Production method

Abstract

This disclosure relates to a method for producing packaged radiopharmaceuticals by operating various manufacturing processes, including inspections in various cold and shielding units to Grade A, B, C, or CNC cleanliness zoning requirements. The invention further relates to a manufacturing unit including the technical equipment required for the method, the pharmaceuticals obtained by the method, and their technical and medical uses.

Description

Technical Field

[0001] The present disclosure relates to a method for producing a packaged radioactive pharmaceutical by operating various manufacturing processes including inspections in various cold units and shielding units with cleanliness zoning requirements of grade A, B, C or CNC. The invention further relates to a manufacturing unit including technical equipment for said method, the pharmaceutical obtained by said method and its technical and medical uses.

Background Art

[0002] The production of radioactive pharmaceuticals is difficult. Such products are usually administered parenterally and thus require aseptic production in a strictly quality-controlled environment to ensure the sterility of the final product.

[0003] Due to the radioactivity of the product, the production is carried out in a shielding unit. In the current approach, the entire production of radioactive pharmaceutical products is carried out in a single shielded isolator, which enables operations via gloves or gripping devices from outside the isolator and material locks for the transfer of raw materials and products to and from the isolator. The isolator must meet the cleanliness zoning requirement grade A for aseptic production of aseptic radioactive pharmaceutical products.

[0004] All process materials that were or are in the box may be contaminated by radioactivity and thus require special waste management.

[0005] Furthermore, the quality control and inspection of the final radioactive pharmaceutical product are also difficult. A container closure integrity test must be performed, but if a leak is identified, there is a risk of contaminating the entire production unit. Also, due to the radioactivity of the product, visual monitoring can only be done through thick lead glass with insufficient transparency, and it is difficult for an operator to visually inspect particulate matter with the naked eye from a short distance.

[0006] In recent years, several new radiopharmaceuticals have demonstrated through pivotal clinical trials as safe and effective cancer treatment options (e.g., LUTATHERA and PLUVICTO). The approval and expanded clinical use of such drugs have led to a significant increase in demand for these radiopharmaceutical products, necessitating large-scale production. Therefore, there is a strong need for more economical production on an industrial scale. [Overview of the project]

[0007] This disclosure provides such a highly economical production method on an unprecedented industrial scale and is suitable for implementation as an automated process line. This significantly reduces radioactive waste, eliminates the risk of radioactive contamination of process lines in the manufacturing process and product quality control process, and provides a highly efficient and reliable means of product inspection. This disclosure further provides novel primary and secondary packaging methods for radiopharmaceutical products.

[0008] This disclosure provides the production method in the following aspects:

[0009] A method for producing packaged radiopharmaceuticals (e.g., radioligand pharmaceuticals), (1) To obtain a radiopharmaceutical, a step of synthesizing and compounding a radiopharmaceutical active pharmaceutical ingredient solution in one or more shielding units of Grade C (cleanliness zoning requirements), (2) A step of providing the primary packaging material by, for example, unpacking the (outer layer) in one or more cold units of grade C, sterilizing it in one or more cold units of grade B, and unpacking the (inner layer) the packaging material in one or more cold units of grade A, (3) In order to obtain a primary packaged radiopharmaceutical, the process includes filling the radiopharmaceutical active pharmaceutical ingredient solution obtained in step (1) into the primary packaging material provided and unpacked in step (2) in a Grade A shielding unit, (4) A step of inspecting the primary packaged radiopharmaceutical obtained in step (3) in one or more shielding units of grade "Controlled, Unclassified" (CNC), (5) A method comprising the step of placing a primary packaged radiopharmaceutical inspected by step (4) into a secondary packaging material shielded in one or more Grade CNC shielding units, in order to optionally obtain primary and secondary packaged radiopharmaceuticals.

[0010] As mentioned above, to prevent the generation of radioactive waste, all packaging materials are unpacked in a cold area before being placed into the filling unit. This prevents the risk of contamination. Therefore, all tabs and bags are treated as non-radioactive and can be disposed of at a lower cost.

[0011] A method for producing the packaged radiopharmaceutical described above, wherein in step (4), a container closure integrity test (CCIT) of the primary packaged radiopharmaceutical is performed as one of the first inspection steps, preferably the CCIT is performed using the primary packaged radiopharmaceutical present in an (additional) container, the container enabling capture / isolation of the pharmaceutical in the container in the event that any leakage is detected or there is a risk of leakage.

[0012] A unique characteristic is that CCIT (Container Seal Integrity Test) is performed as the first step after filling. This allows for... a) The vial is kept inside the container to collect any leaked liquid. b) The vials have been tested for integrity. c) In the event of leakage, the cup and vial will be isolated and will not contaminate the line.

[0013] This configuration serves the following two purposes: In addition to ensuring that the container is intact (avoiding the risk of contamination to users and patients), this also ensures that a leaking container does not contaminate the production line.

[0014] A method for producing the packaged radiopharmaceutical described above, wherein in step (4), a camera-assisted visual inspection (VI) is performed in the form of a video recording, preferably the video recording is then evaluated by the naked eye.

[0015] Visual inspection is usually performed by one of the following methods: a) This is done by viewing the vial with the naked eye, but this is not possible for radiopharmaceutical products due to radioactivity and low resolution through lead-containing glass. b) This is done by a camera, and an image analysis system is used to automatically detect particles (image analysis).

[0016] The novel approach of this disclosure involves recording video and visually evaluating the recording.

[0017] A method for producing the packaged radiopharmaceutical described above, wherein in step (1), the synthesis step is carried out several times, preferably up to four times, preferably the synthesis step is carried out in parallel in several synthesis units, and the resulting synthetic radiopharmaceutical active pharmaceutical ingredient solution is then collected as a combined (bulk) quantity for formulation.

[0018] A method for producing the above-mentioned packaged radiopharmaceutical, wherein the primary packaging material comprises a glass vial and an all-plastic push-on cap, and a rubber stopper is pre-assembled within the cap, for example, a RayDyLyo cap by ARaymond.

[0019] A method for producing the above-described packaged radiopharmaceutical, wherein the shielded secondary packaging material comprises a lead pot having a corresponding lid, preferably with tamper-evident measures, preferably the lead pot and its lid are free from paint coatings, preferably the lead pot and its lid are plastic coated, and preferably a rubber ring is present between the pot and the lid to seal it to prevent leakage.

[0020] A method for producing the above-packaged radioactive pharmaceutical, wherein the container containing the active ingredient and the piping connecting the container are flushed with a protective gas / inert gas, such as nitrogen (N2) and / or argon (Ar).

[0021] A method for producing the above-packaged radioactive pharmaceutical, wherein the solution involved in the method is transferred from one container to another through piping by adding an overpressure protection gas / inert gas, such as nitrogen (N2) and / or argon (Ar), and preferably, prior to said transfer, the piping is tested for flow and leakage, for example, by a pressure test using said protective gas / inert gas.

[0022] A method for producing the above-packaged radioactive pharmaceutical, wherein the product is produced on a scale of at least 30 Ci, preferably at least 32 Ci, more preferably 35 Ci, and even more preferably at least 40 Ci.

Brief Description of the Drawings

[0023] [Figure 1] FIG. 1 shows a plan view of an exemplary production line (having two synthesis units and two formulation units) arranged linearly. Shielding unit for beta (alpha is optional) / gamma radiation, thin line: cold unit; dashed line: optional. [Figure 2] FIG. 2 shows a schematic view of the modules of an exemplary production line (having four synthesis units and one formulation unit). Thick line: shielding unit for beta (alpha is optional) / gamma radiation; thin line: cold unit; dashed line: optional. "BC" indicates the outlet of the grade A filling unit that first passes through grade B and then grade C.

Modes for Carrying Out the Invention

[0024] The present disclosure will be described and illustrated in more detail below.

[0025] Embodiments The therapeutic methods of the present disclosure are provided in particular as the following embodiments.

[0026] 1. A method for producing packaged radiopharmaceuticals (e.g., radioligand pharmaceuticals), (1) To obtain a radiopharmaceutical, a step of synthesizing and compounding a radiopharmaceutical active pharmaceutical ingredient solution in one or more shielding units of Grade C (cleanliness zoning requirements), (2) Providing primary packaging material (e.g., ready-to-use material in a sealed tab) by, for example, unpacking (outer layer) in one or more Grade C cold units, sterilizing in one or more Grade B cold units, and unpacking (inner layer) the packaging material (e.g., removing the Tyvek sheet from the tab) in one or more Grade A cold units, (3) In order to obtain a primary packaged radiopharmaceutical, the process includes filling the radiopharmaceutical active pharmaceutical ingredient solution obtained in step (1) into the primary packaging material provided and unpacked in step (2) in a Grade A shielding unit, (4) A step of inspecting the primary packaged radiopharmaceutical obtained in step (3) in one or more shielding units of grade "Controlled, Unclassified" (CNC), (5) A method comprising the step of placing a primary packaged radiopharmaceutical inspected by step (4) into a secondary packaging material shielded in one or more Grade CNC shielding units, in order to optionally obtain primary and secondary packaged radiopharmaceuticals.

[0027] In a particular embodiment, the unpacking and sterilization in step (2) are carried out as follows: In Grade C cold units, the outer bag surrounding the sealed tab is removed. In a Grade B cold unit, the sealed tabs are sterilized. In a Grade A cold unit, tab opening is performed, for example, by removing the Tyvek sheet from the tab.

[0028] In certain embodiments, the units are arranged linearly, for example, as shown in Figure 1. Linearly arranged units are considered a preferred option.

[0029] 2. A method for producing a packaged radiopharmaceutical according to Embodiment 1, wherein in step (4), a container closure integrity test (CCIT) of the primary packaged radiopharmaceutical is performed as one of the first inspection steps, preferably the CCIT is performed using the primary packaged radiopharmaceutical present in an (additional) container, the container enabling capture / isolation of the pharmaceutical in the container in the event that any leakage is detected or there is a risk of leakage.

[0030] 3. A method for producing a packaged radiopharmaceutical according to Embodiment 1 or 2, wherein in step (4), a camera-assisted visual inspection (VI) is performed in the form of a video recording, preferably the video recording is then evaluated by the naked eye.

[0031] 4. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 3, wherein in step (1), the synthesis step is carried out several times, preferably up to four times, preferably the synthesis step is carried out in parallel in several synthesis units, and the resulting synthetic radiopharmaceutical active pharmaceutical ingredient solution is then collected as a combined (bulk) quantity for formulation.

[0032] 5. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 4, wherein in step (1), the synthesis step is carried out in a cassette-type synthesis unit, preferably the cassette-type manufacturing synthesizer unit is provided by, for example, Trasis, preferably the MiniAIO described in, for example, International Publication No. 2020 / 089379A1, and preferably two dual synthesis units by Trasis are used.

[0033] 6. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 5, wherein in step (1), the compounding step is: (i) A sub-step in which the synthesized solution is filled into a container, for example, a (bulk) vial or bottle, in order to obtain a (concentrated) mother liquor, (ii) A sub-step in which the radioactivity of the (concentrated) mother liquor is optionally measured, (iii) Optionally, a sub-step of transferring the (concentrated) mother liquor to another container, preferably a flexible plastic bag, (iv) A sub-step of adding a certain amount of dilution solution to obtain a drug substance solution with a desired radioactivity concentration, (v) A method comprising a sub-step of mixing the solution resulting from step (iv) by appropriately moving a flexible plastic bag as appropriate, in order to obtain a uniform diluted active pharmaceutical ingredient solution for filling.

[0034] 7. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 6, wherein in step (2), the packaged primary packaging material is (biologically) decontaminated / sterilized, preferably with vaporized hydrogen peroxide (VHP), before being transferred from a Grade B unit to a Grade A unit.

[0035] 8. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 7, wherein in step (4), the inspection step is the following sub-step: (i) CCIT and, (ii) Radioactivity measurement / calibration, (iii) Visual inspection and, (iv) Optionally, headspace analysis and A method comprising, preferably, the above order.

[0036] 9. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 8, wherein the primary packaging material comprises a glass vial and an all-plastic push-on cap, and a rubber stopper is pre-assembled within the cap, for example, a RayDyLyo cap by ARaymond.

[0037] 10. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 9, wherein the shielded secondary packaging material comprises a lead pot having a corresponding lid, preferably with tamper-evident measures, preferably the lead pot and its lid are free from paint coatings, preferably the lead pot and its lid are plastic coated, and preferably a rubber ring is present between the pot and the lid to seal it to prevent leakage.

[0038] 11. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 10, wherein a container for containing the active pharmaceutical ingredient and piping connecting the container are flushed with a protective gas / inert gas, for example, nitrogen (N2) and / or argon (Ar).

[0039] 12. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 11, wherein the solution involved in the method is transferred from one container to another via piping by adding an overpressure protection gas / inert gas, for example, nitrogen (N2) and / or argon (Ar), and preferably, prior to the transfer, the piping is tested for flow and leakage, for example by a pressure test using the protection gas / inert gas.

[0040] 13. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 12, wherein the solution used in the method is purged and / or flushed with a protective gas / inert gas, for example, nitrogen (N2) and / or argon (Ar).

[0041] 14. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 13, wherein at least steps (1) to (3) are automated, and preferably steps (4) and (5) are also automated except for the visual evaluation of the video recording in step (4).

[0042] 15. A method for producing a packaged radiopharmaceutical according to any one of Embodiments 1 to 14, wherein the product is produced on a scale of at least 30 Ci, preferably at least 32 Ci, more preferably 35 Ci, and even more preferably at least 40 Ci.

[0043] 16. Packaged radiopharmaceutical obtained (and / or can be obtained) by the method of any one of Embodiments 1 to 15.

[0044] 17. A manufacturing unit (e.g., in the form of an (automated) process line) comprising technical equipment and facilities for producing a radiopharmaceutical packaged according to the method described in any one of Embodiments 1 to 16.

[0045] 18. Use of the manufacturing unit described in Embodiment 17 for producing packaged radiopharmaceuticals.

[0046] 19. A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a radiopharmaceutical contained in the packaged radiopharmaceutical described in Embodiment 16.

[0047] 20. A radiopharmaceutical contained in a packaged radiopharmaceutical according to Embodiment 16, for use in the treatment of cancer.

[0048] 21. Use of a radiopharmaceutical contained in a packaged radiopharmaceutical as described in Embodiment 16 for the preparation of a pharmaceutical for the treatment of cancer.

[0049] Definitions (and further descriptions of embodiments and features of embodiments) The term "approximately" in relation to a value means ±25%, preferably ±20%, more preferably ±15%, even more preferably ±10%, and even more preferably ±5%.

[0050] Radiopharmaceuticals: In certain embodiments of this disclosure, the term radiopharmaceutical may refer to any pharmaceutical product containing radioactive materials, such as radionuclides, radioisotopes, or radioactive isotopes, such as F-18, Cu-64, Cu-67, Ga-68, Y-90, Tc-99m, I-131, Tb-161, Er-169, Lu-177, Pb-212, Bi-212, Ra-223, and Ac-225. The radionuclide may exist in such pharmaceuticals, for example, in the form of a salt such as an aqueous solution (e.g., radium chloride solution, Xofigo), or in a form covalently bonded to an organic molecule, for example, 18F-DCFPyL, Pylarify, or in a form complexed in a chelator, for example, 177Lu-DOTATATE, Lutathera, or 177Lu-PSMA-617, Pluvicto, where the chelator can conjugate (e.g., via a linker) to a target-binding component, i.e., a radioactive ligand.

[0051] Radioactive ligand drugs: In certain embodiments of this disclosure, the term "radioligand pharmaceutical" may refer to a pharmaceutical product comprising a radioligand for therapeutic use (i.e., a radioligand therapeutic (RLT) agent) or a radioligand for imaging use (i.e., a radioligand imaging (RLI) agent).

[0052] RLT agents consist of at least two components: (1) Radionuclide components and, (2) Ligand components may be included, The radioactive nuclide component (1) is, (a) Preferably, at least one radionuclide selected from the group consisting of alpha particle emitting radionuclides, beta-negative electron emitting radionuclides, and Auger electron emitting radionuclides, more preferably comprising a beta-negative electron emitting radionuclide, The ligand component (2) is (b) at least one target-binding component (e.g., a PSMA-binding component or a somatostatin receptor target component); (c) at least one chelator or prosthetic group residue derived from a radioactive halogenation reaction for chelating a radionuclide or a salt containing a radionuclide; (d) Optionally, at least one linker connecting the PSMA binding component (b) to the chelator or prosthetic group component (c), preferably the linker being a chemical component or a covalent bond; (e) optionally, at least one additional component that modifies the systemic circulation time, tumor accumulation and / or biodistribution of the RLT agent, preferably the modifying component comprising oxyethylene units, for example, oligo or polyoxyethylene-(-CH2-CH2-O-)n- with n=2 to 100, or albumin-binding components (e.g., Evans blue, 4-(p-iodophenyl)butyrate, 4-(p-methylphenyl)butyrate, ibuprofen).

[0053] The radionuclides can be selected from the group consisting of Lu-177, Tb-161, I-131, Tc-99m, Y-90, Sc-47, Cu-67, Re-188, Pb-212, Bi-213, Ac-255, and Th-227, preferably selected from the group consisting of Lu-177 and Tb-161.

[0054] The radionuclides may be beta-negative electron-emitting radionuclides having a half-life of about 2 to about 10 days, preferably about 5 to about 10 days, more preferably about 6 to about 8 days, and even more preferably about 6 or about 7 days, and a maximum beta-negative electron energy of about 0.3 to about 1.0 MeV, preferably about 0.5 to about 0.8 MeV, more preferably about 0.5, 0.6, 0.7 or 0.8 MeV, and even more preferably about 0.5 or about 0.6 MeV.

[0055] Radionuclides can be beta-negative electron-emitting radionuclides with absorption electron energy ratios per decay of 100-300 keV / decay, 120-250 keV / decay, and approximately 150 keV / decay (e.g., 147 keV for Lu-177) to approximately 200 keV / decay (e.g., 196 keV / decay for Tb-161).

[0056] Ligands include PSMA-617, PSMA I&T, PSMA-R2, MIP-1095, MIP-1545, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, rhPSMA-10.1, Ludotadipep, PNT2001, PNT2002, and PSMA-7. The albumin binders may be selected from the group consisting of I&T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, and RPS-074 (or any albumin binder-modified version thereof, e.g., Evans Blue (EB)-PSMA-617), preferably from the group consisting of PSMA-617, PSMA I&T, and PSMA-R2.

[0057] The PSMA-binding component may include at least two amino acids linked via a urea or phosphoramide group, preferably glutamate-urea-lysine (GUL), or an antibody or a fragment thereof, such as TLX591, J591, rosopatamab, IAB2M, GCP-05, 1H8H5, SP29, or FOLHl.

[0058] The radioactive ligand therapeutic agents are [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipivotide tetraxetan), [177Lu]Lu-EB-PSMA-617 (Evans blue modified [177Lu]Lu-PSMA-617) and [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadavotide glaxetan), [161Tb]Tb-PSMA-617 (terbium (161Tb) bipivotide tetraxetan), [161Tb]Tb-EB-PSMA-617 (Evans blue modified [161Tb]Tb-PSMA-617) and [161Tb]Tb-PSMA The following can be selected from the group consisting of I&T (terbium (161Tb) zadabotide tetraxetan), preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipivotide tetraxetan) or [161Tb]Tb-PSMA-617 (terbium (161Tb) bipivotide tetraxetan), more preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipivotide tetraxetan).

[0059] The PSMA binding component may be glutamic acid-urea-lysine (GUL), and the linker may contain residues such as (2-naphthyl)-L-alanine and trans-4-aminomethyl-cyclohexanecarboxylic acid, or the linker may contain residues such as optionally substituted phenylalanine and / or optionally substituted tyrosine, preferably phenylalanine and substituted tyrosine, more preferably phenylalanine and iodine-substituted tyrosine, and even more preferably D-phenylalanine and iodine-substituted D-tyrosine.

[0060] The ligands are DOTA-OC:[DOTA0,D-Phe1]octreotide, DOTA-TOC:[DOTA0,D-Phe1,Tyr3]octreotide, edotreotide (INN), DOTA-NOC:[DOTA0,D-Phe1,1-Nal3]octreotide, DOTA-TATE:[DOTA0,D-Phe1,Tyr3]octreotate, DOTA-Tyr3-octreotide. The following can be selected from the group consisting of tate, DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (cyclo2,7), oxodotreotide (INN), DOTA-LAN:[DOTA0,D-β-Nal1]lanreotide, DOTA-VAP:[DOTA0,D-Phe1,Tyr3]vapreotide, satreotide trizoxetane, and satreotide tetraxetan.

[0061] Radioactive ligand imaging agents are (1) Radionuclide components and, (2) Ligand components may be included, The radioactive nuclide component (1) is, (a) comprising at least one positron-emitting radionuclide, The ligand component (2) is (b) at least one target-binding component (e.g., a PSMA-binding component or a somatostatin receptor-binding peptide, e.g., oxodotreotide or edotreotide); (c) at least one chelator or prosthetic group residue derived from a radiohalogenation reaction for selectively chelating a radionuclide or a salt containing a radionuclide; (d) optionally comprising at least one linker connecting the PSMA binding component (b) to the chelator / prosthetic group component (c), preferably the linker being a chemical component or a covalent bond.

[0062] The radionuclides for the RLI agent can be selected from the group consisting of F-18, Ga-67, Ga-68, and Cu-64.

[0063] Ligands for RLI agents can be selected from the group consisting of PSMA-11 (gozetotide), DCPyL (available as PYLARIFY when labeled with 18F, INN: pifluforastat F-18, also abbreviated as PyL), MIP-1404, rhPSMA07, PSMA-1007, THP-PSMA, iPSMA, P16-093, PSMA-93, rhPSMA, rhPSMA-7, rhPSMA-7.3, PSMA-7, and PSMA I&T.

[0064] The ligands are DOTA-OC:[DOTA0,D-Phe1]octreotide, DOTA-TOC:[DOTA0,D-Phe1,Tyr3]octreotide, edotreotide (INN), DOTA-NOC:[DOTA0,D-Phe1,1-Nal3]octreotide, DOTA-TATE:[DOTA0,D-Phe1,Tyr3]octreotate, DOTA-Tyr3-octreotide. The following can be selected from the group consisting of tate, DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (cyclo2,7), oxodotreotide (INN), DOTA-LAN:[DOTA0,D-β-Nal1]lanreotide, DOTA-VAP:[DOTA0,D-Phe1,Tyr3]vapreotide, satreotide trizoxetane, and satreotide tetraxetan.

[0065] Synthesis (Step 1): In certain embodiments of this disclosure, the term “synthesize” may refer, for example, to complexing a ligand chelator with a radioactive metal and radiolabeling the target-binding ligand. Such radiolabeling may require heating a solution of radionuclides and ligands for a specific time (e.g., about 5 to 15 minutes) and a specific temperature (e.g., about 95°C). The solution may contain a buffer (e.g., an acetate buffer for a pH of about 4 to 6) to ensure that the pH is optimal for complex formation, and a stabilizer against radiolysis (auto-radiolysis), such as gentisic acid or ascorbic acid or salts thereof. The result of this radiolabeling may be called a mother liquor or concentrated mother liquor.

[0066] The synthesis process may be carried out in a cassette-type synthesis unit, preferably the cassette-type synthesizer unit provided by, for example, Trasis, preferably the MiniAIO as described in, for example, International Publication No. 2020 / 089379A1 (the contents of which are incorporated by reference), and preferably two dual synthesis units by Trasis are used.

[0067] Formulation (Step 1): In certain embodiments of this disclosure, the term “compound” may mean diluting the concentrated mother liquor by adding, for example, water or optionally a metal ion chelating agent (e.g., DTPA), a stabilizer against radiolysis (auto-radiolysis), such as gentisic acid or ascorbic acid or salts thereof, optionally further an isotonic agent, such as NaCl, to adjust the tonicity of the resulting solution, and optionally a pH adjuster, such as NaOH or HCl, to adjust the pH to be closer to a physiological pH. The purpose of this dilution step is to adjust the radioactivity concentration to a target concentration suitable for a filling step to produce patient dose units, for example, about 1000 MBq / mL (27 mCi / mL).

[0068] The compounding process is as follows: (i) A sub-step in which the synthesized solution is filled into a container, for example, a (bulk) vial or bottle, in order to obtain a (concentrated) mother liquor, (ii) A sub-step in which the radioactivity of the (concentrated) mother liquor is optionally measured, (iii) Optionally, a sub-step of transferring the (concentrated) mother liquor to another container, preferably a flexible plastic bag, (iv) A sub-step of adding a certain amount of dilution solution to obtain the active pharmaceutical ingredient solution with a desired radioactivity concentration, (v) To obtain a uniform diluted active pharmaceutical ingredient solution for filling, the process may preferably include a sub-step of mixing the solution resulting from step (iv) by appropriately moving a flexible plastic bag as appropriate.

[0069] Shielding unit: In some embodiments of this disclosure, the term “shielding unit” may refer to a manufacturing unit shielded with a material suitable for preventing ionizing radiation (e.g., alpha particles, beta-negative electrons, gamma rays) from escaping the unit. Thus, radioactive materials can be safely handled within the shielding unit.

[0070] Cold unit: In certain embodiments of this disclosure, the term “cold unit” may refer to a manufacturing unit that is not shielded from ionizing radiation. Therefore, radioactive materials should not be handled in such cold units.

[0071] Primary packaging material: In certain embodiments of this disclosure, the term “primary packaging material” may refer to a container in direct contact with a pharmaceutical product, such as a radioactive solution. Such primary packaging material may be a glass vial having a rubber stopper and cap; or a glass vial having an all-plastic push-in cap, wherein the rubber stopper is a glass vial pre-assembled in a cap, such as the RayDyLyo cap by A Raymond; or a cartridge, such as a glass cylinder closed by a rubber component, wherein at least one rubber component is movable, and the cartridge can then be used by loading it into a syringe device; or a pre-filled syringe. Such primary packaging material may be provided in a tab sealed with, for example, foil, such as that commercially available from DuPont under the name Tyvek (e.g., made from high-density polyethylene (HDPE)). Such a sealed tab containing the primary packaging material may then be wrapped in a further bag.

[0072] Inspection (Process 4): In certain embodiments of this disclosure, the term “inspect” may refer to processes that control the quality and integrity of a pharmaceutical product. These inspections or inspection processes may be process controls or end-product controls. These inspection processes may be container closure integrity tests (CCIT), radioactivity measurements / calibration, visual inspections, headspace analysis, or any other product quality control.

[0073] Cleanliness zoning requirements: Cleanrooms and clean air systems are classified according to EN ISO 14644-1. The maximum permissible airborne particle concentrations for each grade are shown in the table below.

[0074] [Table 1]

[0075] The approximate classification of airborne particles according to the ISO 14644-1 standard is listed in the table below.

[0076] [Table 2]

[0077] Grade "Controlled, Unclassified" (CNC) refers to a cGMP manufacturing area designed to create a stable, controlled environment, but not necessarily monitored against a specific environmental classification. Unclassified areas may not have controlled levels of airborne particles, but temperature and humidity are still maintained. Unclassified areas may be non-process areas or areas where products do not come into direct contact with the air.

[0078] References To the same extent that each individual publication, patent, or patent application is explicitly shown to be incorporated in whole by reference, all publications, patents, and patent applications referenced herein are incorporated in whole by reference. [Examples]

[0079] The present invention will be described in more detail and clearly below with respect to examples, but this is not intended to limit the present invention.

[0080] Example 1: Overview, Preparation The production of radioactive chemicals takes place within the synthesis module, using a new cassette, a new set of reagents, and new piping each time. All consumables are sterile and single-use.

[0081] All solution transfer lines are sterile and single-use. Throughout all stages of the production and distribution process, starting materials, intermediate products, and final products come into contact with sterile, single-use materials.

[0082] The manufacturing isolators are decontaminated before production of each batch using a qualified vaporized hydrogen peroxide cycle. Due to the high level of radioactivity exposure, the isolators cannot be cleaned immediately after production and must be cleaned when the radioactivity levels have decreased or when all items have been collected and can be removed in a manner that promotes the ALARA principle.

[0083] Therefore, cleaning of the hot cells is performed before each production cycle each day. The cleanroom is cleaned daily after production according to the procedure.

[0084] Sterile radiopharmaceuticals for injection are produced using an automated synthesis module and diluted under sterile conditions using sterile techniques. The radionuclides used are supplied by IDB, MURR, or ITM.

[0085] Synthesis is carried out using a radiosynthesis module. This module is enclosed within a shielded hot cell, utilizing 0.2 μm filtration when the active pharmaceutical ingredient is transferred into the hot cell. The module is automated and managed by software that includes method checks and parameter registration. The software also records and reports the conditions under which the manufacturing takes place.

[0086] 177 The aqueous solution containing LuCl3 is transferred to the radiosynthesis module and then to the reactor via a capillary tube. The reaction buffer and ligand peptide are also transferred to the same reactor. The solution undergoes a radiolabeling step of approximately 5 minutes before being transferred to the dispensing hot cell.

[0087] The active pharmaceutical ingredient is filtered through a 0.2 μm filter and transferred to a sterile mother vial. The active pharmaceutical ingredient is then diluted with the pharmaceutical agent and dispensed into sterile containers through a sterile filter.

[0088] Packaging and labeling The packaging of radioactive chemicals requires special measures such as radiation protection. The packaging essentially consists of three parts: a glass vial (primary packaging), a lead container (secondary packaging), and a Type A container (secondary packaging).

[0089] The packaging system complies with ADR regulations regarding the transport of hazardous materials on roads and uses gel packs for temperature control to ensure product stability.

[0090] The markings are applied to the primary packaging, secondary packaging, and secondary packaging.

[0091] Preservation of the finished product Due to its short shelf life (72-120 hours), radioactive drugs are shipped to hospitals after lot release by the quality department. Generally, doses are produced on day 1, released by the quality department on day 2, shipped to hospitals, and then administered to patients on day 2 or 3 after manufacturing is complete.

[0092] Automation process line A schematic diagram of the modules within the new filling line is provided in Figure 1 for an overview, and in Figures 2 and 3 for details.

[0093] The process line units are described below.

[0094] Grade C unit (synthetic)

[0095] Description of the task: - Measure the amount of radioactivity in advance. - Add materials through the open door (including the transfer and connection of radioactive isotopes) -Synthesis -Optional:- An automated system for attaching all needles to reagent containers containing radioisotopes. -Transfer the product to the compounding cell via disposable piping (Note: Install the tubing before starting operations). -Transfer the waste to waste box 1. -EM sampling (start)

[0096] Equipment: - Isolator-type box, Grade C / shielding - Optional: Tools for attaching / confirming reagents - N2 for transport - Transfer system to compound - Transfer system to waste box 1 - Gloves inside the plexi panel & access port inside the shielding door -Two (dual) composite units (Trasis) & disposable instruments are installed by the operator.

[0097] Important notes: -Grade C conditions during shutdown and operation -IQ / OQ is provided by the equipment supplier. - The Grade Qualification (PQ) of operational equipment, synthesis equipment, and processes is performed by the operator.

[0098] Waste box

[0099] Task description: - Collection of waste from both the synthetic box and the filling unit. - The transfer mechanism and arrangement will be determined by the supplier. - Proposals regarding the maximum reduction in waste volume will be made by the supplier.

[0100] Equipment: - Equipment to reduce the amount of waste as needed. - The box can be in an unclassified (shielded) environment. - Gloves inside the plexi panel & access port inside the shielding door

[0101] Important notes: - Important work not subject to GMP

[0102] Grade C formulation

[0103] Task description: - Add materials through the open door. Includes sterile, pre-assembled, disposable utensils. - The area is used for dose calibration of radioactive isotopes or concentrated mother liquor for synthesis. -Product-specific: Optionally, flush the closed system using N2 in all relevant processes. -Can be processed according to a series of steps: 1. Add and mix the buffer solution to the physiological saline solution.* 2. The labeled product from the synthetic cell is transferred via disposable piping. 3. Dose measurement of the mother liquor (250 ml) 4. Adding mother liquor to buffer solution 5. Adjust to final concentration and mix. - Alternative scenarios must be developed in case of synthesis failure (in the case of partial failure, the dilution factor can be corrected by software). - Batch size of 0.5 to 5 liters of solution. - The finished product is transported via disposable piping. 1. Note: The solution remains in the mixing unit during filling. 2. Note: Install several tubes before starting operations. -EM sampling (at startup) *This task must be performed in sections based on time or space. - That is, prepare the buffer outside the shielding unit, mix it, and flush it with nitrogen. - That is, before adding radioactive material, prepare and mix a buffer solution in the shielding unit and flush with nitrogen. -Note: The first method requires an additional balance, shaker, and pump.

[0104] Equipment: - Isolator Box Grade C / Shielding - Sterile grade disposable filters -balance - Peristaltic pump and / or nitrogen for transfer - Dose Calibrator (Range: Incoming Lu / Targeted API) - Mixing system proposed by the supplier (inclined platform, recirculation) - N2 for flushing the container and solution - Gloves and telepliers inside plastic panels

[0105] Important notes: -Grade C conditions during shutdown and operation -IQ / OQ is provided by the equipment supplier. - Disposable instruments certified by the equipment supplier (sterile, leachables-free, and complete). - Conduct process certification (PQ grade & process)

[0106] Grade C / B material input, VHP

[0107] Task description: - Disposable filling materials (provided by the machine supplier) and ready-to-use sterile equipment (vials, stoppers / caps) are added through the open door (typically 150 vials per batch). - Place / hang items on a shelf - Close the box - Remove and eliminate secondary packaging using gloves. - Place the tab into the transport unit ("Train"). -EM sampling (start) -VHP cycle -EM sampling (completed)

[0108] Equipment: - Isolator box before VHP: Grade C / Grade B after VHP - Gloves (for removing the primary bag and placing it on the rack) - Glove integrity tester - VHP generator & detection system & safety alarm system for operators (technical area & cleanroom) - Hanger / Shelving / Transportation System

[0109] Important notes: -Grade C / B conditions during shutdown and operation -IQ / OQ is provided by the equipment supplier. - Qualified disposable instruments (sterility, leachate, integrity) -Cycle development (reduction to 1 / 1,000,000 (6 log reduction) & aeration <1 ppm must be completed within approximately 120 minutes) -PQ (Grade and VHP Cycle) is performed by the operator.

[0110] VHP Generator

[0111] Task description: -Please refer to the relevant section. -Each generator must be connectable to the following: - Material input unit (sterilization upon input of each material) - Material unpacking unit (sterilized after each operation (e.g., daily)) - Filling line unit (sterilization after each operation (e.g., daily))

[0112] Equipment: - Generator - Designed by Steris or the supplier

[0113] Important notes: -Please refer to the relevant section.

[0114] A => Grade A Equipment unpacking, VHP

[0115] Work Description: Phase 1: Preparation Part A - VHP cycle for empty boxes (only at the start of operations) - Transfer of materials from the material input box -Tools: Removal of Tyvec layer from tubes; removal of packaging material from stoppers / caps and piping; Optional: Automated process - Positioning of tools for automated equipment Processing in the filling unit - Remove waste -EM sampling (from start to finish)

[0116] Equipment: - Isolator box before VHP: Grade C / Grade A after VHP - VHP generator & detection system & safety alarm system for operators (technical area & cleanroom) - Equipment transport system - Gloves in a slightly shielded panel with lead glass - Glove integrity tester

[0117] Important notes: -Pre-cycle Grade C conditions, post-cycle Grade A conditions -IQ / OQ is provided by the equipment supplier. -Cycle development must be carried out by the equipment supplier (reduction to 1 part per million & aeration <1 ppm must be completed within approximately 120 minutes). -PQ (grading, medium packing, and VHP) is performed by the operator.

[0118] Work Description: Phase 1: Operation Part A - Intervention is generally not required (except to clearing malfunctions): The device is automatically deployed. -EM sampling (from start to finish)

[0119] Equipment: - See above

[0120] Important notes: - See above

[0121] Task Description: Phase 1: Completion of Operation Part A -End of operation (cleaning) or return to "Preparation A"

[0122] Equipment: - See above

[0123] Important notes: - See above

[0124] B => Grade A filling, VHP

[0125] Work Description: Phase 1: Preparation Part B - VHP cycle for empty boxes (only at the start of operations) - Transfer of material from the previous box - Installation of unpacked disposable tools (piping, needles, etc.) - Connections to the following for piping / needles / filters Feeding line, pump & needle holder - Install the N2 flushing needle. -EM sampling (from start to finish) -Filter integrity test (at startup; (Wetness caused by the product) -Note: The remaining bulk solution is Remains in the blending unit

[0126] Equipment: - Isolator box before VHP: Grade C / Grade A after VHP - VHP generator & detection system & safety alarm system for operators (technical area & cleanroom) - Gloves in plexi panels & access ports in shielded doors & telepliers / robot arm manipulators for intervention - Glove integrity tester

[0127] Important notes: - Grade C conditions before the cycle - Grade A conditions after the cycle -IQ / OQ is provided by the equipment supplier. -Cycle development must be carried out by the equipment supplier (reduction to 1 part per million & aeration <1 ppm must be completed in approximately 60-120 minutes). -PQ (grade, filter integrity test parameters, culture medium packing, and VHP) is performed by the operator.

[0128] Work Description: Phase 1: Operation Part B - Vial filling, stopper / cap - 2D code reading and filling parameters and linking - Intervention is generally not required (except to clearing malfunctions). -Product specific: Flushing with N2 -Optionally, fill the entire area with N2. -EM sampling (from start to finish)

[0129] Equipment: - See above (intervention via teleplier only) - An integrated balance-based filling and capping unit. Avoiding liquid dripping after filling is important. - Camera (2D code reading) - Oxygen detection system & safety alarm system for operators - LAF (mouth hole) to protect the outlet (additional valve / shuttle may need to be installed as needed)

[0130] Important notes: - See above -PQ (see above, accuracy of filling and closing) is performed by the operator.

[0131] Task Description: Phase 1: Completion of Operation Part B - Activate empty lines - Return to normal air (optional N2) - Disconnect the feeding line. - Move disposable equipment to the radioactive waste box. -End of operation (cleaning) or Return to "AABB" - Filter integrity test

[0132] Equipment: - Filter integrity tester

[0133] Important notes: - See above

[0134] CCIT inspection; if defective, hold (pre-labeled pot).

[0135] Task description: - Present the vial to the CCIT tester. - The unit is transferred from the CCIT tester. - Place the suspicious unit into pre-labeled lead pots labeled "Suspicious CCIT" (10 temporary storage vials) until the investigation is complete. - Document and return the complete vial to the line.

[0136] Equipment: -CCIT testing equipment will be proposed by the vendor: -VD (Pressure Damping Method) -ME (Mass Extraction Method) -10µm leakage detected - Pick and place unit for vial transport - Camera (2D code reading) (checks that it is unique at least within the batch) - Gloves inside the plexi panel & access port inside the shielding door - Pre-labeled lead pot - Ensure temperature stability / Avoid condensation after the filling process

[0137] Important notes: - Certification of testing equipment -IQ / OQ must be provided by the equipment supplier. -PQ (Equipment Qualification) is performed by the operator.

[0138] Dose measurement

[0139] Task description: - Present the vial to the dose calibrator. - If the results are as follows, provide feedback to the software (see below) and the operator: - Not meeting the target (x%) or - Deviation from expected value (bulk measurement & quantity) (y%) -(Parameters x and y can be input into the software) - The unit is transferred (regardless of its status).

[0140] Equipment: - Dosage calibrator for finished products - Identify non-compliant vials and classify them as defective. - Camera (2D code reading) - Gloves inside the plexi panel & access port inside the shielding door - Pick and place unit for vial transport

[0141] Important notes: -IQ / OQ must be provided by the equipment supplier. -PV (Process and Test Equipment Certification) is performed by the operator.

[0142] Visual inspection (VI)

[0143] Task description: - The vials are presented by machine against a black and white background. - Rotation speed and light intensity are adjustable. - Record the entire process on video. - The production department evaluates the entire process on screen, and the quality level (AQL) is evaluated by the quality department. - The unit is moved (unrelated to the visual inspection status). - All surveys will be conducted offline.

[0144] Equipment: - Camera for visual inspection - Camera for 2D code reading - Computer screen (remote) and pass / fail key (operator in the production department & quality department) - A data storage server and software to present the entire process to one or two operators (based on availability) and to present AQL samples to operators in the quality department. -(Please also refer to the slides on the visual inspection software.) - Gloves inside the plexi panel & access port inside the shielding door

[0145] Important notes: - Test conditions In accordance with the pharmacopoeia (Lighting / Time) - Software certification -IQ / OQ must be provided by the equipment supplier. -PV (process) and operator are performed by the operator.

[0146] (Optional) Headspace analysis

[0147] Task description: - Present the vial to the HSA tester. - The unit is transferred from the HSA tester.

[0148] Equipment: - HSA tester (specifications TBD) - Pick and place unit for vial transport - Camera (2D code reading) - Gloves inside the plexi panel & access port inside the shielding door

[0149] Important notes: - Certification of testing equipment -IQ / OQ must be provided by the equipment supplier. -PQ (Equipment Qualification) is performed by the operator.

[0150] Labeling and sealing vials and lead pots

[0151] Task description: - Identify the 2D code of the vial using a camera. -Note: The system must ensure that the correct version of the sign (country & revision number) is being used. - Print paper labels and attach them to the vials (mark defective vials with a note indicating this*). - Put the vial into a lead container. - Print paper labels and attach them to the lead containers. Seal the containers. (Mark defective lead pots accordingly*) - The operator will evaluate the lot-dependent information and marking ID codes at the fixed window location to ensure consistency. However, the variation in pre-printed color information is very large, and color printing within the line will likely be necessary. -Note: Vials that fail visual inspection may require relabeling later.

[0152] Equipment: -camera - Reading the 2D code on the vial - Version of pre-printed information (Country & Revision = Sign ID) - Confirm information that may vary by lot. -Seal - Photographs of labeling vials and lead pots as part of batch documentation Batch Document - 2 sign printers & applicators - Gloves inside the plexi panel & access port inside the shielding door

[0153] Important notes: - Certification of the labeling process -IQ / OQ must be provided by the equipment supplier. -PQ is performed by the operator.

[0154] If defective, it will be put on hold (pre-marked pot); finished product; VI; defective

[0155] Task description: - Lead pots are automatically sorted into the release line or defective line (based on fill volume, CCIT, dose, visual inspection, and headspace (optional)). - Up to 150 processed lead pots are collected outside the line. - In addition, units that fail visual inspection are manually sorted, scanned, and added to the "defective" vial units. They are labeled as defective and an additional label is attached (confirmed by scanning).

[0156] Equipment: - Camera for reading the labels on lead pots - Transport belt

[0157] Important notes: - Certification of the sorting process -IQ / OQ must be provided by the equipment supplier. -PQ is performed by the operator.

[0158] Temperature, relative humidity, pressure, and particle count monitoring system A general environmental monitoring system is installed and verified to ensure that the following conditions are being properly monitored: Temperature: 16~25℃ (61°F~77°F). Relative humidity: 28-70%RH. cooling capacity Differential pressure Number of non-viable particles The particle counter is used to monitor the Class A distribution and preparation isolators during production. In each pharmaceutical area, the pressure difference is monitored by a Digihelic pressure monitoring device.

[0159] Gas supply system: Compressed air and nitrogen The compressed air used to pressurize gaskets in the production / isolator line is produced by AtlasSF8+ and AtlasSF15+ compressed air generators, which collect compressed air in a vertical air receiver located in the air compressor room. The compressed air passes through a PTFE(P)-SRF filter and leads to the production line, sterility testing laboratory, QC laboratory, and technical operation room. Nitrogen is supplied to parts of the facility from compressed nitrogen gas cylinders connected to a distribution manifold in the packaging room. The manifold supplies nitrogen to production lines 1-4 and the QC testing room, passing the gas through a PTFE(P)-SRF filter. The manifold has the capacity to accommodate up to four cylinders, which are regulated by the manifold itself. An additional single cylinder supplies nitrogen to production lines 5-6 and the technical operations room, passing the gas through a PTFE(P)-SRF filter. The distribution lines are made of stainless steel and distribute the gas by opening and closing valves.

Claims

1. A method for producing packaged radiopharmaceuticals (e.g., radioligand pharmaceuticals), (1) To obtain a radiopharmaceutical, a step of synthesizing and compounding a radiopharmaceutical active pharmaceutical ingredient solution in one or more shielding units of Grade C (cleanliness zoning requirement), (2) A step of providing the primary packaging material by, for example, unpacking the (outer layer) in one or more cold units of grade C, sterilizing it in one or more cold units of grade B, and unpacking the (inner layer) the packaging material in one or more cold units of grade A, (3) To obtain a primary packaged radiopharmaceutical, the process includes filling the primary packaging material provided and unpacked in step (2) in a Grade A shielding unit with the radiopharmaceutical active pharmaceutical ingredient solution obtained in step (1), (4) A step of inspecting the primary packaged radiopharmaceutical obtained in step (3) in one or more shielding units of grade "Controlled, Unclassified" (CNC), (5) A method comprising the steps of: (5) to optionally obtain a primary and secondary packaged radiopharmaceutical; the primary packaged radiopharmaceutical inspected in step (4); and (6) to place the primary packaged radiopharmaceutical in a secondary packaging material shielded in one or more Grade CNC shielding units.

2. A method for producing a packaged radiopharmaceutical according to claim 1, wherein in step (4), a container closure integrity test (CCIT) of the primary packaged radiopharmaceutical is performed as one of the first inspection steps, preferably the CCIT is performed using the primary packaged radiopharmaceutical present in an (additional) container, the container enabling capture / isolation of the pharmaceutical in the container if any leakage is detected or there is a risk of leakage.

3. A method for producing a packaged radiopharmaceutical according to claim 1 or 2, wherein in step (4), a camera-assisted visual inspection (VI) is performed in the form of a video recording, preferably the video recording is then evaluated by the naked eye.

4. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 3, wherein in step (1), the synthesis step is carried out several times, preferably up to four times, preferably the synthesis step is carried out in parallel in several synthesis units, and the resulting synthetic radiopharmaceutical active pharmaceutical ingredient solution is then collected in a combined (bulk) quantity for formulation.

5. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 4, wherein in step (1), the synthesis step is carried out in a cassette-type synthesis unit, preferably the cassette-type manufacturing synthesizer unit is provided by, for example, Trasis, preferably the MiniAIO described in, for example, International Publication No. 2020 / 089379A1, and preferably two dual synthesis units by Trasis are used.

6. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 5, wherein in step (1), the compounding step is: (i) A sub-step in which the synthesized solution is filled into a container, for example, a (bulk) vial or bottle, in order to obtain a (concentrated) mother liquor, (ii) A sub-step in which the radioactivity of the (concentrated) mother liquor is optionally measured, (iii) Optionally, a sub-step of transferring the (concentrated) mother liquor to another container, preferably a flexible plastic bag, (iv) A sub-step of adding a certain amount of dilution solution to obtain the active pharmaceutical ingredient solution with a desired radioactivity concentration, (v) A method comprising a sub-step of mixing the solution resulting from step (iv) by appropriately moving the flexible plastic bag as appropriate, in order to obtain a uniform diluted active pharmaceutical ingredient solution for filling.

7. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 6, wherein in step (2), the packaged primary packaging material is (biologically) decontaminated / sterilized, preferably with vaporized hydrogen peroxide (VHP), before being transferred from a Grade B unit to a Grade A unit.

8. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 7, wherein step (4) is an inspection step, the following sub-steps: (i) CCIT and, (ii) Radioactivity measurement / calibration and (iii) Visual inspection and, (iv) Optionally, headspace analysis and A method comprising, preferably, the above order.

9. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 8, wherein the primary packaging material comprises a glass vial and an all-plastic push-on cap, and a rubber stopper is pre-assembled within the cap, for example, a RayDyLyo cap by ARaymond.

10. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 9, wherein the shielded secondary packaging material comprises a lead pot having a corresponding lid, preferably with tamper-evident measures, preferably the lead pot and its lid are free from paint coatings, preferably the lead pot and its lid are plastic coated, and preferably a rubber ring is present between the pot and the lid to seal it to prevent leakage.

11. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 10, wherein the container for containing the active pharmaceutical ingredient and the piping connecting the container are provided with a protective gas / inert gas, for example nitrogen (N ２ A method of flushing using argon (Ar) and / or argon (Ar).

12. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 11, wherein the solution involved in the method is an overpressure protection gas / inert gas, for example nitrogen (N ２ A method comprising transferring a gas from one container to another via piping by adding a protective gas / inert gas (AR) and / or argon (Ar), wherein, preferably, the piping is tested for flow and leakage prior to the transfer, for example by a pressure test using the protective gas / inert gas.

13. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 12, wherein the solution used in the method is a protective gas / inert gas, for example nitrogen (N ２ A method of purging and / or flushing with argon (Ar).

14. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 13, wherein at least steps (1) to (3) are automated, and preferably steps (4) and (5) are also automated except for the visual evaluation of the video recording in step (4).

15. A method for producing a packaged radiopharmaceutical according to any one of claims 1 to 14, wherein the product is produced on a scale of at least 30 Ci, preferably at least 32 Ci, more preferably 35 Ci, and even more preferably at least 40 Ci.

16. A packaged radiopharmaceutical obtained (and / or can be obtained) by the method described in any one of claims 1 to 15.

17. A manufacturing unit (for example, in the form of an (automated) process line) comprising technical equipment and facilities for producing a radiopharmaceutical packaged according to the method of any one of claims 1 to 16.

18. Use of the manufacturing unit according to claim 17 for producing the aforementioned packaged radiopharmaceutical.

19. A method for treating cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of the radiopharmaceutical contained in the packaged radiopharmaceutical described in claim 16.

20. A radiopharmaceutical contained in a packaged radiopharmaceutical according to claim 16, for use in the treatment of cancer.

21. Use of the radiopharmaceutical contained in a packaged radiopharmaceutical according to claim 16 for the preparation of a pharmaceutical for the treatment of cancer.

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