiting examples of the fittings include screw fittings (e.g., luer lock fittings), slip tip fittings, quick disconnect fittings, barbed-9- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)fittings, compression fittings, and push-to-connecting fittings. In some embodiments, the inlet 112 and the outlet 114 may include different types of fittings. For example, the inlet 112 may include a screw fitting (e.g., luer lock) and the outlet 114 may include a slip tip fitting.

[0048] The device 110 may include one or more caps sealing the inlet 112 and / or the outlet 114. The caps may provide a seal to the device 110 to prevent or reduce the risk of leaking from the device 110. In some embodiments, the caps may be removable or puncturable by the liquid transfer module 120.

[0049] The solid-phase exchange column 116 may include a resin to retain a plurality of metal radionuclides. The system may include the plurality of metal radionuclides retained on the resin, for example when the system is in transport. Examples of the resin may include, but are not limited to N,N,N’,N’-tetra-n-octyldi glycolamide (DGA).

[0050] The solid-phase exchange column 116 may include one or more porous frit filters. The frit filters maybe disposed in the column 116 towards each end of the column and on one or both sides of the resin. The porous frit filter may provide porosity to the liquid added to the column to reduce or prevent pressure buildup in the column 116 and provide fluid transfer through the column 116. The porous frit filter may be formed of a polymer, glass (e.g., quartz). Nonlimiting examples of the polymer of the frit filter include polyethylene (PE), polyethylene terephthalate (PET), polyether ether ketone (PEEK), poly(methyl methacrylate) (PMMA), polycarbonate (PC), cyclic olefin copolymer (COC), cyclic olefin polymer (COP), and a combination of any two or more thereof. The material may be selected for chemical compatibility with solvent (e.g., COP and COC may be used with alcohols, acetone, acids and bases, polar organic solvents, DMSO, and fluorinated oils; PC may be used with alcohols, fats and organic oils, and fluorinated oils, PMMA may be used with fats and organic oils, and fluorinated oils). The material may be selected for chemical compatibility with solvent (e.g., COP and COC may be used with alcohols, acetone, acids and bases, polar organic solvents, DMSO, and fluorinated oils; PC may be used with alcohols, fats and organic oils, and fluorinated oils, PMMA may be used with fats and organic oils, and fluorinated oils).

[0051] The solid-phase exchange column 116 may include one or more pieces of packable porous material that support the resin in the column and serve as a filtration medium. For example, the packable porous material may be a wool made of a chemically inert material (e.g., quartz).-10- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0052] The device 110 may be a microfluidic device, for example where smaller amounts of metal radionuclides are shipped. The solid-phase exchange column 116 may have an internal volume of about 0.05 mL to about 5 mL (e.g., about 0.05 mL to about 2 mL, about 0.05 mL to about 1 mL, about 0.05 mL to about 0.5 mL, about 0.1 mL to about 0.5 mL, about 0.1 mL, about 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or any value or subrange therebetween). The solid-phase exchange column 116 may have a diameter of about 1 mm to about 100 mm (e.g., about 1 mm to about 50 mm, about 1 mm to about 20 mm, about 5 mm to about 15 mm, about 10 mm to about 11 mm, or any value or subrange therebetween).

[0053] The device 110 may be formed of a material that is stable at temperatures of about 15°C to about 250°C, about 15°C to about 240°C, about 15°C to about 230°C, 20°C to about 250°C, about 20°C to about 240°C, about 20°C to about 230°C, or any value or subrange therebetween. The material may be chemically inert to the radionuclide and acids and bases used with the device. Nonlimiting examples of the material may include polyamide, polyimide, polyether ether ketone (PEEK), polyethylene (PE), polyethylene terephthalate (PET), poly(methyl methacrylate) (PMMA), polycarbonate (PC), cyclic olefin copolymer (COC), cyclic olefin polymer (COP), copolymers thereof, and combinations of any two or more thereof. In some embodiments, the material may be a material formed from a resin used for three-dimensional (3D) printing. The material may be selected for chemical compatibility with solvent (e.g., COP and COC may be used with alcohols, acetone, acids and bases, polar organic solvents, DMSO, and fluorinated oils; PC may be used with alcohols, fats and organic oils, and fluorinated oils, PMMA may be used with fats and organic oils, and fluorinated oils).

[0054] The system 100 may include the liquid transfer module 120. The liquid transfer module 120 may be configured to facilitate liquid transfer into and out of the device 110. The liquid transfer module 120 may include an inlet 122 and an outlet 124 that may be removably coupled to the outlet 114 and the inlet 112 of the device 110, respectively. The liquid transfer module 120 may include tubing 126 coupled to the outlet 124 and tubing 128 coupled to the inlet 122. The tubing 126 may be coupled to a container comprising a solution comprising a plurality of metal radionuclides. The container may be a part of or receive metal radionuclides from a radionuclide source (e.g., a cyclotron or nuclear reactor). The system 100 may further include the radionuclide source. The tubing 126 may be coupled to a gas source to direct gas through the device 110 to push liquid in the device 110 out of the device 110. The gas may be-11- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)gas compatible with the radionuclide (e.g., air, nitrogen, or a noble gas). The tubing 126 may be coupled to a container comprising an elution solution. The tubing 128 may be coupled to a waste collection container for collecting waste liquid from the device 110. The tubing 128 may be coupled to a system or device for end-use of the radionuclide. The system or device for end-use may include synthesizer for formation of a radiopharmaceutical product. For example, the synthesizer may be an automated radiopharmaceutical product synthesizer.

[0055] The solution comprising the plurality of radionuclides may be an aqueous solution of about 0.1 M to about 12 M hydrochloric acid (e.g., about 1 M to about 12 M, about 2 M to about 10 M, about 3 M to about 10 M, about 4 M to about 10 M, about 5 M to about 10 M, about 5 M to about 8 M, about 5 M to about 7 M, or any value or subrange therebetween). The solution may have a radioactivity of about 1 milliCurie (mCi) to about 1000 mCi (e.g., about 10 mCi to about 1000 mCi, about 10 mCi to about 500 mCi, about 10 mCi to about 200 mCi, or any value or subrange therebetween).

[0056] The elution solution may include an aqueous solution of about 0.01 M to about 0.1 M hydrochloric acid (e.g., about 0.01 M to about 0.9 M, about 0.01 M to about 0.8 M, about 0.01 M to about 0.7 M, about 0.05 M to about 0.7 M, about 0.1 M to about 0.7 M, about 0.2 M to about 0.8 M, about 0.2 M to about 0.7 M, or any value or subrange therebetween).

[0057] The system 100 may include a radiation shielding container 130 configured to receive the device 110. The radiation shielding container 130 may include a cavity 134 configured to receive the device 110 and removably contain the device 110. The radiation shielding container 130 may include a cap 132 configured to seal the radiation shielding container 130 when engaged. The radiation shielding container 130 may be formed of a material for radiation shielding. Nonlimiting examples of radiation shielding materials include, but are not limited to lead, tungsten, tungsten alloy (e.g., W-C, W-Cu), aluminum, and aluminum alloys (e.g., Ni-Ti-Al, Al-Li, AhsZn).

[0058] FIGS. 2A-2C illustrates another device 210 for transporting a radionuclide that may be used instead of or in addition to device 110. FIG. 2A is a perspective view of the device 210. FIG. 2B is a cross-sectional view of the device 210. FIG. 2C is a view of the inlet side of the device 210. The device 210 may include inlet 212, outlet 214, and solid-phase exchange column 216.-12- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0059] The device 210 includes inlet 212 and outlet 214. The inlet 212 and the outlet 214 of the device 210 may include fittings to provide removable coupling with a liquid transfer module. Nonlimiting examples of the fittings include screw fittings (e.g., luer lock fittings), slip tip fittings, quick disconnect fittings, barbed fittings, compression fittings, and push-to-connecting fittings. In some embodiments, the inlet 212 and the outlet 214 may include different types of fittings. For example, the inlet 212 may include a screw fitting (e.g., luer lock) and the outlet 214 may include a slip tip fitting.

[0060] The device 210 may include one or more caps sealing the inlet 212 and / or the outlet 214. The caps may provide a seal to the device 210 to prevent or reduce the risk of leaking from the device 210. In some embodiments, the caps may be removable or puncturable by the liquid transfer module 220.

[0061] The solid-phase exchange column 216 may include a resin to retain a plurality of metal radionuclides. The system may include the plurality of metal radionuclides retained on the resin, for example when the system is in transport. Examples of the resin may include, but are not limited to DGA.

[0062] The solid-phase exchange column 216 may include one or more porous frit filters. The frit filters maybe disposed in the column 116 towards each end of the column and on one or both sides of the resin. The porous frit filter may provide porosity to the liquid added to the column to reduce or prevent pressure buildup in the column 216 and provide fluid transfer through the column 216. The porous frit filter may be formed of a polymer, glass (e.g., quartz). Nonlimiting examples of the polymer of the frit filter include polyethylene (PE), polyethylene terephthalate (PET), polyether ether ketone (PEEK), poly(methyl methacrylate) (PMMA), polycarbonate (PC), cyclic olefin copolymer (COC), cyclic olefin polymer (COP), and a combination of any two or more thereof. The material may be selected for chemical compatibility with solvent (e.g., COP and COC may be used with alcohols, acetone, acids and bases, polar organic solvents, DMSO, and fluorinated oils; PC may be used with alcohols, fats and organic oils, and fluorinated oils, PMMA may be used with fats and organic oils, and fluorinated oils).

[0063] The solid-phase exchange column 216 may include one or more pieces of packable porous material that support the resin in the column and serve as a filtration medium. For-13- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)example, the packable porous material may be a wool made of a chemically inert material (e.g., quartz).

[0064] The system 100 may include a 3D printer, injection molder, or another apparatus for forming the device 110.Methods of Transporting Radionuclides

[0065] In an aspect, a method of transporting a radionuclide is disclosed herein. FIG. 3 is an illustrated flow chart showing a general scheme 300 for transporting a radionuclide.

[0066] The scheme 300 may include deploying an apparatus 340 for forming the device including the solid-phase exchange column for transporting the metal radionuclide. The apparatus 340 may include a 3D printer, injection molder, or another apparatus for forming the device including the solid-phase exchange column. The scheme 300 may include 3D printing the device 310A or injection molding the device 310A.

[0067] At step 301, the scheme 300 may include the apparatus 340 forming the device 310A. The device 310A may include features of the device 110 described with reference to FIG. 1 or the device 210 described with reference to FIG. 2 A.

[0068] At step 302, the scheme 300 may include loading the device 310B into the radiation shielding container 330A. The radiation shielding container 330A may include features of the radiation shielding container 130 described with reference to FIG. 1.

[0069] At step 303, the scheme 300 may include coupling the liquid transfer module 320A to the device 310C disposed in the radiation shielding container 330B. The liquid transfer module 320A may include features of the liquid transfer module 120 describe with respect to FIG. 1.

[0070] At step 305, the scheme 300 may include transferring a liquid phase solution 344 containing a plurality of metal radionuclides into the device 310C disposed in the radiation shielding container 330C via the liquid transfer module 320B . The scheme 300 may include at step 304 forming the liquid phase solution 344 containing the plurality of metal radionuclides using a cyclotron or reactor 342. Metal radionuclides may be retained by the solid-phase exchange column in the device 310C as the liquid phase solution 344 is transferred to the device 310C. Following transfer of the liquid phase solution 344 to the device 310C, the scheme 300-14- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)may include administering a gas to the device 3 IOC via the liquid transfer module 320A to remove at least a portion of the liquid phase solution 344 from the device 3 IOC. The gas may remove at least 10 wt.% to about 99.99% of the liquid phase solution 344 (e.g., about 10 wt.% to about 99.9%, about 20 wt.% to about 99 wt.%, about 30 wt.% to about 99 wt.%, about 40 wt.% to about 99 wt.%, about 50 wt.% to about 99 wt.%, about 60 wt.% to about 99 wt.%, about 70 wt.% to about 99 wt.%, about 80 wt.% to about 99 wt.%, about 90 wt.% to about 99 wt.%, or any value or subrange therebetween).

[0071] At step 306, the scheme 300 may include decoupling the liquid transfer module 320B from the device 310C in the radiation shielding container 330D, and engaging the radiation shielding cap 332A to seal the radiation shielding container 330D for transport.

[0072] At step 307, the scheme 300 may include transporting the radiation shielding container 330E containing the device 310C loaded with a plurality of radionuclides. For example, the radiation shielding container 330E may be transported from a facility for forming the radionuclides to an end-use location. The facility for forming the radionuclides may be a facility including the cyclotron or reactor 342. The end-use location may be a clinical or research facility for using the radionuclides. For example, the end-use location may be a clinical or research facility for forming the radionuclide into a radiopharmaceutical product.

[0073] At step 308, the scheme 300 may include receiving the radiation shielding container 330F containing the device 310C loaded with a plurality of radionuclides at the end-use location and connecting the device 310C to a radiopharmaceutical synthesizer 346 (e.g., an automated radiopharmaceutical synthesizer) for forming the radionuclide into the radiopharmaceutical product. The scheme 300 may include disengaging the radiation shielding cap 332C from the radiation shielding container 330F and coupling a liquid transfer module 320C to the device 310C. The liquid transfer module 320C may dispense the elution solution into the device 310C to elute at least a portion of the radionuclides from the solid-phase exchange column in the device 310C. The scheme 300 may include collecting the eluted solution containing the radionuclides and transferring the eluted solution to the radiopharmaceutical synthesizer 346 via the liquid transfer module 320C. The scheme 300 may include forming the radionuclides into radiopharmaceutical products for use in research and / or clinical setting using the radiopharmaceutical synthesizer 346.-15- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)Methods of Preparing Radionuclides for Transport

[0074] In an aspect, a method of preparing a radionuclide for transport is disclosed. FIG.5 is a flow chart showing the general scheme 500 for preparing a radionuclide for transport. The general scheme 500 may include features of the general scheme 300 for transporting a radionuclide described with respect to FIG. 3 and / or the system 100 described with respect to FIG. 1

[0075] In step 505, the scheme 500 may include applying a solution of radionuclides to a solid-phase exchange column, thereby retaining radionuclides on the resin of the solid-phase exchange column. The solid-phase exchange column may be part of a device or system (e.g., the system 100 described with respect to FIG. 1, the device 200 described with respect to FIGS. 2A-2C, or the device 310 described with respect to FIG. 3).

[0076] In step 510, the scheme 500 may include applying a gas through the solid-phase exchange column to remove solvent from the solid-phase exchange column. The solvent may be solvent from the solution of radionuclides applied to the solid-phase exchange column in step 505. The gas may remove at least 10 wt.% to about 99.99 wt.% of the solvent from the radionuclide solution (e.g., about 10 wt.% to about 99.9 wt.%, about 20 wt.% to about 99 wt.%, about 30 wt.% to about 99 wt.%, about 40 wt.% to about 99 wt.%, about 50 wt.% to about 99 wt.%, about 60 wt.% to about 99 wt.%, about 70 wt.% to about 99 wt.%, about 80 wt.% to about 99 wt.%, about 90 wt.% to about 99 wt.%, or any value or subrange therebetween). The gas flow may provide a substantially dry solid-phase exchange column, which may be more suitable for transport. The gas may be gas compatible with the radionuclide (e.g., air, nitrogen, or a noble gas).

[0077] Applying the solution in step 505 and / or applying the gas in step 510 to the solidphase exchange column may be facilitated via a liquid transfer module. The liquid transfer module may include features of the liquid transfer module 120 described with respect to FIG.1 or the liquid transfer module 320 described with respect to FIG. 3. Steps 505 and / or 510 may include coupling the liquid transfer module to the solid-phase exchange column. Coupling may include coupling the fittings of the liquid transfer module with the fittings of the solidphase exchange column.-16- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0078] In step 515, the scheme 500 may include disposing the solid-phase exchange column in a radiation shielding container for transport. The radiation shielding container may include features of the radiation shielding container 130 described with respect to FIG. 1.

[0079] The scheme 500 may further include receiving the plurality of metal radionuclides from a cyclotron or nuclear reactor; and / or forming the solution comprising the plurality of metal radionuclides and the solvent.

[0080] The solution comprising the radionuclides may be an aqueous solution of about 0.1 M to about 12 M hydrochloric acid (e.g., about 1 M to about 12 M, about 2 M to about 10 M, about 3 M to about 10 M, about 4 M to about 10 M, about 5 M to about 10 M, about 5 M to about 8 M, about 5 M to about 7 M, or any value or subrange therebetween). The solution may have a radioactivity of about 1 milliCurie (mCi) to about 1000 mCi (e.g., about 10 mCi to about 1000 mCi, about 10 mCi to about 500 mCi, about 10 mCi to about 200 mCi, or any value or subrange therebetween). The solution comprising the radionuclides may include any suitable solvent (e.g., alcohol (e.g., isopropyl alcohol, ethanol, and combinations thereof), acetone, fats and organic oil, acid, base, polar organic solvent, DMSO, fluorinated oil (e.g., FC-40), chlorinated solvent (e.g., di chloromethane), or a combination of any two or more thereof).

[0081] The scheme 500 may further include forming the device including the solid-phase exchange column. The scheme 500 may include 3D printing the device and / or molding (e.g., injection molding) the device.

[0082] The scheme 500 may further include loading the resin into the solid-phase exchange column. Examples of the resin may include, but are not limited to N,N,N’,N’-tetra-n-octyldiglycolamide (DGA). The resin may be disposed between two porous frit filters in the solid-phase exchange column.

[0083] The scheme 500 may further include transporting the metal radionuclides on the resin in the device disposed in a radiation shielding container.

[0084] The metal radionuclides may be transported while retained in the solid-phase exchange column from a facility for forming the radionuclides to an end-use location. The facility for forming the radionuclides may be a facility including a cyclotron or reactor. The end-use location may be a clinical or research facility for using the radionuclides. For example,-17- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)the end-use location may be a clinical or research facility for forming the radionuclide into a radiopharmaceutical product.Methods of Receiving Transported Radionuclides

[0085] In an aspect, a method of receiving a transported radionuclide is disclosed herein.FIG. 6 is a flow chart showing the general scheme 600 for receiving a transported radionuclide and forming a radiopharmaceutical product.

[0086] In step 605, the scheme 600 may include receiving a device at a second location transported from a first location. The device may be a solid-phase exchange column including a radionuclide. The device may include features of the system 100 described with respect to FIG. 1, the device 200 described with respect to FIG. 2, and / or the device 310 described with respect to FIG.3. The device may be disposed in a radiation shielding container. The radiation shielding container may include features of the radiation shielding container 130 described with respect to FIG. 1.

[0087] The first location may be a facility for forming the radionuclides. The facility may include a cyclotron or reactor. The second location may be an end-use location. The end-use location may be a clinical or research facility for using the radionuclides. For example, the end-use location may be a clinical or research facility for forming the radionuclide into a radiopharmaceutical product.

[0088] In step 610, the scheme 600 may include applying an elution solution to the solidphase exchange column including the radionuclide to elute the radionuclide from the solidphase exchange column. Applying the elution solution to the solid-phase exchange column may elute a portion of the radionuclides from the solid-phase exchange column. The portion of radionuclides eluted from the solid-phase exchange column may be about 10 % to about 99.99% of the radionuclides transported on the solid-phase exchange column (e.g., about 10% to about 99.9%, about 20% to about 99%, about 30% to about 99%, about 40% to about 99%, about 50% to about 99%, about 60% to about 99%, about 70% to about 99%, about 80% to about 99%, about 90% to about 99%, or any value or subrange therebetween).

[0089] The elution solution may include an aqueous solution of about 0.01 M to about 0.1 M hydrochloric acid (e.g., about 0.01 M to about 0.9 M, about 0.01 M to about 0.8 M, about-18- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)0.01 M to about 0.7 M, about 0.05 M to about 0.7 M, about 0.1 M to about 0.7 M, about 0.2 M to about 0.8 M, about 0.2 M to about 0.7 M, or any value or subrange therebetween).

[0090] Applying the elution solution in step 610 to the solid-phase exchange column may be facilitated via a liquid transfer module. The liquid transfer module may include features of the liquid transfer module 120 described with respect to FIG. 1 or the liquid transfer module 320 described with respect to FIG.3. Step 610 may include coupling the liquid transfer module to the device comprising the solid-phase exchange column. Coupling may include coupling the fittings of the liquid transfer module with the fittings of the device.

[0091] In step 615, the radionuclide may be formed into a radiopharmaceutical product.FIG. 4 is a block diagram of a system 400 for receiving a transported radionuclide and forming a radiopharmaceutical product using the transported radionuclide. The system 400 may be an automated radiopharmaceutical product synthesizer.

[0092] The system 400 may include a nitrogen gas source 480 and a vacuum 482 to provide flow through the components of the system 400. Components 401, 402, 403, 404, 405, 406, 407, 408, and 409 are three-way valves to divert liquids and gases through the system 400.

[0093] Component 420 may be an inlet configured to provide precursor solutions to the system 400. Precursor solutions may include, but are not limited to, a solution to adjust pH (e.g., ammonium acetate solution), a solution including a linker conjugate to conjugate the radionuclide to a biologic, and a functionalized biologic (e.g. an azide-functionalized biologic) to be conjugated to the linker. Examples of the biologic may include, but are not limited to, antibodies, biological cells, gene therapies, tissues, proteins, and vaccines.

[0094] The device 410 may include a solid-phase exchange column containing a radionuclide. The device 410 may include features of the system 100 described with respect to FIG. 1, the device 200 described with respect to FIG. 2, and / or the device 310 described with respect to FIG. 3. Valves 402 and 403 may provide flow of the elution solution through the solid-phase exchange column to elute the radionuclide from the solid-phase exchange column into the system 400.

[0095] Component 430 may be an inlet configured to provide one or more formulation buffers (e.g., diethylenetriamine pentaacetatic acid) to the system 400.-19- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0096] Reactor 440 may be to conjugate the radionuclide to the linker and biologic. Valve 405 may divert the radionuclide to the reactor 440 for reaction. The reactor 440 may include a container coupled with a nitrogen gas source and a vacuum to provide an inert gas headspace in the reactor container. The reactor 440 may be heated at a temperature of about 25°C to about 95°C. The reaction solution include the radionuclide biologic conjugates formed in the reactor 440 may be introduced back into the system 400 at valve 405.

[0097] Following reaction in the reactor 440, the reaction solution may be introduced into column 450 for filtration and / or separation. The column 450 may be a desalting column for desalting, buffer exchange, removal of small contaminants (e.g., unreacted radionuclides), or a combination of any two or more thereof. For example, the column 450 may be a PD-10 desalting column. Valves 406 and 407 may provide flow through of the reaction solution through the column 450.

[0098] The radionuclide biologic conjugate may be collected into container 460 (e.g., a vial for use in a research or clinical setting) via valve 408. Component 470 may be a driver (e.g., a syringe driver) to provide waste product collection and / or purification.EXAMPLES

[0099] The present technology is further illustrated by the following Examples, which should not be construed as limiting in any way. The examples herein are provided to illustrate advantages of the present technology and to further assist a person of ordinary skill in the art with preparing or using the methods of the present technology. The examples should in no way be construed as limiting the scope of the present technology, as defined by the appended claims. The examples can include or incorporate any of the variations, aspects, or embodiments of the present technology described above. The variations, aspects, or embodiments described above may also further each include or incorporate the variations of any or all other variations, aspects, or embodiments of the present technology.Example 1: Compatibility of 3D Printed Solid-Phase Exchange Column Device

[0100] In this study, a 3D printed solid-phase exchange column device for transporting radionuclides was tested for compatibility with the radionuclide177LuCh. The device had the features of the device 210 described with respect to FIG. 2. The device was formed of a Formlabs clear resin SLA with a luer lock inlet and outlet to provide connectivity. The device had an internal volume of 0.213 mL.-20- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0101] To test the compatibility of the device to high concentration acid and177LuCh,177LuCh (2.38 mCi) was diluted into 1 mL of 6 M HC1. The solution was passed through the empty device (without resin) at a dropwise rate into a collection vial. The device was rinsed with 500 pL of water. Then the activity of the components was measured. Activity remaining on the device was 103.7 pCi. Activity from the collection vial was 2.18 mCi. Therefore, the percent activity retained on the device was less than 5%.Example 2: Retention / Elution Efficiency of 3D Printed Solid-Phase Exchange Column Device

[0102] The device from Example 1 was used in Example 2. The device was formed by packing the solid-phase exchange column with packing quartz wool to prevent pass through of the resin; adding a porous polyethylene frit filter to the solid-phase exchange column to create porosity, prevent pressure buildup, and facilitate fluid transfer through the solid-phase exchange column; adding about 30 mg DGA resin to the solid-phase exchange column; and adding another porous polyethylene frit filter to maintain resin packing integrity.

[0103] Retention was tested using177LuCh (2.38 mCi) diluted into 1 mL of 6 M HC1. The177LuCh solution was passed through the device packed with the resin at a dropwise rate, and was collected into a collection vial. Excess solution was removed from the column by pushing air through the column using a syringe. Then the activity of the components was measured. Activity remaining on the device was 2.24 mCi. Activity in the collection vial was below the detection limit. Therefore, the percent activity retained on the resin was about 96%.

[0104] Elution was tested by passing an elution solution through the device following the retention test. The activity from the device (2.24 mCi) was eluted using 300 pL of 0.05 M HC1 and collected into a collection vial. Then the activity of the components was measured. Activity remaining on the device was 104 pCi. Activity in the collection vial was 2.14 mCi. Therefore, the percent activity eluted from the chip was greater than about 95%.Example 3: Quality of Radioisotopes Eluted from 3D Printed Solid-Phase Exchange Column Device

[0105] Following the retention and elution tests in Example 2, the quality of the eluted177LuCh was tested. Quality was tested by determining chelation of the177LuCh to the DOTA chelator (CAS no. 60239-18-1). 10 pL of the eluted177LuCh was mixed with 15 pL of DOTA in 0.1 N NH4OH (2.5 pmol / mL) at pH of 5. The content was heated at 95°C for 30 minutes.-21- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)The resulting solution was tested with thin-layer chromatography (TLC). Results are shown in FIG. 7 FIG. 7 is a graph illustrating chelation of177LuCh with DOTA, where the77LuCh was eluted from a device for transporting the77LuCh. Results indicated chelation of the77LuCh by the DOTA chelator.EQUIVALENTS

[0106] Having now described some illustrative implementations, it is apparent that the foregoing is illustrative and not limiting, having been presented by way of example. In particular, although many of the examples presented herein involve specific combinations of method acts or system elements, those acts and those elements may be combined in other ways to accomplish the same objectives. Acts, elements, and features discussed in connection with one implementation are not intended to be excluded from a similar role in other implementations or implementations.

[0107] The phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including” “comprising” “having” “containing” “involving” “characterized by” “characterized in that” and variations thereof herein, is meant to encompass the items listed thereafter, equivalents thereof, and additional items, as well as alternate implementations consisting of the items listed thereafter exclusively. In one implementation, the systems and methods described herein consist of one, each combination of more than one, or all of the described elements, acts, or components.

[0108] The present technology is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the present technology. It is to be understood that this present technology is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.-22- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0109] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0110] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.[OHl] Embodiments of the subject matter and the operations described in this specification can be implemented in digital electronic circuitry, or in computer software, firmware, or hardware, including the structures disclosed in this specification and their structural equivalents, or in combinations of one or more of them. The subject matter described in this specification can be implemented as one or more computer programs, e.g., one or more circuits of computer program instructions, encoded on one or more computer storage media for execution by, or to control the operation of, data processing apparatus. Alternatively or in addition, the program instructions can be encoded on an artificially generated propagated signal, e.g., a machine-generated electrical, optical, or electromagnetic signal that is generated to encode information for transmission to suitable receiver apparatus for execution by a data processing apparatus. A computer storage medium can be, or be included in, a computer-readable storage device, a computer-readable storage substrate, a random or serial access memory array or device, or a combination of one or more of them. Moreover, while a computer storage medium is not a propagated signal, a computer storage medium can be a source or destination of computer program instructions encoded in an artificially generated propagated signal. The computer storage medium can also be, or be included in, one or more separate components or media (e.g., multiple CDs, disks, or other storage devices).-23- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0112] The operations described in this specification can be performed by a data processing apparatus on data stored on one or more computer-readable storage devices or received from other sources. The term “data processing apparatus” or “computing device” encompasses various apparatuses, devices, and machines for processing data, including by way of example a programmable processor, a computer, a system on a chip, or multiple ones, or combinations of the foregoing. The apparatus can include special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit). The apparatus can also include, in addition to hardware, code that creates an execution environment for the computer program in question, e.g., code that constitutes processor firmware, a protocol stack, a database management system, an operating system, a cross-platform runtime environment, a virtual machine, or a combination of one or more of them. The apparatus and execution environment can realize various different computing model infrastructures, such as web services, distributed computing, and grid computing infrastructures.

[0113] A computer program (also known as a program, software, software application, script, or code) can be written in any form of programming language, including compiled or interpreted languages, declarative or procedural languages, and it can be deployed in any form, including as a stand-alone program or as a circuit, component, subroutine, object, or other unit suitable for use in a computing environment. A computer program may, but need not, correspond to a file in a file system. A program can be stored in a portion of a file that holds other programs or data (e.g., one or more scripts stored in a markup language document), in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more circuits, subprograms, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communication network.

[0114] Processors suitable for the execution of a computer program include, by way of example, microprocessors, and any one or more processors of a digital computer. A processor can receive instructions and data from a read only memory or a random-access memory or both. The elements of a computer are a processor for performing actions in accordance with instructions and one or more memory devices for storing instructions and data. A computer can include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto optical disks, or optical disks. A computer need not have such devices. Moreover, a computer can be embedded in-24- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)another device, e.g., a personal digital assistant (PDA), a Global Positioning System (GPS) receiver, or a portable storage device (e.g., a universal serial bus (USB) flash drive), to name just a few. Devices suitable for storing computer program instructions and data include all forms of non-volatile memory, media, and memory devices, including by way of example semiconductor memory devices, e.g., EPROM, EEPROM, and flash memory devices; magnetic disks, e.g., internal hard disks or removable disks; magneto optical disks; and CD ROM and DVD-ROM disks. The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry.

[0115] The implementations described herein can be implemented in any of numerous ways including, for example, using hardware, software, or a combination thereof. When implemented in software, the software code can be executed on any suitable processor or collection of processors, whether provided in a single computer or distributed among multiple computers.

[0116] A computer employed to implement at least a portion of the functionality described herein may comprise a memory, one or more processing units (also referred to herein simply as “processors”), one or more communication interfaces, one or more display units, and one or more user input devices. The memory may comprise any computer-readable media, and may store computer instructions (also referred to herein as “processor-executable instructions”) for implementing the various functionalities described herein. The processing unit(s) may be used to execute the instructions. The communication interface(s) may be coupled to a wired or wireless network, bus, or other communication means and may therefore allow the computer to transmit communications to or receive communications from other devices. The display unit(s) may be provided, for example, to allow a user to view various information in connection with execution of the instructions. The user input device(s) may be provided, for example, to allow the user to make manual adjustments, make selections, enter data or various other information, or interact in any of a variety of manners with the processor during execution of the instructions.

[0117] The various methods or processes outlined herein may be coded as software that is executable on one or more processors that employ any one of a variety of operating systems or platforms. Additionally, such software may be written using any of a number of suitable programming languages or programming or scripting tools, and also may be compiled as-25- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)executable machine language code or intermediate code that is executed on a framework or virtual machine.

[0118] In this respect, various inventive concepts may be embodied as a computer readable storage medium (or multiple computer readable storage media) (e.g., a computer memory, one or more floppy discs, compact discs, optical discs, magnetic tapes, flash memories, circuit configurations in Field Programmable Gate Arrays or other semiconductor devices, or other non-transitory medium or tangible computer storage medium) encoded with one or more programs that, when executed on one or more computers or other processors, perform methods that implement the various embodiments of the solution discussed above. The computer readable medium or media can be transportable, such that the program or programs stored thereon can be loaded onto one or more different computers or other processors to implement various aspects of the present solution as discussed above.

[0119] The terms “program” or “software” are used herein to refer to any type of computer code or set of computer-executable instructions that can be employed to program a computer or other processor to implement various aspects of embodiments as discussed above. One or more computer programs that when executed perform methods of the present solution need not reside on a single computer or processor, but may be distributed in a modular fashion amongst a number of different computers or processors to implement various aspects of the present solution.

[0120] Computer-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices. Program modules can include routines, programs, objects, components, data structures, or other components that perform particular tasks or implement particular abstract data types. The functionality of the program modules can be combined or distributed as desired in various embodiments.

[0121] Also, data structures may be stored in computer-readable media in any suitable form. For simplicity of illustration, data structures may be shown to have fields that are related through location in the data structure. Such relationships may likewise be achieved by assigning storage for the fields with locations in a computer-readable medium that convey relationship between the fields. However, any suitable mechanism may be used to establish a relationship between information in fields of a data structure, including through the use of pointers, tags or other mechanisms that establish relationship between data elements.-26- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0122] Any references to implementations or elements or acts of the systems and methods herein referred to in the singular can include implementations including a plurality of these elements, and any references in plural to any implementation or element or act herein can include implementations including only a single element. References in the singular or plural form are not intended to limit the presently disclosed systems or methods, their components, acts, or elements to single or plural configurations. References to any act or element being based on any information, act or element may include implementations where the act or element is based at least in part on any information, act, or element.

[0123] Any implementation disclosed herein may be combined with any other implementation, and references to “an implementation,” “some implementations,” “an alternate implementation,” “various implementations,” “one implementation” or the like are not necessarily mutually exclusive and are intended to indicate that a particular feature, structure, or characteristic described in connection with the implementation may be included in at least one implementation. Such terms as used herein are not necessarily all referring to the same implementation. Any implementation may be combined with any other implementation, inclusively or exclusively, in any manner consistent with the aspects and implementations disclosed herein.

[0124] References to “or” may be construed as inclusive so that any terms described using “or” may indicate any of a single, more than one, and all of the described terms. References to at least one of a conjunctive list of terms may be construed as an inclusive OR to indicate any of a single, more than one, and all of the described terms. For example, a reference to “at least one of ‘A’ and ‘B’” can include only ‘A’, only ‘B’, as well as both ‘A’ and ‘B’. Elements other than ‘A’ and ‘B’ can also be included.

[0125] The systems and methods described herein may be embodied in other specific forms without departing from the characteristics thereof. The foregoing implementations are illustrative rather than limiting of the described systems and methods.

[0126] Where technical features in the drawings, detailed description or any claim are followed by reference signs, the reference signs have been included to increase the intelligibility of the drawings, detailed description, and claims. Accordingly, neither the reference signs nor their absence have any limiting effect on the scope of any claim elements.-27- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)

[0127] The systems and methods described herein may be embodied in other specific forms without departing from the characteristics thereof. The foregoing implementations are illustrative rather than limiting of the described systems and methods. Scope of the systems and methods described herein is thus indicated by the appended claims, rather than the foregoing description, and changes that come within the meaning and range of equivalency of the claims are embraced therein.

[0128] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

[0129] The present technology may include, but is not limited to, the features and combinations of features recited in the following lettered paragraphs, it being understood that the following paragraphs should not be interpreted as limiting the scope of the claims as appended hereto or mandating that all such features must necessarily be included in such claims:A. A method of preparing a plurality of metal radionuclides for transport comprising: applying a solution comprising a plurality of metal radionuclides in a solvent to a device comprising a solid-phase exchange column comprising a resin, retaining at least a portion of the plurality of metal radionuclides on the resin;flowing a gas through the device to remove at least a portion of the solvent from the solid-phase exchange column; anddisposing the device in a radiation shielding container for transport.B. The method of paragraph A, wherein the plurality of metal radionuclides comprise64Cu,67Cu,89Zr,86Y,90Y,153Sm,161Tb,225Ac,177Lu, or a combination of any two or more thereof.C. The method of paragraph A or paragraph B, further comprising receiving the plurality of metal radionuclides from a cyclotron or nuclear reactor; and forming the solution comprising the plurality of metal radionuclides and the solvent.D. The method of any one of paragraphs A-C, wherein the solvent comprises about 0.1 M to about 12 M hydrochloric acid.-28- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)E. The method of any one of paragraphs A-D, further comprising forming the device.F. The method of paragraph E, wherein forming the device comprises three-dimensionally printing the device.G. The method of paragraph E, wherein forming the device comprises molding the device.H. The method of one of paragraphs A-G, wherein the device comprises an inlet coupled to the solid-phase exchange column, an outlet coupled to the solid-phase exchange column, and a first side of the device, wherein the inlet and the outlet are on the first side of the device.I. The method of one of paragraphs A-G, wherein applying the solution to the device comprises coupling a liquid transfer module to an inlet of the device coupled to the solid-phase exchange column.J. The method of paragraph I, wherein coupling the liquid transfer module to the device comprises coupling a screw fitting of the liquid transfer module to the inlet of the device.K. The method of one of paragraphs A-J, further comprising loading the resin into the solid-phase exchange column between two porous frit filters.L. The method of one of paragraphs A-K, wherein the resin comprises N,N,N’,N’-tetra-n-octyldiglycolamide (DGA).M. The method of one of paragraphs A-L, further comprising transporting the at least the portion of the plurality of metal radionuclides on the resin in the device disposed in the radiation shielding container.N. The method of paragraph M, wherein transporting comprises transporting the at least the portion of the plurality of metal radionuclides on the resin in the device disposed in the radiation shielding container from a facility forming the plurality of metal radionuclides to an end-use location.O. A method comprising:receiving at a second location transported from a first location a device comprising a solid-phase exchange column, the solid-phase exchange column comprising a plurality of metal radionuclides retained on a resin therein, the device disposed in a radiation shielding container.-29- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)P. The method of paragraph O, further comprising eluting at least a portion of the metal radionuclides from the resin.Q. The method of paragraph P, wherein eluting the at least the portion of the metal radionuclides comprises applying an elution solution of about 0.01 M to about 0.1 M hydrochloric acid to the solid-phase exchange column.R. The method of paragraph Q, wherein eluting the at least the portion of the metal radionuclides comprises coupling a liquid transfer module to an inlet of the device coupled to the solid-phase exchange column to apply the elution solution and collecting the at least the portion of the metal radionuclides from an outlet of the device.S. The method of paragraph R, wherein coupling the liquid transfer module to the device comprises coupling a screw fitting from the liquid transfer module to the inlet of the device.T. The method of paragraph P, further comprising forming the at least the portion of the metal radionuclides into a radiopharmaceutical product.U. The method of any one of paragraphs O-T, wherein the plurality of metal radionuclides comprise64Cu,67Cu,89Zr,86Y,90Y,153Sm,161Tb,225Ac,177Lu, or a combination of any two or more thereof.V. The method of any one of paragraphs O-Q, wherein the device comprises an inlet coupled to the solid-phase exchange column, an outlet coupled to the solid-phase exchange column, and a first side of the device, wherein the inlet and the outlet are on the first side.W. The method of any one of paragraphs O-V, wherein the first location is a facility forming the plurality of metal radionuclides and the second location is an end-use location.X. A system for transporting a radionuclide comprising:a device comprising a solid-phase exchange column, an inlet of the solid-phase exchange column, an outlet of the solid-phase exchange column, and a first side of the device, wherein the inlet and the outlet are disposed on the first side of the device;the solid-phase exchange column comprising a resin to retain a plurality of metal radionuclides; anda radiation shielding container configured to receive the device.-30- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)Y. The system of paragraph X, further comprising the plurality of metal radionuclides retained on the resin.Z. The system of paragraph X or paragraph Y, wherein the plurality of metal radionuclides comprise64Cu,67Cu,89Zr,86Y,90Y,153Sm,161Tb,225Ac,177Lu, or a combination of any two or more thereof.AA. The system of any one of paragraphs X-Z 24-26, wherein the resin comprises N,N,N’,N’-tetra-n-octyldi glycolamide (DGA).AB. The system of any one of paragraphs X-AA, wherein the inlet comprises a screw fitting and the outlet comprises a slip tip fitting.AC. The system of any one of paragraphs X-AB, further comprising a liquid transfer module to couple to the inlet of the solid-phase exchange column to apply a solution to the solid-phase exchange column.AD. The system of any one of paragraphs X-AC, wherein the solid-phase exchange column comprises two porous frit filters with the resin disposed therebetween.-31- 4910-4396-3161.5

Claims

Atty. Dkt. No.: 642631-0113 (MDA24-078)CLAIMS1. A method of preparing a plurality of metal radionuclides for transport comprising: applying a solution comprising a plurality of metal radionuclides in a solvent to a device comprising a solid-phase exchange column comprising a resin, retaining at least a portion of the plurality of metal radionuclides on the resin;flowing a gas through the device to remove at least a portion of the solvent from the solid-phase exchange column; anddisposing the device in a radiation shielding container for transport.

2. The method of claim 1, wherein the plurality of metal radionuclides comprise64Cu,67Cu,89Zr,86Y,90Y,153Sm,161Tb,225Ac,177Lu, or a combination of any two or more thereof.

3. The method of claim 1 or claim 2, further comprising receiving the plurality of metal radionuclides from a cyclotron or nuclear reactor; and forming the solution comprising the plurality of metal radionuclides and the solvent.

4. The method of any one of claims 1-3, wherein the solvent comprises about 0.1 M to about 12 M hydrochloric acid.

5. The method of claim one of claims 1-4, further comprising forming the device.

6. The method of claim 5, wherein forming the device comprises three-dimensionally printing the device.

7. The method of claim 5, wherein forming the device comprises molding the device.

8. The method of one of claims 1-7, wherein the device comprises an inlet coupled to the solid-phase exchange column, an outlet coupled to the solid-phase exchange column, and a first side of the device, wherein the inlet and the outlet are on the first side of the device.

9. The method of one of claims 1-7, wherein applying the solution to the device comprises coupling a liquid transfer module to an inlet of the device coupled to the solid-phase exchange column.

10. The method of claim 9, wherein coupling the liquid transfer module to the device comprises coupling a screw fitting of the liquid transfer module to the inlet of the device.-32- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)11. The method of one of claims 1-10, further comprising loading the resin into the solidphase exchange column between two porous frit filters.

12. The method of one of claims 1-11, wherein the resin comprises N,N,N’,N’-tetra-n-octyldiglycolamide (DGA).

13. The method of one of claims 1-12, further comprising transporting the at least the portion of the plurality of metal radionuclides on the resin in the device disposed in the radiation shielding container.

14. The method of claim 13, wherein transporting comprises transporting the at least the portion of the plurality of metal radionuclides on the resin in the device disposed in the radiation shielding container from a facility forming the plurality of metal radionuclides to an end-use location.

15. A method comprising:receiving at a second location transported from a first location a device comprising a solid-phase exchange column, the solid-phase exchange column comprising a plurality of metal radionuclides retained on a resin therein, the device disposed in a radiation shielding container.

16. The method of claim 15, further comprising eluting at least a portion of the plurality of metal radionuclides from the resin.

17. The method of claim 16, wherein eluting the at least the portion of the plurality of metal radionuclides comprises applying an elution solution of about 0.01 M to about 0.1 M hydrochloric acid to the solid-phase exchange column.

18. The method of claim 17, wherein eluting the at least the portion of the plurality of metal radionuclides comprises coupling a liquid transfer module to an inlet of the device coupled to the solid-phase exchange column to apply the elution solution and collecting the at least the portion of the plurality of metal radionuclides from an outlet of the device.

19. The method of claim 18, wherein coupling the liquid transfer module to the device comprises coupling a screw fitting from the liquid transfer module to the inlet of the device.

20. The method of claim 16, further comprising forming the at least the portion of the plurality of metal radionuclides into a radiopharmaceutical product.-33- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)21. The method of any one of claims 15-20, wherein the plurality of metal radionuclides comprise64Cu,67Cu,89Zr,86Y,90Y,153Sm,161Tb,225Ac,177Lu, or a combination of any two or more thereof.

22. The method of any one of claims 15-17, wherein the device comprises an inlet coupled to the solid-phase exchange column, an outlet coupled to the solid-phase exchange column, and a first side of the device, wherein the inlet and the outlet are on the first side.

23. The method of any one of claims 15-22, wherein the first location is a facility forming the plurality of metal radionuclides and the second location is an end-use location.

24. A system for transporting a radionuclide comprising:a device comprising a solid-phase exchange column, an inlet of the solid-phase exchange column, an outlet of the solid-phase exchange column, and a first side of the device, wherein the inlet and the outlet are disposed on the first side of the device;the solid-phase exchange column comprising a resin to retain a plurality of metal radionuclides; anda radiation shielding container configured to receive the device.

25. The system of claim 24, further comprising the plurality of metal radionuclides retained on the resin.

26. The system of claim 24 or claim 25, wherein the plurality of metal radionuclides comprise64Cu,67Cu,89Zr,86Y,90Y,153Sm,161Tb,225Ac,177Lu, or a combination of any two or more thereof.

27. The system of any one of claims 24-26, wherein the resin comprises N,N,N’,N’-tetra-n-octyldiglycolamide (DGA).

28. The system of any one of claims 24-27, wherein the inlet comprises a screw fitting and the outlet comprises a slip tip fitting.

29. The system of any one of claims 24-28, further comprising a liquid transfer module to couple to the inlet of the solid-phase exchange column to apply a solution to the solid-phase exchange column.-34- 4910-4396-3161.5Atty. Dkt. No.: 642631-0113 (MDA24-078)30. The system of any one of claims 24-29, wherein the solid-phase exchange column comprises two porous frit filters with the resin disposed therebetween.-35- 4910-4396-3161.5

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