Method for synthesizing radionuclide complexes

Abstract

The present disclosure relates to the synthesis of radionuclide complex solutions, in particular, their use in the commercial production of radiopharmaceutical substances for diagnostic and / or therapeutic purposes. In particular, the synthesis method comprises the following steps in the following order: a. providing a radionuclide precursor solution to a first vial, b. transferring the radionuclide precursor solution to a reactor, c. providing a reaction buffer to the first vial containing residual radionuclide precursor solution, d. transferring the reaction buffer and residual radionuclide precursor solution from the first vial to the reactor, e. transferring a solution containing the somatostatin receptor binding peptide linked to a chelator to the reactor, f. reacting the somatostatin receptor binding peptide linked to a chelator with the radionuclide in the reactor to obtain the radionuclide complex, and g. recovering the radionuclide complex.

Description

Technical Field

[0001] The present invention relates to synthetic radionuclide complex solutions and in particular to their use in the commercial production of radiopharmaceutical substances for diagnostic and / or therapeutic purposes. Background Art

[0002] The concept of targeted drug delivery is based on the overexpression of cell receptors in target cells compared to non-targeted cells. If a drug has binding sites for those overexpressed cell receptors, it allows the drug to be delivered to those target cells at high concentrations after its systemic administration, while leaving other cells of no interest unaffected. For example, if tumor cells are characterized by overexpression of a specific cell receptor, a drug with binding affinity for said receptor will accumulate in tumor tissue at high concentrations after intravenous infusion, while leaving normal tissues unaffected.

[0003] This targeted drug delivery concept has also been used in radiomedicine to selectively deliver radionuclides to target cells for diagnostic or therapeutic purposes. For such radiomedicine applications, the target cell receptor binding moiety is typically connected to a chelating agent that can form a strong complex with the metal ion of the radionuclide. Then, this radionuclide complex is delivered to the target cell, and the subsequent decay of the radionuclide releases high-energy electrons, positrons or alpha particles and gamma rays at the target site.

[0004] Such radiopharmaceutical substances are preferably produced in a shielded closed system; the preparation, purification and formulation process of the drug substance is part of a continuous process. In practice, the decay of the radionuclide does not allow sufficient time for any interruption. Therefore, preferably no testing is performed at critical steps and no synthetic intermediates are isolated and controlled during the production process.

[0005] Therefore, it is desirable to provide an automated synthesis method for producing such radionuclide complexes. Ideally, an automated synthesis method for producing radionuclide complexes as radiopharmaceutical substances may also have the following advantages:

[0006] - high labeling yields associated with high radiochemical purity,

[0007] - High labeling yields with minimal levels of free (uncomplexed) radionuclides,

[0008] -Mass production of large quantities of doses. SUMMARY OF THE INVENTION

[0010] The present invention relates to a method for synthesizing a radionuclide complex formed by a radionuclide and a somatostatin receptor binding peptide linked to a chelator, characterized in that the method comprises the following steps in the following order:

[0011] a) providing a radionuclide precursor solution into a first vial,

[0012] b) transferring the radionuclide precursor solution into a reactor,

[0013] c) providing a reaction buffer to said first vial containing residual radionuclide precursor solution,

[0014] d) transferring the reaction buffer and the remaining radionuclide precursor solution from the first vial to the reactor,

[0015] e) transferring the solution comprising the somatostatin receptor binding peptide linked to the chelator into the reactor,

[0016] f) reacting the somatostatin receptor binding peptide linked to a chelator with the radionuclide in the reactor to obtain the radionuclide complex, and,

[0017] g) recovering the radionuclide complex.

[0018] The present disclosure also relates to an aqueous pharmaceutical solution comprising a radionuclide complex, which solution can be obtained by the method described herein or directly obtained by the method described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 and Figure 2 The main steps of the preparation processes described in the examples are shown.

[0020] Figure 3A and 3B The arrangement of the cassettes used in the manufacturing process before and after modification is shown.

[0021] Figure 4A : Final box installation for use in the TRACERlab MX synthesis module.

[0022] Figure 4B : Final box installation for use in the Trasis synthesis module. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present disclosure relates to the synthesis of a radionuclide complex formed of a radionuclide and a somatostatin receptor binding peptide linked to a chelator, the method comprising:

[0025] a) providing radionuclide precursors,

[0026] b) providing a somatostatin receptor binding peptide linked to a chelator,

[0027] c) providing a reaction buffer,

[0028] d) mixing the radionuclide precursor and the somatostatin receptor binding peptide linked to the chelator with the reaction buffer in a reactor,

[0029] e) reacting the somatostatin receptor binding peptide linked to the chelator with the radionuclide in a reactor to obtain a radionuclide complex,

[0030] f) recovering the radionuclide complex.

[0031] Such radionuclide complexes are preferably radiopharmaceutical substances for use in nuclear medicine as diagnostic or therapeutic agents.

[0032] The method of the present disclosure is advantageously suitable for automation. Therefore, in a preferred embodiment, the method of the present disclosure is an automated synthesis method. The term "automated synthesis" refers to a chemical synthesis performed without human intervention. Advantageously, the synthesis according to the method of the present disclosure can provide a radionuclide complex drug with a specific activity exceeding 45 GBq in a final batch volume of 13-24 mL, i.e., a specific activity concentration greater than 1875 MBq / mL, such as 1875-3500 MBq / mL. For example, considering a single dose of 177 Lu-DOTATOC or 177 Lu-DOTATATE will typically contain between 4-5 GBq (e.g., about 4.7 GBq), and the present method can provide radionuclide complexes (e.g., 177 Lu-DOTATOC or 177 The invention relates to a mother solution of a concentrate of Lu-DOTATATE) to obtain at least 5, preferably at least 6, 7, 8, 9, 10 or more single doses of the drug product after dilution and formulation of the mother solution.

[0033] The synthetic method can also advantageously provide a synthetic yield exceeding 60%.

[0034] definition

[0035] As used herein, the term "radionuclide precursor solution" refers to a solution containing a radionuclide used as a starting material. The method of the present disclosure is particularly suitable for the use of radionuclides of metallic nature and can be used in medicine for diagnostic and / or therapeutic purposes. Such radionuclides include, but are not limited to, radioisotopes of In, Tc, Ga, Cu, Zr, Y and Lu, in particular: 111 In, 99m Tc, 68 Ga, 64 Cu, 89 Zr, 90 Y. 177Lu. The metal ions of this radioisotope are capable of forming non-covalent bonds with the functional groups of the chelating agent (eg, amines or carborboxylic acids).

[0036] In a preferred embodiment, the radionuclide precursor solution comprises Lutetium-177 ( 177 Lu). For example, the radionuclide precursor solution contains 177 In a particular embodiment, the radionuclide precursor solution is 177 LuCl3 in HCl solution, with a specific activity concentration higher than 40 GBq / mL.

[0037] Typically, a batch of 177 Lu-DOTATOC or 177 Lu-DOTATATE stock solution 177 The Lu chloride solution may have a specific activity of 74 GBq or 148 GBq (±20%).

[0038] As used herein, the term "somatostatin receptor binding peptide" refers to a peptide portion having a specific binding affinity to a somatostatin receptor. Such a somatostatin receptor binding peptide can be selected from octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate.

[0039] As used herein, the term "chelating agent" refers to an organic moiety comprising a functional group that is capable of forming a non-covalent bond with a radionuclide in the reaction step of the method, thereby forming a stable radionuclide complex. In the context of the present invention, the chelating agent may be 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or a mixture thereof, preferably DOTA.

[0040] This chelator is directly linked to the somatostatin receptor binding peptide, or linked through a linker molecule, preferably directly linked. The linking bond is a covalent bond or a non-covalent bond between the cell receptor binding organic part (and the linker) and the chelator, preferably, the bond is covalent.

[0041] According to a preferred embodiment of the synthesis method disclosed herein, the somatostatin receptor binding peptide linked to the chelator is selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

[0042] Particularly preferred embodiments encompass 177 Lu-DOTA-TOC( 177 Lu-edotreotide) or 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide), preferably 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide) synthesis method. 177 Lu-DOTA-TOC( 177 Lu-edotreotide) or 177 Lu-DOTA-TATE( 177 In an embodiment of Lu-oxodotreotide, the radionuclide precursor solution comprises 177 LuCl3 in HCl solution, and the peptide solution contained DOTA-TOC or DOTA-TATE, respectively.

[0043] For example, a DOTA-TATE or DOTA-TOC peptide solution is an aqueous solution containing 0.8 mg / mL-1.2 mg / mL of DOTA-TATE or DOTA-TOC (e.g., 1 mg / mL). Before starting the synthesis method, the peptide solution can be obtained by dissolving the dry powder of the peptide salt in sterile water. Typically, a peptide solution for a batch may contain 2 or 4 mg (± 5%) of DOTA-TATE or DOTA-TOC.

[0044] As used herein, the reaction buffer is an aqueous solution, preferably comprising at least a stabilizer against radiation degradation and a buffer having a pH of 4.0-6.0, preferably 4.5-5.5.

[0045] As used herein, the term "stabilizer against radiation degradation" refers to a stabilizer that protects organic molecules from radiation degradation, for example, when the gamma rays emitted by the radionuclide break the bonds between the atoms of the organic molecule and form free radicals, these free radicals are subsequently scavenged by the stabilizer, which prevents the free radicals from undergoing any other chemical reactions that may result in undesirable, potentially ineffective or even toxic molecules. Therefore, these stabilizers are also called "free radical scavengers" or simply "free radical scavengers". Other alternative terms for these stabilizers are "radiation stability enhancers", "radiation stabilizers" or simply "quenchers".

[0046] The stabilizer present in the reaction buffer may be selected from gentisic acid (2,5-dihydroxybenzoic acid) or a salt thereof, ascorbic acid (L-ascorbic acid, vitamin C) or a salt thereof (e.g. sodium ascorbate), methionine, histidine, melatonin, ethanol and selenomethionine, preferably selected from gentisic acid or a salt thereof. In a particular embodiment, the reaction buffer does not contain ascorbic acid, preferably it contains gentisic acid instead of ascorbic acid as a stabilizer.

[0047] "Buffer having a pH of 4.0-6.0, preferably 4.5-5.5" can be an acetate buffer, a citrate buffer (e.g., citrate + HCl or citric acid + disodium hydrogen phosphate) or a phosphate buffer (e.g., sodium dihydrogen phosphate + disodium hydrogen phosphate), preferably the buffer is an acetate buffer, preferably, the acetate buffer consists of acetic acid and sodium acetate.

[0048] For example, the reaction buffer is an aqueous solution containing 35-45 mg / mL gentisic acid, such as 39 mg / mL gentisic acid, in acetate buffer. Before starting the synthesis method, the reaction buffer can be obtained by dissolving the dry powder (lyophilisate) of gentisic acid in acetate buffer in sterile water. Typically, for a batch of synthesis, 177 Lu-DOTA-TOC( 177 Lu-edotreotide) or 177 Lu-DOTA-TATE( 177 The reaction buffer for the stock solution of Lu-oxodotreotide can contain 157 mg or 314 mg (±5%) gentisic acid as the only stabilizer.

[0049] Mixing and reaction steps of the synthetic method

[0050] The synthesis of the radionuclide complex was started after mixing the three solutions in the reactor vial:

[0051] - radionuclide precursor solutions, such as Lu-177 chloride solutions,

[0052] - a reaction buffer, for example a solution comprising gentisic acid,

[0053] - A peptide solution, for example a solution comprising DOTA-TOC or DOTA-TATE, preferably DOTA-TATE.

[0054] According to a preferred embodiment of the synthesis method, the above three solutions are transferred to the reactor vial in the following order:

[0055] 1) Radionuclide precursor solution, such as Lu-177 chloride solution,

[0056] 2) a reaction buffer, such as a solution containing gentisic acid, and,

[0057] 3) A peptide solution, for example a solution comprising DOTA-TOC or DOTA-TATE, preferably DOTA-TATE.

[0058] In particular, according to an advantageous aspect of this preferred embodiment, the reaction buffer is mixed with the radionuclide precursor solution, which is then mixed with the peptide solution.

[0059] More specifically, the inventors have noticed that incomplete transfer of high concentration radionuclide precursor solutions has a substantial impact on labeling yield and synthesis yield. Therefore, in a more preferred embodiment, the synthesis method comprises the following steps in the following order:

[0060] a. providing a radionuclide precursor solution to a first vial,

[0061] b. transferring the radionuclide precursor solution to a reactor,

[0062] c. providing a reaction buffer to said first vial containing the residual radionuclide precursor solution,

[0063] d. transferring the reaction buffer and the remaining radionuclide precursor solution from the first vial to the reactor,

[0064] e. transferring the solution comprising the somatostatin receptor binding peptide linked to the chelator to the reactor,

[0065] f. reacting the somatostatin receptor binding peptide linked to a chelator with the radionuclide in the reactor to obtain the radionuclide complex,

[0066] g. Recovering the radionuclide complex.

[0067] According to the above scheme, the reaction buffer is advantageously used to rinse the vial containing the radionuclide precursor solution and ensure complete (or nearly complete) transfer of the radionuclide precursor solution in the reactor, while maintaining a relatively high specific activity concentration at the labeling time. 177Lu-DOTA-TOC( 177 Lu-edotreotide) or 177 Lu-DOTA-TATE( 177 In a specific embodiment of Lu-oxodotreotide, the radionuclide precursor solution is 177 LuCl3 chloride solution, wherein the specific activity at the reaction time is at least 370 GBq / mg, preferably 370 GBq / mg to 1110 GBq / mg.

[0068] The reaction step of the synthesis method includes chelation of a radionuclide (e.g., lutetium-177) with a chelating agent (e.g., DOTA for DOTA-TOC or DOTA-TATE). The inventors have also shown that a molar excess of peptide relative to the radionuclide is preferred to ensure an acceptable radiochemical labeling yield. Therefore, in another specific embodiment, the molar ratio between the somatostatin receptor binding peptide linked to the chelating agent (e.g., DOTA-TOC or DOTA-TATE) and the radionuclide (e.g., lutetium-177) in the reaction step is at least 1.2, preferably 1.5-3.5.

[0069] Advantageously, in certain preferred embodiments of the synthetic method disclosed herein, the synthetic method does not include any purification step to remove free (non-chelated) lutetium-177, such as a tC18 solid phase extraction (SPE) purification step. Using a tC18 column to perform a solid phase extraction (SPE) purification step to remove free (non-chelated) lutetium-177 has some disadvantages. In particular, the use of this column may require elution of the product with ethanol, which is undesirable (A.Mathur et al., Cancer Biother. Radiopharm. 2017, 32, 266-273). Using a tC18 column can also remove stabilizers, which then need to be added again (S.Maus et al. Int. J. Diagnostic imagin 2014, 1, 5-12).

[0070] In certain embodiments, particularly for 177 Lu-DOTA-TOC( 177 Lu-edotreotide) or 177 Lu-DOTA-TATE( 177 The reaction step can be advantageously carried out at a pH of 4.5-5.5.

[0071] In a specific embodiment, the reaction step has a reaction time of 2-15 minutes, typically 5 or 12 minutes, and / or a temperature of 80-100°C, preferably 90-95°C.

[0072] The method may further comprise at least one or more flushing steps to optimize the recovery of the radionuclide complexes formed during the reaction step. Typically, one or more volumes of water are added to the reactor and recovered in a final volume comprising the radionuclide complexes.

[0073] Preferably, the volume of the mixture for the reaction step is 4-12 mL and the final volume containing the radionuclide complex after the recovery step (thus including the volume of water used for the washing step) is 13-24 mL.

[0074] synthesis 177 Lu-DOTA-TATE( 177 Specific embodiment of Lu-oxodotreotide) mother solution

[0075] The synthetic method disclosed herein can be advantageously used to synthesize 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide), in particular for use in the preparation of ready-to-use 177 Stock solution of Lu-DOTA-TATE infusion solution.

[0076] As used herein, the term "stock solution" refers to a solution used to prepare the final drug product by dilution in a formulation buffer. The stock solution advantageously enables the preparation of at least 5 therapeutic doses. 177 Lu-DOTA-TATE. For example, the therapeutic dose for the treatment of somatostatin receptor-positive gastrointestinal pancreatic neuroendocrine tumors 177 Lu-DOTA-TATE comprised 7,400 MBq of total radioactivity at the date and time of infusion in a final adjusted volume of typically 20.5 mL-25.0 mL.

[0077] In the synthesis 177 In a specific embodiment of the mother solution of Lu-DOTA-TATE, the synthesis method comprises the following steps in the following order:

[0078] a. providing a radionuclide precursor solution to a first vial,

[0079] b. transferring the radionuclide precursor solution to a reactor,

[0080] c. providing a reaction buffer to said first vial containing the residual radionuclide precursor solution,

[0081] d. transferring the reaction buffer and the remaining radionuclide precursor solution from the first vial to the reactor,

[0082] e. transferring the solution comprising the somatostatin receptor binding peptide linked to the chelator to the reactor,

[0083] f. reacting the somatostatin receptor binding peptide linked to the chelator with the radionuclide in the reactor to obtain the radionuclide complex,

[0084] g. Recovering the radionuclide complex.

[0085] And use the following solution:

[0086] (i) The radionuclide precursor solution is 74 GBq ± 20% in a volume of 1-2 mL, typically 1.5 mL. 177 LuCl3 solution,

[0087] (ii) the solution comprising a somatostatin receptor binding peptide linked to a chelator is a solution comprising 2 mg ± 5% DOTA-TATE in a volume of 1.5-2.5 mL, typically 2 mL,

[0088] (iii) the reaction buffer contains 157 mg ± 5% gentisic acid in a volume of 1.5-2.5 mL, typically 2 mL,

[0089] And the pH value of the reaction step is 4.5-5.5.

[0090] Advantageously, according to the above method, the radionuclide complex recovered in step g can be an aqueous concentrated mother solution containing a specific activity at least equal to 45.0 GBq in a final volume of 13-24 mL. 177 Lu-DOTA-TATE.

[0091] In synthesis 177 In another specific embodiment of the mother solution of Lu-DOTA-TATE, the synthesis method comprises the following steps in the following order:

[0092] a. providing a radionuclide precursor solution to a first vial,

[0093] b. transferring the radionuclide precursor solution to a reactor,

[0094] c. providing a reaction buffer to said first vial containing the residual radionuclide precursor solution,

[0095] d. transferring the reaction buffer and the remaining radionuclide precursor solution from the first vial to the reactor,

[0096] e. transferring the solution comprising the somatostatin receptor binding peptide linked to the chelator to the reactor,

[0097] f. reacting the somatostatin receptor binding peptide linked to the chelator with the radionuclide in the reactor to obtain the radionuclide complex,

[0098] g. Recovering the radionuclide complex.

[0099] And use the following solution:

[0100] (i) The radionuclide precursor solution is 148 GBq ± 20% in a volume of 2-3 mL, typically 2.5 mL. 177 LuCl3,

[0101] (ii) the solution comprising a somatostatin receptor binding peptide linked to a chelator is a solution comprising 4 mg ± 5% DOTA-TATE in a volume of 3.5-4.5 mL, typically 4 mL,

[0102] (iii) the reaction buffer contains 314 mg ± 5% gentisic acid in a volume of 3.5-5.5 mL, typically 4 mL,

[0103] And the pH value of the reaction step is 4.5-5.5.

[0104] Advantageously, according to the above method, the radionuclide complex recovered in step g can be an aqueous concentrated mother solution containing a specific activity at least equal to 59.0 GBq in a final volume of 19-24 mL. 177 Lu-DOTA-TATE.

[0105] The specific method described above allows synthesis yields higher than 60%.

[0106] Synthesis module with disposable kits

[0107] The above-described synthesis methods can advantageously be automated and performed in a synthesis module with disposable reagent kits.

[0108] For example, a disposable test kit is mounted on the front of a synthesis module containing a fluid path (tube), a reactor vial, and a sealed reagent vial. The disposable box assembly is made of specially selected materials to be compatible with the reagents used in the process. In particular, these assemblies are designed to minimize potential leaching from surfaces in contact with the process fluid while maintaining the mechanical properties and integrity of the box.

[0109] Preferably, the synthesis method is fully automated and the synthesis is performed within a computer-assisted system.

[0110] A typical kit may include

[0111] (1) reaction vial (reactor),

[0112] (2) Connectors for inflow and outflow of fluids,

[0113] (3) a spike for connecting a reagent vial, and,

[0114] (4) Optional solid phase column.

[0115] A skilled artisan can adapt commercially available kits for preparing radiopharmaceuticals, such as F-18 labeled radiopharmaceuticals.

[0116] In certain embodiments, the synthesis modules and kits include the following:

[0117] (i) at a first location, positioning a needle to be inserted into the top of said first vial containing a radioactive precursor solution,

[0118] (ii) at a second location, positioning a needle to be inserted into the top of a vial containing the solution comprising a somatostatin receptor binding peptide linked to a chelator,

[0119] (iii) at a third location, a bag with water for injection is installed to perform a flushing step,

[0120] (iv) at the fourth position, installing a reaction buffer, and,

[0121] (v) At a fifth location, an extension cable is installed to transfer the radionuclide complex from the synthesis module to a distribution isolator.

[0122] Specific examples of synthesis modules and kits are described in the Examples.

[0123] The present disclosure also relates to a kit for carrying out the method defined above, comprising:

[0124] (i) a first container comprising a reaction buffer or a lyophilisate of the reaction buffer,

[0125] (ii) a second container comprising a peptide solution or a lyophilisate of a peptide solution, wherein the peptide solution comprises the somatostatin receptor binding peptide linked to a chelator, preferably DOTA-TATE or DOTA-TOC, and

[0126] (iii) a third container comprising the radionuclide precursor solution, preferably a lutetium-177 chloride solution.

[0127] Preparation of radionuclide complexes as pharmaceutical products

[0128] A skilled person will be able to prepare the radionuclide complexes as pharmaceutical products using the synthetic methods described above.

[0129] In certain embodiments of the synthesis method, the synthesis method further comprises the step of diluting the radionuclide complex recovered from the above synthesis method (typically as a concentrated stock solution) in a formulation buffer.

[0130] As used herein, the term "formulation buffer" refers to a solution used to obtain a "ready-to-use" aqueous pharmaceutical solution. For example, 177 Lu-DOTA-TATE or 177 The Lu-DOTA-TOC formulation buffer is used to obtain an infusion 177 Lu-DOTA-TATE or 177 A solution of Lu-DOTA-TOC, preferably an aqueous solution with a specific activity concentration of 370 MBq / mL (±5%). The formulation buffer may contain one or more excipients selected from the following: a chelating agent (e.g., diethylenetriaminepentaacetic acid=valeric acid=DTPA), a radiation stabilizer (e.g., ascorbic acid), and a pH adjuster (e.g., NaOH).

[0131] Aqueous drug solutions obtained by synthetic methods

[0132] The present disclosure also relates to an aqueous pharmaceutical solution obtainable by or obtained by the above-mentioned synthesis method of the present disclosure.

[0133] In a specific embodiment, the aqueous pharmaceutical solution obtainable by the above-mentioned synthesis method or obtained by the above-mentioned synthesis method is 177 Lu-DOTA-TATE or 177 The mother solution of Lu-DOTA-TOC preferably has a specific activity concentration higher than 1875 MBq / mL, typically 1875-3400 MBq / mL.

[0134] In other embodiments, it further comprises a formulation step, for example, as described in the previous paragraph, the aqueous pharmaceutical solution obtained by the above synthesis method or obtained by the above synthesis method is for infusion 177 Lu-DOTA-TATE or 177 The Lu-DOTA-TOC solution preferably has a specific activity concentration of 370 MBq / mL (±5%). DETAILED DESCRIPTION

[0135] 1. A method for synthesizing a radionuclide complex formed by a radionuclide and a somatostatin receptor binding peptide linked to a chelating agent, characterized in that the method comprises the following steps in the following order:

[0136] a) providing a radionuclide precursor solution into a first vial,

[0137] b) transferring the radionuclide precursor solution into a reactor,

[0138] c) providing a reaction buffer to said first vial containing residual radionuclide precursor solution,

[0139] d) transferring the reaction buffer and the remaining radionuclide precursor solution from the first vial to the reactor,

[0140] e) transferring the solution comprising the somatostatin receptor binding peptide linked to the chelator into the reactor,

[0141] f) reacting the somatostatin receptor binding peptide linked to the chelator with the radionuclide in the reactor to obtain the radionuclide complex,

[0142] g) recovering the radionuclide complex.

[0143] 2. The method according to embodiment 1, wherein the chelating agent is selected from the group consisting of DOTA, DTPA, NTA, EDTA, DO3A, NOC and NOTA, preferably DOTA.

[0144] 3. The method according to embodiment 1 or 2, wherein the somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably from octreotide and octreotate.

[0145] 4. A method according to any one of embodiments 1 to 3, wherein the somatostatin receptor binding peptide linked to the chelator is selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

[0146] 5. The method according to any one of embodiments 1-4, wherein the radionuclide complex is 177 Lu-DOTA-TOC( 177 Lu-edotreotide) or 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide), preferably 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide).

[0147] 6. The method according to embodiment 5, wherein the radionuclide precursor solution is 177LuCl3 chloride solution, wherein the specific activity of the reaction step is at least 407 GBq / mg, preferably 407 GBq / mg-1110 GBq / mg.

[0148] 7. The method according to any one of embodiments 1 to 6, wherein the molar ratio between the somatostatin receptor binding peptide linked to the chelator and the radionuclide of the reaction step f) is at least 1.2, preferably 1.5-3.5.

[0149] 8. The method according to any one of embodiments 1 to 7, wherein the reaction buffer comprises at least a stabilizer against radiation degradation, preferably selected from gentisic acid.

[0150] 9. The method according to any one of embodiments 1-8, wherein the reaction buffer comprises sodium acetate.

[0151] 10. The method according to any one of embodiments 1 to 9, wherein the reacting step f is carried out at a pH of 4.5 to 5.5.

[0152] 11. The method according to any one of embodiments 1-10, wherein the reaction buffer does not contain ascorbic acid.

[0153] 12. The method according to any one of embodiments 1-11, wherein the reaction time of the labeling step f is 2-15 minutes, typically 5 or 12 minutes, and the temperature is 80-100°C, preferably 90-95°C.

[0154] 13. The method according to any one of embodiments 1-12, further comprising at least one or more flushing steps for effectively recovering the radionuclide complex.

[0155] 14. The method according to any one of embodiments 1-13, wherein the volume of the mixture in the reaction step is 4-12 mL, and the final volume containing the radionuclide complex after the recovery step is 13-24 mL.

[0156] 15. The method according to any one of embodiments 1 to 14, wherein

[0157] (i) The radionuclide precursor solution is 74 GBq ± 20% in a volume of 1-2 mL, typically 1.5 mL. 177 LuCl3 solution,

[0158] (ii) the solution comprising a somatostatin receptor binding peptide linked to a chelator is a solution comprising 2 mg ± 5% DOTA-TATE in a volume of 1.5-2.5 mL, typically 2 mL,

[0159] (iii) the reaction buffer contains 157 mg ± 5% gentisic acid in a volume of 1.5-2.5 mL, typically 2 mL,

[0160] And the pH value of the reaction step is 4.5-5.5.

[0161] 16. The method according to any one of embodiments 1 to 14, wherein

[0162] (i) The radionuclide precursor solution is 148 GBq ± 20% in a volume of 2-3 mL, typically 2.5 mL. 177 LuCl3,

[0163] (ii) the solution comprising a somatostatin receptor binding peptide linked to a chelator is a solution comprising 4 mg ± 5% DOTA-TATE in a volume of 3.5-4.5 mL, typically 4 mL,

[0164] (iii) the reaction buffer contains 314 mg ± 5% gentisic acid in a volume of 3.5-5.5 mL, typically 4 mL,

[0165] And the pH value of the reaction step is 4.5-5.5.

[0166] 17. The process according to any one of embodiments 1 to 16, wherein the synthesis yield is at least 60%.

[0167] 18. The method according to any one of embodiments 1 to 17, wherein the radionuclide complex recovered in step g is an aqueous concentrated mother liquor comprising a specific activity of at least 45.0 GBq 177 Lu-DOTA-TATE.

[0168] 19. The method according to any one of embodiments 1 to 18, wherein the radionuclide complex recovered in step g is an aqueous concentrated mother liquor comprising a specific activity of at least 59.0 GBq 177 Lu-DOTA-TATE.

[0169] 20. The method according to any one of embodiments 1-19, which is automated and performed in a synthesis module with disposable reagent kits.

[0170] 21. The method according to embodiment 20, wherein the synthesis module comprises:

[0171] a) a disposable kit comprising the required fluid pathways, and,

[0172] b) A disposable kit comprising reagents for carrying out the synthetic method.

[0173] 22. The method according to any one of embodiments 1-21, wherein the synthesis is performed within a computer-assisted system.

[0174] 23. The method according to any one of embodiments 20-22, wherein the synthesis module and the kit comprise the following:

[0175] a) at a first location, positioning a needle to be inserted into the top of said first vial containing a radioactive precursor solution,

[0176] b) at a second location, positioning a needle to be inserted into the top of a vial containing the solution comprising a somatostatin receptor binding peptide linked to a chelating agent,

[0177] c) in a third position, a bag with water for injection is installed to perform a flushing step,

[0178] d) at the fourth position, installing a reaction buffer, and,

[0179] e) At a fifth location, an extension cable is installed to transfer the radionuclide complex from the synthesis module to a distribution isolator.

[0180] 24. The method according to any one of embodiments 1 to 23, further comprising the following steps:

[0181] h. Dilute the radionuclide complex in formulation buffer.

[0182] 25. The method according to embodiment 24, wherein the radionuclide complex is 177 Lu-DOTA-TATE or 177 Lu-DOTA-TOC.

[0183] 26. The method according to embodiment 24, wherein the formulation buffer is a solution for infusion.

[0184] 27. A method according to any one of embodiments 1-26, wherein the method does not comprise any purification step to remove free (non-chelated) radionuclides, preferably, the method does not comprise a tC18 solid phase extraction (SPE) purification step.

[0185] 28. An aqueous pharmaceutical solution comprising a radionuclide complex, said solution being obtainable by the method of any one of embodiments 1-27 or directly obtainable by the method of any one of embodiments 1-27.

[0186] 29. The solution according to embodiment 28, which is 177 Lu-DOTA-TATE or 177 Mother solution of Lu-DOTA-TOC.

[0187] 30. The solution according to embodiment 29, which has a specific activity concentration higher than 1875 MBq / mL, for example 1875-3400 MBq / mL. 177 Lu-DOTA-TATE or 177 Mother solution of Lu-DOTA-TOC.

[0188] 31. The solution according to embodiment 28, which is for infusion 177 Lu-DOTA-TATE or 177 Solution of Lu-DOTA-TOC.

[0189] 32. A solution according to embodiment 28, which is for infusion of 370 MBq / mL ± 5% 177 Solution of Lu-DOTA-TATE.

[0190] 33. A kit for carrying out the method defined in any one of embodiments 1-27, comprising:

[0191] a) a first container comprising a reaction buffer or a lyophilisate of said reaction buffer,

[0192] b) a second container comprising a solution comprising the somatostatin receptor binding peptide linked to a chelator, preferably DOTA-TATE or DOTA-TOC, and

[0193] c) a third container comprising the radionuclide precursor solution. DETAILED DESCRIPTION

[0195] Example 1: Production 177 Sterile aqueous concentrate of Lu-DOTA-TATE (so-called stock solution)

[0196] 1.1 Introduction

[0197] Radiopharmaceutical substances 177 Lu-DOTA-TATE, hereinafter also referred to as 177 Lu-DOTA0-Tyr 3 -Octreotate, is a sterile aqueous concentrate (the so-called stock solution).

[0198] The drug substance synthesis steps are carried out in a self-contained closed system synthesis module which is automatically and remotely controlled by GMP compliant software and automatically monitors and records process parameters.

[0199] In each production run of the synthesis module, a single-use disposable kit containing one fluid path (tubing), reactor vial and sealed reagent vials is used. The synthesis module is protected from human intervention during the production run. The synthesis module is placed in a lead-shielded hot chamber to provide filtered air.

[0200] Drug substances ( 177 Lu-DOTA0-Tyr 3 -Octreotate) and its preparation into a pharmaceutical product ( 177 Lu-DOTA0-Tyr 3 -Octreotate 370 MBq / mL solution for infusion) is part of an automated continuous process that does not allow the isolation and testing of the drug substance due to its radioactive decay.

[0201] The general preparation method and corresponding steps are as follows Figure 1 and 2 As explained.

[0202] 1.2 Preparation of starting materials

[0203] The chemical precursors, radioactive precursors and intermediates of the drug substances used in the preparation methods were prepared according to Table 1 below.

[0204]

[0205] Table 1

[0206] The details of the reaction buffer lyophilisate are provided in Table 2 below:

[0207] Components Amount (mg / vial) Quantity / Batch Function Gentisic acid 157.5mg 39.38g Radiation stability enhancers Acetic acid 120.2mg 28.76mL pH Adjusters Sodium acetate 164.0mg 41.00g pH Adjusters Water for injection qs to 4mL Up to 1000mL Solvents

[0208] Table 2

[0209] 1.3 Preparation of synthesis modules and kits

[0210] The preparation method was validated using two different Lu-177 chloride batch sizes: 74.0 GBq±20% (2 Ci±20%) or 148.0 GBq±20% (4 Ci±20%).

[0211] Synthesis was performed using a single-use disposable kit mounted on the front of the synthesis module, which contained fluid pathways (tubing), reactor vials, and sealed reagent vials.

[0212] Table 3 summarizes the different types of equipment and materials that can be used in the drug substance preparation process depending on the batch size chosen.

[0213] Table 3: Kits and synthesis modules for the method of preparing drug substances

[0214]

[0215] 1.4 Kit for MiniAIO Synthesis Module

[0216] The kit is ready to use.

[0217] 1.5 Kits for TRACERlab MX Synthesis Module

[0218] Before starting to synthesize the drug substance, some modifications were introduced into the kit to adapt it to 177 Lu-DOTA 0 -Tyr 3 -Octreotate synthesis (see Figure 3A and Figure 3B , corresponding to the arrangement of the boxes before and after improvement).

[0219] The parts to be replaced were assembled under a laminar flow hood (Class A) and then installed on the synthesis module in a Class C environment.

[0220] The "Kit for Modified TRACERlab MX Kit" includes 2 tubes to replace the 2 spikes in the original kit, a connecting tube to replace one column and some plastic plugs to close unused valves:

[0221] · The first tube replaces the spike in position 3 of the kit,

[0222] The second tube replaces the spike in position 5 in the kit,

[0223] A connecting tube (shorter) is used to replace the first tC18 column that usually connects manifold 2 to manifold 3,

[0224] • Remove the alumina column and the second tC-18 column from positions 11 and 12.

[0225] The tube previously connected at position 12 and position 13 of the tC18 column is connected at position 12 and the other end directly to the extension cable (the extender used to transfer the drug substance into the Class A dispensing hot chamber),

[0226] Positions 9, 10, 11 and 13 are closed with plastic plugs.

[0227] 1.6 Step 1c: Dissolution of lyophilized product in reaction buffer

[0228] Prior to use in drug substance synthesis, the reaction buffer lyophilisate (RBL) is reconstituted by the drug substance preparation site by dissolution with water for injection (WFI) to obtain reaction buffer.

[0229] Reconstruction is done immediately before synthesis begins.

[0230] To dissolve RBL:

[0231] For 74GBq batch size (2Ci batch size) : Use a sterile disposable syringe to reconstitute one vial of RBL with 2 mL of WFI.

[0232] For 148GBq batch size (4Ci batch size) : Reconstitute two vials of RBL with 2 mL of WFI using a sterile disposable syringe. Transfer the contents of one vial of dissolved reaction buffer to another vial using a sterile disposable syringe and mix to obtain one vial containing 4 mL of product.

[0233] After reconstitution, the composition of the reaction buffer is shown in Table 4.

[0234] Table 4: Reaction buffer composition after reconstitution

[0235] Components Acceptance of limits Reference Standards Function Gentisic acid 157.5±5%mg internal Radiation stability enhancers Acetic acid 120.2±5%mg internal pH Adjusters Sodium acetate 164.0±5%mg Ph.Eur.0411 / USP pH Adjusters Water for Injection (WFI) qs 2.00mL Ph.Eur.0169 / USP Solvents

[0236] 1.7 Step 1d: DOTA-Tyr 3 -Octreotate dissolution (chemical precursor)

[0237] DOTA-Tyr 3 -Octreotate is provided in vials as a dry powder. Each vial contains 2 mg of DOTA-Tyr 3 -Octreotate. Before the synthesis reaction, DOTA-Tyr 3 -Octreotate is dissolved in water for injection (WFI).

[0238] To dissolve DOTA-Tyr 3 -Octreotate:

[0239] - For 74GBq batch size (2Ci batch size) : Use a sterile disposable syringe to reconstitute one vial of DOTA-Tyr with 2 mL of WFI. 3 -Octreotate.

[0240] - For 148GBq batch size (4 Ci batch size) : Use a sterile disposable syringe to reconstitute two vials of DOTA-Tyr with 2 mL of WFI. 3 -Octreotate. Use a sterile disposable syringe to place one dissolved DOTA-Tyr 3 -The contents of the Octreotate vial were transferred to another vial and mixed to obtain one vial containing 4 mL of product.

[0241] 1.8 Step 3: Install the kit and components on the synthesis module

[0242] Install the kit components in front of the corresponding synthesis module. Install the other components on the corresponding column positions according to the synthesis module. Assembly is performed in a Class C environment.

[0243] · Positions used on GE Medical System modified kits with TRACERlab MX synthesis module

[0244] o Position 1 - Left: Sterile Millex gas filter (hydrophobic membrane) connected to the gas inlet of the synthesis module,

[0245] oPositions 4 and 14: Two sterile 30 mL syringes with Luer Lock 1 Crimp onto the corresponding syringe driver,

[0246] o Position 3: Place a needle at the end of the tube (this needle will be inserted into the top of the vial to aspirate the DOTA-Tyr 3 -Octreotate chemical precursor),

[0247] o Position 5: Place a needle at the end of the tube (this needle will be inserted into the top of the vial to aspirate 177 LuCl3 solution (radioactive precursor),

[0248] oPosition 12: Connect the extension cable 6 To transfer drug substances from the synthesis module to the distribution isolator (level A).

[0249] The final installation of the box is as follows Figure 4A shown.

[0250] · Positions used on TRASIS kits with TRASIS synthesis modules

[0251] Install the required components in the following box locations:

[0252] o Position 1 - Top: Place the needle (this needle will be inserted into the top of the vial to aspirate 177 LuCl3 solution radioactive precursor),

[0253] oPosition 1 Left: Connect the gas filter of the reagent cartridge connected to Position 1 Left to the gas inlet,

[0254] o Position 4: Place the needle (this needle will be inserted into the top of the vial to aspirate the reaction buffer),

[0255] o Position 5: Placement of needle (this needle will be inserted into the top of the vial to aspirate DOTA-Tyr 3 -Octreotate chemical precursor),

[0256] oPosition 6 right: Connect the extension cable to transfer the drug substance from the synthesis module into the dispensing isolator (Grade A),

[0257] o On position 6: Connect a 20 mL sterile syringe with Luer Lock.

[0258] The final installation of the box is as follows Figure 4B shown.

[0259] 1.9 Step 5: Install the starting material on the kit

[0260] Depending on the synthesis module used, the reaction buffer solution, WFI and precursors are installed in the corresponding box positions. The installation is carried out in a Class C environment.

[0261] Synthesis reaction components on a GE Medical System modified kit with the TRACERlab MX synthesis module Location

[0262] o Position 3: Insert the needle into the top of the vial to aspirate DOTA-Tyr 3 -Octreotate chemical precursor. Breathing filter 5 Also inserted into the vial septum,

[0263] oPosition 5: Insert the needle into the top of the vial to aspirate 177 LuCl3 solution (radioactive precursor). A vent filter was also inserted into the vial septum.

[0264] o Position 7: Install WFI bag,

[0265] oPosition 8: Install the reaction buffer solution vial.

[0266] The final installation of the box is as follows Figure 4A shown.

[0267] Position of synthesis reaction components on a TRASIS kit with a TRASIS synthesis module

[0268] oPosition 1-Top: Insert needle into top of vial to aspirate 177 LuCl3 solution radioactive precursor. A vent filter was also inserted into the vial septum.

[0269] o Position 3: Install WFI bag,

[0270] oPosition 4: Insert the needle into the top of the vial to aspirate the reaction buffer. Also insert the vent filter into the vial septum.

[0271] o Position 5: Insert the needle into the top of the vial to aspirate DOTA-Tyr dissolved in WFI 3 -Octreotate chemical precursor. A vent filter was also inserted into the vial septum,

[0272] The final installation of the box is as follows Figure 4B shown.

[0273] 1.10 Step 6: Mix Lu-177 chloride solution, reaction buffer solution and DOTA-Tyr 3 -Octreotate solution transferred to the reactor

[0274] The synthesis was initiated by pressing the "Start Synthesis" button on the synthesis module PC control software program. The first step of the synthesis consisted of the automatic transfer of all components required for labeling into the cassette reactor.

[0275] Transfer the radioactive and chemical drug substance precursors and the reaction buffer solution into the reactor in the following order:

[0276] 1. Lu-177 chloride solution

[0277] 2. Reaction Buffer

[0278] 3.DOTA-Tyr 3 -Octreotate solution

[0279] When the valves (positions 5 and 6 of the GE cartridge or positions 1 and 2 of the MiniAIO cartridge) are opened and negative pressure is applied to the reactor, the Lu-177 chloride solution is drawn into the reactor.

[0280] The Lu-177 chloride solution is highly concentrated, so incomplete transfer of the solution into Reactor 1 can affect the labeling yield. Therefore, before transferring the Lu-177 chloride solution to the reactor, add reaction buffer to the Lu-177 chloride solution vial to ensure complete transfer of the Lu-177 chloride solution. Use a syringe to transfer the reaction buffer to the Lu-177 chloride sample vial (right, for TRACERlab MX synthesis module, 30 mL syringe 1 ; For MiniAIO synthesis module, 30mL syringe 2 ). The solution (reaction buffer + Lu-177 residue) was transferred from the vial to the reactor by applying negative pressure.

[0281] The final step in the synthesis of the drug substance is to convert DOTA-Tyr 3 -Octreotate solution is transferred to the reactor. This is done automatically by applying negative pressure to the reactor.

[0282] 1.11 Step 7: Marking Steps

[0283] The synthetic route is summarized as follows:

[0284]

[0285] Where DHB = gentisic acid (2,5-dihydroxybenzoic acid)

[0286]

[0287] Labeling involves chelating Lu-177 to DOTA-Tyr 3 -Octreotate peptide in the DOTA portion. Labeling was performed at 94°C (±4°C):

[0288] 12 min (± 0.5 min) using TRACERlab MX (GE) synthesis module

[0289] 5 minutes (±0.5 minutes) using MiniAIO (TRASIS) synthesis module

[0290] In the reactor, DOTA-Tyr 3 -Octreotate was present in a molar excess relative to Lu-177 to ensure acceptable radiochemical labeling yields (see also Example 2 regarding process optimization).

[0291] 1.12 Step 8: Transfer and initial filtration of drug substance (pre-filtration)

[0292] Once synthesis is completed in the synthesis module, the obtained 177 Lu-DOTA 0 -Tyr 3 -Octreotate mother liquor. During filtration, 177 Lu-DOTA 0 -Tyr 3 -Octreotate stock solution was automatically transferred from the synthesis hot room (Class C) to the dispensing isolator Class A under positive nitrogen pressure through an extended sterile cable and collected in a central 30 mL sterile vial. A vent filter with a micro-spray gun needle was used to equalize the pressure in the central 30 mL sterile vial.

[0293] Rinse the kit and reactor 3 times with 3 mL of injection water each time to recover the residual 177 Lu-DOTA 0 -Tyr 3 -Octreotate.

[0294] At the end of the transfer process, 177 Lu-DOTA 0 -Tyr 3 The volume of the -Octreotate stock solution is:

[0295] · For 74GBq batch size (2Ci batch size) :≥13.0mL

[0296] · For 148GBq batch size (4Ci batch size) :≥19.0mL

[0297] Control and monitor at the end of synthesis 177 Lu-DOTA 0 -Tyr 3 -Octreotate stock solution volume and radioactivity. Calculate the synthetic yield.

[0298] Example 2: Method Optimization

[0299] The method was industrialized for batch production of larger doses of drug substance and used an automated synthesis module to produce the drug substance. Considerations for optimizing the method included:

[0300] DOTA-Tyr 3 -Octreotate and 177 The labeling reaction between Lu,

[0301] High labeling yields associated with high radiochemical purity,

[0302] ·The free 177 High labeling yield with minimized Lu+3 levels.

[0303] Starting from the prior art process for the preparation of drug substances, some changes were made to the intermediate steps, especially changing the order of addition of the excipients.

[0304] In order to produce the drug substance formulation and integrate the necessary excipients (ie excipients ensuring good stability of the drug substance solution) into the automated synthesis process, we modified the formulation of the reaction mixture, ie the reaction buffer, in the present method.

[0305] Compared to the compositions of the prior art, the reaction buffer does not contain peptides. Likewise, some components have been removed to be added only when formulating the drug product. Specifically, ascorbic acid is not added during the labeling reaction and can be included in the formulation buffer. This change was made because it was found that ascorbic acid has a high probability of precipitation in the small reaction volume used during labeling. In order to promote pH buffering during the labeling reaction, the reaction buffer also contains a low concentration of sodium acetate. Studies have shown that these changes have no effect on the quality characteristics of the drug product, but significantly improve the automation of the total synthesis and have a good synthesis yield.

[0306] 2.1 Optimization of drug substance synthesis: molar ratio of reactants

[0307] In order to avoid the purification step after labeling, DOTA-Tyr 3 The effect of the molar ratio of -Octreotate to Lu-177 on the radiochemical purity of the drug substance synthesis to optimize the labeling reaction.177 Lu solution contains 177 Lu, 176 Lu and 175 Lu isotope, so when 177 When Lu decays, due to the stable isotope 176 Lu and 175 As the abundance of Lu increases, the specific activity (SA) decreases. Therefore, higher Lu-177 specific activity contains fewer moles of "Lu".

[0308] For a batch size of 74 GBq (batch size of 2 Ci), 2 mg of DOTA-Tyr 3 -Octreotate and 74GBq (2Ci) of Lu-177 (as 177 LuCl3 was used for synthesis; for 148GBq batch size (4Ci batch size), the peptide amount was doubled (4mg). 3 -Octreotate has a molecular weight of 1435.6 Da, and the specific activity of Lu-177 radiochemicals when synthesized is 499.5-1110 GBq / mg, DOTA-Tyr 3 The molar ratio of -Octreotate to Lu was increased from 1.5 to 3.5 (see Table 5).

[0309] Further testing indicated that the lowest specific activity of Lu-177 allowed for synthesis was 407 GBq / mg (peptide to Lu molar ratio = 1.2) while the resulting radiochemical purity of the drug substance still met the specifications.

[0310] Table 5: DOTA-Tyr used in the synthesis of drug substances 3 -Octreotate with 177 Molar ratio of Lu

[0311]

[0312] *Specific activity values ​​are at the time of synthesis

[0313] To ensure efficient radiolabeling, DOTA-Tyr 3 -Octreotate should be present in a molar excess relative to Lu- 177. Under these conditions, no free Lu- 177 is expected at the end of the synthesis; therefore, no purification step is required at the end of labeling.

[0314] 2.2 Study of chemical and physical properties and optimization of pH

[0315] Use of drug substances 175 Lu-DOTA 0 -Tyr3 -Octreotate is a non-radioactive analogue of lutetium that has been used in some non-clinical studies. 175 Lu-DOTA 0 -Tyr 3 -Octreotate, 97.4% of which consists of the isotope Lu-175. 175 The atomic mass of Lu is 175Da. Non-radioactive 175 Lu-DOTA 0 -Tyr 3 -Octreotate has the same chemical and physical properties as the radiopharmaceutical substance.

[0316] 175 Lu-DOTA 0 -Tyr 3 -Octreotate production is consistent with the use of DOTA-Tyr 3 -Octreotate and 175 Non-clinical solution for using Lu as starting material. 177 Lu-DOTA 0 -Tyr 3 The synthesis was carried out using the same synthesis module of -Octreotate and the same reaction conditions (pH and reactor temperature).

[0317] Omit gentisic acid from the reaction buffer as it is not required as a free radical scavenger.

[0318] Characterization of the cold drug substance included RP-HPLC for conformational identification and purity determination, and mass spectrometry for molecular weight (identity) determination.

[0319] It has been determined that the pH of the reaction buffer during the synthesis of drug substances is an important factor in controlling and preventing colloid formation. When pH>7, Lu can be converted to the colloidal form of Lu(OH) - 4. It has been found that when the pH of the reaction buffer is between 4.5 and 5.5, colloid formation is prevented and optimal labeling occurs.

[0320] 2.3 Optimizing synthesis parameters

[0321] During process development, the synthesis 177 Lu-DOTA 0 -Tyr 3 -Critical steps in Octreotate.

[0322] 2.3.1 Labeling yield

[0323] DOTA-Tyr 3-Octreotate with 177 The labeling reaction between Lu and DOTA-Tyr is a key step, so the labeling yield was determined using the sample in progress. 3 The metal-DOTA complex formation between -Octreotate and Lu is a spontaneous reaction; Lu 3 + Chelated by DOTA: oxygen electrons from the carboxyl group of DOTA bind to free Lu 3+ Shell sharing.

[0324] 2.3.2 Reaction time

[0325] Although the labeling reaction is spontaneous, the activation energy is high, so if labeling occurs at room temperature (25°C), the reaction time can be very long.

[0326] The radiochemical purity (in terms of DOTA-Tyr 3 -Octreotate:Lu ratio) to optimize the reaction time.

[0327] The reaction time range was verified to be 2-15 minutes. Depending on the synthesis module, the reaction time range selected was 5-12 minutes.

[0328] 2.3.3 Reaction temperature

[0329] Reaction temperatures have been tested at 80°C-100°C with a labeling time of 5 minutes.

[0330] Generally, temperatures below 90°C do not ensure quantitative labeling yields (considering safety margins), while at temperatures above 95°C, solution loss due to solvent evaporation becomes a problem and does not affect labeling yields. The effects of reactor temperatures of 80 and 100°C on radiochemical purity are shown in Table 6.

[0331] Table 6: Effect of reaction temperature on radiochemical purity

[0332]

[0333] The temperature range is verified to be 80-100°C. The selected reaction temperature is fixed at 94°C, with an acceptable variation of ±4°C (90-98°C)

[0334] 2.3.4 Reaction volume

[0335] The reaction volumes (volume of reagent solution entering the reactor) were tested for an activity range of 37 GBq (1 Ci) to 185 GBq (5 Ci). For both batch sizes, the stoichiometric ratio between the reagents was kept fixed (1 μg DOTA-Tyr 3-Octreotate / 1mCi Lu-177). Both production methods were performed using the MiniAIO synthesis module with a reaction time of 5 minutes and a reactor temperature of 95°C. 3 The molar ratio of -Octreotate:Lu was fixed at 1.5.

[0336] The effect of reaction volume on the resulting radiochemical purity is shown in Table 7. The table shows the results of tests using reaction solutions having radioactivity concentrations of 6.17 GBq / mL (181.8 mCi / mL) and 16.82 GBq / mL (454.5 mCi / mL).

[0337] Table 7: Effect of reaction volume on radiochemical purity at t0

[0338]

[0339] The reaction volume was set as:

[0340] For 74GBq batch size (2Ci) production method :5.5mL

[0341] Production method for 185GBq batch size (5Ci) :11.0mL:

[0342] 2.3.5 Reaction buffer pH

[0343] The pH of the reaction solution must be:

[0344] pH below 7 (to prevent Lu colloid formation)

[0345] Above pH 3 (below pH 3, the DOTA ligand is protonated and the metal complex formation is not efficient)

[0346] Design of drug substance starting materials (Lu-177, DOTA-Tyr 3 -Octreotate and reaction buffer) to make the pH range of the reaction solution 4.2-4.7. Table 8 shows the effect of reaction buffer pH on radiochemical purity and purity.

[0347] Table 8: Effect of reaction buffer pH on radiochemical purity

[0348]

[0349]

[0350] From the data obtained from these tests, the appropriate pH range for labeling has been set at 4.0-5.5, while the expected reactor pH range is 4.2-4.7.

[0351] 2.3.6 Preparation of Lyophilized Reaction Buffer

[0352] As part of an industrial process, it is preferred to limit the amount of materials that are mixed extemporaneously in the process. Therefore, the reaction buffer is designed to be reconstituted from a lyophilisate vial rather than from the starting components.

Claims

1. A method for synthesizing a radionuclide complex formed by a radionuclide and a somatostatin receptor binding peptide linked to a chelator, characterized in that The method comprises the following steps in the following order: a) providing a radionuclide precursor solution into a first vial, b) transferring the radionuclide precursor solution into a reactor, c) providing a reaction buffer to said first vial containing residual radionuclide precursor solution, d) transferring the reaction buffer and the remaining radionuclide precursor solution from the first vial to the reactor, e) transferring the solution comprising the somatostatin receptor binding peptide linked to the chelator into the reactor, f) reacting the somatostatin receptor binding peptide linked to a chelator with the radionuclide in the reactor to obtain the radionuclide complex, and g) recovering the radionuclide complex, wherein the radionuclide complex is 177 Lu-DOTA-TOC( 177 Lu-edotreotide) or 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide); and wherein the specific activity of the radionuclide precursor solution in the reaction step f) is at least 407 GBq / mg; wherein the molar ratio between the somatostatin receptor binding peptide linked to the chelator and the radionuclide in the reaction step f) is 1.5 and the pH is 4.5-5.5; wherein the final volume containing the radionuclide complex after the recovery step is 14-25 mL; and The method does not comprise any purification step to remove free non-chelated radionuclides.

2. The method according to claim 1, wherein the radionuclide complex is 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide).

3. The method according to claim 1 or 2, wherein the radionuclide precursor solution is 177 LuCl3 chloride solution.

4. The method according to claim 3, wherein the specific activity of the reaction step f) is 407 GBq / mg to 1110 GBq / mg. The method according to claim 1 , wherein the reaction buffer comprises at least a stabilizer against radiation degradation.

6. The method of claim 5, wherein the stabilizer is gentisic acid. The method of claim 1 , wherein the reaction buffer does not contain ascorbic acid.

8. The method according to claim 1, wherein the reaction time of the reaction step f is 2-15 minutes and the temperature is 80-100°C.

9. The method according to claim 1, further comprising at least one or more washing steps for effectively recovering the radionuclide complex.

10. The method according to claim 1, wherein the volume of the mixture in the reaction step is 4-12 mL.

11. The method according to claim 1, wherein (i) The radionuclide precursor solution is 74 GBq ± 20% in a volume of 1-2 mL. 177 LuCl3 solution, (ii) the solution comprising the somatostatin receptor binding peptide linked to a chelator is a solution comprising 2 mg ± 5% DOTA-TATE in a volume of 1.5-2.5 mL, (iii) the reaction buffer contains 157 mg ± 5% gentisic acid in a volume of 1.5-2.5 mL, And the pH value of the reaction step is 4.5-5.

5.

12. The method according to claim 1, wherein (i) The radionuclide precursor solution is 148 GBq ± 20% in a volume of 2-3 mL. 177 LuCl3, (ii) the solution comprising the somatostatin receptor binding peptide linked to a chelator is a solution comprising 4 mg ± 5% DOTA-TATE in a volume of 3.5-4.5 mL, (iii) the reaction buffer contains 314 mg ± 5% gentisic acid in a volume of 3.5-5.5 mL, And the pH value of the reaction step is 4.5-5.

5.

13. The method of claim 11, wherein the radionuclide complex recovered in step g is an aqueous concentrated mother liquor containing a specific activity of at least 45.0 GBq and / or a concentration of 1875-3400 MBq / mL. 177 Lu-DOTA-TATE.

14. The method of claim 12, wherein the radionuclide complex recovered in step g is an aqueous concentrated mother liquor comprising a specific activity of at least 59.0 GBq and / or a concentration of 1875-3400 MBq / mL. 177 Lu-DOTA-TATE.

15. The method of claim 1 which is automated and performed in a synthesis module with disposable reagent kits.

16. The method of claim 15, wherein the synthesis module comprises: a) a disposable kit comprising the required fluid pathways, and, b) A disposable kit comprising reagents for carrying out the synthetic method.

17. The method of claim 1, wherein the synthesizing is performed within a computer-assisted system.

18. The method according to any one of claims 16-17, wherein the synthesis module and the kit comprise the following: a) at a first location, positioning a needle to be inserted into the top of said first vial containing a radioactive precursor solution, b) at a second location, positioning a needle to be inserted into the top of a vial containing the solution comprising a somatostatin receptor binding peptide linked to a chelating agent, c) in a third position, a bag with water for injection is installed to perform a flushing step, d) at the fourth position, installing a reaction buffer, and, e) At a fifth location, an extension cable is installed to transfer the radionuclide complex from the synthesis module to a distribution isolator.

19. The method according to claim 1, further comprising the steps of: h. Dilute the radionuclide complex in formulation buffer.

20. The method according to claim 19, wherein the solution obtained directly after step h is a solution for infusion.

21. The method according to claim 20, wherein the solution obtained directly after step h is ready for use in treating a subject in need thereof.

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