Radiopharmaceuticals for Different ARTs

Abstract

The present invention relates to a method and an apparatus for producing a product containing a radionuclide, said product having substantially the same required radioactivity at different application times based on a given calibration time. Compared with the procedures of the prior art, the method according to the present invention allows ensuring the consistent composition of a required radionuclide-labeled medicament at all application times during the shelf life by a single production process. Using the present invention, for example, [n.c.a. Lu-177]Lu-DOTATOC can be provided on each working day of the week, which maintains a constant activity at each application time in a single production step.

Description

Technical Field

[0001] The invention relates to a method for producing a radionuclide-containing product having substantially the same desired radioactivity at different application times based on a given calibration time, and to an apparatus for carrying out said method. Background Art

[0002] Radiopharmaceuticals are radioactive compounds used in nuclear medicine. A distinction is made between diagnostic and therapeutic radiopharmaceuticals or so-called theranostics, which can be used both therapeutically and diagnostically. Such drugs are usually produced directly at the site of their use, which seems to be necessary, especially for diagnostic compounds, due to their short half-life or lifetime. Until a few years ago, complex therapeutic radiopharmaceuticals were usually only produced locally in small batches in a patient-oriented manner. To date, only easy-to-prepare, less complex radiopharmaceuticals consisting of one radionuclide or a simple radionuclide formulation have been produced centrally and distributed to nuclear medicine users. Such drugs include, for example, [I-131]NaI, [Ra-223]RaCl2 and [Sm-153]Sm-EDTMP.

[0003] A variety of suitable radioisotopes are now available to those skilled in the art in sufficient quantities and pharmaceutical quality. Here, only the important isotopes Lu-177 and Ga-68 are listed as examples in recent years:

[0004] For example, the applicant of the present patent application describes in EP2546839B1 a patented method for producing carrier-free, high-purity Lu-177 compounds (half-life = 6.64 days, β-decay) for medical use. In particular, a preparative column chromatography method for producing such carrier-free, high-purity 177Lu compounds is disclosed. A cation exchanger and a suitable complexing agent are used in the 177Lu-production method. By means of the above method, for the first time, carrier-free, high-purity 177Lu compounds for pharmaceutical-medical purposes can be provided in milligram quantities in high purity form by using thermal neutron irradiated 176Yb compounds, wherein the mass ratio of the radionuclides 177Lu and 176Yb used for purification is about 1:102 to 1:1010.

[0005] In addition, WO / 2018 / 122250A1 of the applicant of this patent application discloses a 68Ge / 68Ga generator, which can be used to continuously produce pharmaceutical-quality positron emitter Ga-68 (half-life = 67.71 minutes) on-site, such as in a nuclear medicine laboratory in a hospital, for the production of therapeutic diagnostic agents.

[0006] For example, an overview of the prior art stable complexing agents for concentrated radionuclides is given in US10596278B2.

[0007] The chelating agent component and the targeting component of the radionuclide are described in detail, for example, in EP1289571B1 and are thus well known to those skilled in the art. The above-mentioned literature generally relates to pre-chelating agents and chelating agents for radioactively metal-labeled molecules.

[0008] Therein, macrocyclic polyaza compounds for radiolabeling with radioactive metals are described, which contain an Nn-system, where n is 4, 5 or 6, having different ring sizes, and where at least one N atom is substituted with a free carboxyl group for coupling to an amino functional group in a bioactive effector molecule, and where all N-atoms carry protected side chains for the synthesis of the final molecule.

[0009] Specifically, EP1289571B1 describes a chelating agent for radiolabeling bioactive molecules, which has the following general formula:

[0010]

[0011] where:

[0012] The two Y groups can be trans or cis, as shown in the figure;

[0013] A represents an effector molecule, such as a peptide (especially octreotide, CCK, substance P or gastrin), a protein (especially an antibody or an enzyme), a sugar or a radiosensitizer (such as doxorubicin);

[0014] R represents hydrogen, C1-C3-alkyl or alcohol;

[0015] X represents a spacer group, especially (CH2)n-X′, where n represents 1-10 and X′ represents COOH, NH2, SH, OH or O-halogen, where the halogen is especially Br, I or Cl,

[0016] or a molecule of the following formula

[0017]

[0018] or a molecule of the following formula,

[0019]

[0020] Y represents COO–, CH2CONH2 or CH2CH2OH,

[0021] Optionally complexed with a radioactive metal.

[0022] In addition, BREEMAN (2012) [Wouter A.P. BREEMAN; Practical Aspects of labeling DTPA- and DOTA-Peptides with 90Y, 111In, 177Lu, and 68Ga for Peptide-Receptor Scintigraphy and Peptide-Receptor Radionuclide Therapy in Preclinical and Clinical Applications The University of New Mexico Health Sciences Center, Volume 16, Lesson 5: 11 / 16 / 2012] outlined the practical aspects of using 90Y, 111In, 177Lu, and 68Ga to label DTPA and DOTA peptides for peptide-receptor scintigraphy and peptide-receptor radionuclide therapy in preclinical and clinical applications.

[0023] HEPPELER et al. (1999) described a somatostatin analogue derivatized with a radiometal-labeled macrocyclic chelator component [HEPPELER et al.:, Radiometal-labelled macrocyclic chelator-derivatized somatostatin analogue with superb tumour-targeting properties and potential for receptor-mediated internal radiotherapy“, Chem.-Eur. J., 1999, 5(7), 1974-1981].

[0024] EISENWIENER et al. (2001) disclosed the synthesis and peptide coupling of DOTA-based prochelators, which form neutral complexes with yttrium-90 and indium-111. [Eisenwiener et al.:, "Synthesis and peptide coupling of a new DOTA based prochelator, forming neutral complexes with Yttrium-90 and Indium-111", Journal of Labelled Compounds and Radiopharmaceuticals, May 2001, Vol. 44, No. Supplement 1, pp. S694-S696. PRINT. Conference information: 14th International Symposium on Radiopharmaceutical Chemistry, Interlaken, Switzerland, June 10-15, 2001].

[0025] ANDRé et al. (1998) described 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA) as a bifunctional chelator for radiolabeling of biomolecules with radioactive gallium [André, J. et al.: "1,4,7-Triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA): a new bifunctional chelator for radio gallium-labelling of biomolecules", Chem. Commun., 1998, 12, 1301-1302].

[0026] Thus, those skilled in the art can obtain a large number of different radionuclides, chelator components and target molecule components suitable for them, as well as labeling techniques and the use of labeled molecules for medical purposes.

[0027] For therapeutic radiopharmaceuticals composed of extremely complex formulations and components as described above, their centralized production faces various challenges. For example, the decay of radioactive components with usually short lifetimes makes it difficult to ensure the same composition of the drug at all application times related to the calibration time (activity reference time, ART). This problem has been solved currently and in the past by the so-called kit reconstruction at the time of use. Among them, the radioactive components of the drug are provided separately, and complex synthesis and quality control must be carried out on-site before use. Examples thereof are Octreoscan ([In-111]In-Pentetreotid) and Zevalin ([Y-90]Y-Ibritumomab-Tiuxetan).

[0028] Another possibility to overcome this difficulty is to produce a radiopharmaceutical for a fixed use time and make it available to the user. Depending on the design, this has disadvantages for the manufacturer or the user. In order to be able to supply the drug every day of the working week (Monday to Friday), the manufacturer must notify at least 5 separate small batches at fixed use times every week and provide the corresponding production plan and organizational arrangements for the ordering process. This production method of the prior art is shown in Figure 1. This method is both time-consuming and costly for the manufacturer, especially for regulatory reasons for drug approval, because in addition to checking whether the amount of radioactivity used is correct, each individual daily batch of the drug is also associated with strict quality control and drug legal approval. If this concept is to be implemented, the existing production facilities will be fully occupied and it will be difficult to use them for manufacturing other radiopharmaceuticals.

[0029] An alternative prior art concept is to produce one large batch per week. This enables the manufacturer to avoid the above disadvantages and produce in a more cost-effective manner. However, the disadvantage of this procedure is that the radiopharmaceutical is provided to the user only at a predetermined time determined by the manufacturer, and the user has to subordinate their entire plan to the manufacturer. This is particularly disadvantageous for clinical users, which may lead to a lower acceptance of the corresponding radiopharmaceutical product and, according to experience, also results in this situation. This production scheme is schematically shown in Figure 2 in.

[0030] Another alternative is to individually produce the radiopharmaceutical for the specified use time. By calculating the decay of the isotope used, less solution can be removed at a specified time before the use time so that the activity corresponds to the activity at the target time. However, in this process, neither the radioactivity concentration nor the concentration of the compounds contained therein is constant, and the amount of the target biomolecule is also variable. This may lead to poor drug absorption in the patient's body. Summary of the Invention

[0031] In this context, the object of the present invention is to provide an accurate and identical amount of radioactivity in a radiopharmaceutical product at specific use times based on calibrated times during the working week in multiple separate batches without having to accept the disadvantages described above.

[0032] The above object is solved by a method according to the present invention.

[0033] In terms of device technology, the above object is achieved by a device according to the present invention.

[0034] Specifically, the present invention relates to a method for producing a product containing a radionuclide, the product having substantially the same required radioactivity at different times of use (ART + 1, ART + 2, ART + 3, ART + 4) based on a given calibration time (ART), wherein

[0035] - providing a concentrate containing a radionuclide, the required radionuclide contained therein having an activity such that a plurality of required batches can be obtained from the concentrate, each having a defined number of partial fills at the filling time, wherein the partial fills of each batch are based on the calibration time (ART) and each have substantially the same radionuclide activity at different application times (ART + 1, ART + 2, ART + 3, ART + 4);

[0036] - converting the radionuclide of the concentrate into the required radionuclide-labeled product and thereby obtaining a stock solution which, in addition to the radionuclide-labeled product, contains all other components required for the intended use;

[0037] - setting the activity of the radionuclide-labeled product in the stock solution to the latest desired application time (ART + 4);

[0038] - removing a partial fill of the first batch from the stock solution containing the radionuclide-labeled product at a first filling time before the application time, which has an activity set to the latest application time (ART + 4) and which has an activity corresponding to the calibration time (ART) at its actual application time;

[0039] - providing a dilution solution which, in addition to the radionuclide-labeled product, contains all other components required for the intended use;

[0040] - diluting the remaining stock solution set to the latest required application time (ART + 4) with the dilution solution such that, based on the latest application time (ART + 4), a required reduced activity is set at the filling time in order to remove a partial fill of the second batch for use at the previous application time, which has an activity set to the earlier application time (ART + 3) and which has an activity corresponding to the calibration time (ART) at its actual application time;

[0041] - gradually further diluting the remaining stock solution set to the earlier application time (ART + 3) with the dilution solution until the application time corresponds to the calibration time (ART); and

[0042] - removing more partial fills of further batches at each further application time (ART + 2, ART + 1), which have an activity set to the corresponding application time (ART + 2, ART + 1), wherein the last batch has an activity at the calibration time (ART).

[0043] The present invention enables the production of pharmaceutical preparations for all possible ARTs in a single production batch (Herstellansatz) in a small and compact facility (registered trademark of ITM Isotopen Technologies München AG), which also includes filling. Thus, compared to the prior art, far fewer batches are required (see Figure 5 ). This saves the manufacturer manufacturing, testing, and approval costs without restricting the availability of the drug. In addition, the production facility gains additional capacity for other products, which means increased productivity and efficiency. There is no theoretical limit to the batch size. Compared to alternative 1, in alternative 2 according to the present invention, the second filling unit can be dispensed with, which in turn saves investment, maintenance, and qualification costs.

[0044] The present invention also relates to a device for performing the method according to the present invention, which has a fluid logic system connected to the following components:

[0045] An adjustable heating element;

[0046] An adjustable vacuum pump with a pneumatic device (Pneumatik) and an exhaust valve;

[0047] An adjustable inert gas pneumatic device;

[0048] At least one reactor;

[0049] A container for formulating a solution fluidly connected to the reactor;

[0050] A container for diluting the solution;

[0051] A reaction buffer container;

[0052] A receiving container for radiochemical precursors

[0053] A filling metering device;

[0054] A batch storage and mixing container;

[0055] An aeration sterile filter;

[0056] An air filter;

[0057] A bypass line between the non-sterile side of the sterile filter and the batch storage and mixing container fluidly connected thereto via a three-way joint;

[0058] A filling device; and

[0059] A first joint group (Hahnenbank) with a multi-way valve; and

[0060] Second connector set with a multi-way valve;

[0061] Wherein, the first connector set is fluidly connected to an inert gas pneumatic device, a container, a sterile filter, and a filling metering device; and

[0062] Wherein the second connector set is fluidly connected to a reactor, a receiving container, a reaction buffer container, a bypass line, a batch storage and mixing container, and an air filter, wherein the batch storage and mixing container is fluidly connected to a vacuum pump.

[0063] In principle, radiopharmaceuticals for different application times can be produced according to the following alternative 1:

[0064] Produce a concentrate for the latest calibration time (ART + 4). 100% of ART + 4 is directly filled with the said concentrate. In addition, all other ART (ART1 - 3) can be prepared from the said concentrate and a dilution solution, wherein a correspondingly smaller amount of the concentrate is filled into the respective vials and filled to the volume compliant with the specifications with the dilution solution. However, this would require two corresponding filling units in the filling production line, namely a filling production line for the concentrate and a filling production line for the dilution solution respectively. However, the disadvantage is that from the perspective of pharmaceutical law or GMP, each vial is prepared as a single-piece product (Unikat), which may lead to unrepresentative sampling (Probenzug), especially for the quality control required in pharmaceutical practice. Homogenization also has to be carried out in the respective vials. This means that the filling process requires a large amount of validation work and is expensive and rather impracticable considering the aforementioned aspects of pharmaceutical law. The filling scheme of alternative 1 according to the prior art is as Figure 3 shown.

[0065] This is where the present invention comes from (alternative 2):

[0066] Produce a concentrate for the latest calibration time (ART + 4) according to the present invention. ART + 4 is directly and 100% filled with the said concentrate. In addition, all other ART (ART1 - 3) can be prepared from the said concentrate and a dilution solution. For this purpose, first fill all ART + 4 from the batch container. Then, different from the separate dilution filling in the vials mentioned above, dilute the batch filling to ART + 3 and then fill it. Finally are ART + 2 and ART + 1, etc. The advantage of the concept of the present invention is a significantly smaller facility, which consists of only a single filling unit in the filling production line. In addition, the said separate fillings are all generated from a homogeneous batch filling. This makes the image of sampling for quality control significantly more uniform. The filling scheme of the method of the present invention according to alternative 2 is as Figure 4 shown.

[0067] Preferred embodiments of the present invention are described below:

[0068] The method according to the invention can be carried out particularly advantageously with all currently relevant radionuclides. For example, they are selected from the group consisting of: gallium-68, yttrium-90, molybdenum-99, indium-111, gadolinium-146, gadolinium-147, holmium-166, lutetium-177, tungsten-188, rhenium-188, bismuth-205, bismuth-206 and thorium-227.

[0069] Theranostic agents based on the short-lived radionuclides mentioned - i.e., substances that can be used for therapy and / or diagnosis - have repeatedly proven themselves in nuclear medicine and can be made available to clinical users by the method according to the invention, each with precisely calibrated activity, sufficient quantity at all times during a working week and consistent high quality.

[0070] Generally, products labeled with radionuclides are used within the scope of the present invention, which contain at least one chelator component and at least one target molecule component, wherein the target molecule component is capable of binding to a specific target within or on a target cell, and wherein the chelator component is covalently bound to the target molecule component to form a chelator-target molecule unit and the radionuclide is coordinatively bound to the chelator component. Thereby, the optimal chemical structure for each radionuclide and target is given.

[0071] Products are preferably used in which a cyclic polyaza system having 4 to 8 N atoms is used as the chelator component. Such chelators have proven beneficial for many transition metals. In the synthesis of the complexing product, they can also easily and reversibly provide protective groups to avoid unwanted side reactions.

[0072] Preferred pharmaceutically acceptable chelator components are commercially available 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or one of its ionic forms or a pharmaceutically acceptable salt.

[0073] The target molecule component used within the scope of the present invention depends in principle on the intended medical application.

[0074] For example, somatostatin-like peptides have proven useful for tumor therapy and diagnosis. Particularly preferably, the target molecule component is selected from the group consisting of: peptides, especially cyclic peptides having 4 to 20 amino acids, wherein at least one amino acid is a D-amino acid, especially D-phenylalanine; and proteins, especially receptor proteins, preferably PSMA.

[0075] The reason for the replacement of L - amino acids by D - amino acid enantiomers in the target molecule component is that the coupled target peptide will thus be less exposed to in - vivo attack by proteases or peptidases, as these usually degrade physiologically present L - amino acid peptides and proteins that serve as natural substrates. The biological half - life is significantly extended by integrating D - amino acids into the target molecule component, as proteolytic degradation is thus significantly delayed.

[0076] Octreotide or an octreotide analogue, in particular TOC, as a somatostatin analogue, has been provided as a target molecule.

[0077] A particularly preferred system is to use edotreotide (DOTATOC) or a pharmaceutically acceptable salt thereof as the chelator - target molecule unit. In the context of the present invention, it is particularly preferred to use [n.c.a.Lu - 177]Lu - DOTATOC as the product containing a radionuclide.

[0078] The product produced by the method according to the present invention can selectively bind to the tumor tissue of so - called GEP - NET and destroy it by releasing a cytotoxic, ionizing radiation dose. Gastro - enteropancreatic (GEP) neuroendocrine tumors (NET) [GEP - NET] include a group of tumors with widely different growth and hormonal behaviors. The range of the clinical course is equally broad: on the one hand, there are benign tumors that are diagnosed as incidental findings in the imaging or histological processing of surgical specimens ; on the other hand, due to the rapid growth of the tumor, there is a clinically unfavorable course.

[0079] The present invention is of particular clinical significance for this type of tumor.

[0080] The [n.c.a.Lu - 177]Lu - DOTATOC obtained by the method according to the present invention is currently being tested by the applicant of the present invention in a clinical phase III (as of February 2021) in the so - called COMPETE study as a treatment for GEP - Nets. The formulation consists of two molecular components: one is the targeting molecule edotreotide (Edotreotid) (DOTATOC), which is a somatostatin analogue, and the other is an EMA - approved β - emitter (lutetium - 177 without carrier addition, a registered trademark of ITM Isotopen Technologies München AG).

[0081] Other product - peptide combinations that can be used according to the present invention include, for example, [Lu - 177]Lu - PSMA for the treatment and diagnosis of prostate cancer.

[0082] Preferably, in addition to the active pharmaceutical ingredient (API), auxiliaries such as common excipients and / or buffer systems are used in the stock solution and the dilution solution.

[0083] Ascorbic acid / ascorbate buffers, which have been proven in practice many times, can advantageously be used as the buffer system.

[0084] To carry out the method according to the invention, a leak-free fluid logic system under negative pressure is advantageously used, since radioactive contamination can thereby be completely avoided.

[0085] In a preferred embodiment, the radionuclide is converted into a labeled product via a precursor, which reacts with a concentrate containing the radionuclide in a temperature-controlled reactor that is cycled into the fluid logic system. By controlling the temperature, different reaction conditions required for the respective chemical systems can be achieved. Thus, for example, the desired reaction can take place in the reactor at a temperature of 20 °C to 100 °C for a time of 5 minutes to several hours, depending on the product.

[0086] To meet the usual GMP hygiene standards, each partial fill is passed through a sterile filter before entering a pharmaceutically acceptable vial. For this purpose, a commercially common vented sterile filter with a pore diameter of 220 nm or a multi-layer filter with a first layer pore diameter of 450 nm and a second layer pore diameter of 220 nm is advantageously used.

[0087] Generally, a bypass line is provided on the non-sterile side of the sterile filter that returns to the batch container, whereby on the one hand the next batch fill and / or partial fill is prepared and on the other hand the fill line and the non-sterile side of the sterile filter can advantageously be rinsed with substantially no loss via the bypass line between the individual batches, so that no radioactivity is uncontrollably carried over into the next fill and the calibration of the ART is also correct for subsequent fills.

[0088] To ensure quality, samples meeting GMP standards are taken from each batch for quality control. It has thus been proven that each batch shows a uniform picture.

[0089] The method according to the invention is preferably used for the production of [Lutetium-177] Lu-DOTATOC as a radionuclide-containing product where a concentrate is used that has the following activities and components based on the calibration time (ART):

[0090] - Lutetium-177 7.5 ± 0.7 GBq

[0091] - Dota-Tyr3-octreotide (DOTATOC) 150 ± 15 μm

[0092] - Ascorbic acid 20 ± 2 mg

[0093] - Sodium ascorbate 80 ± 8 mg

[0094] - Ultrapure water 1.00 ± 0.01 ml

[0095] - 0.1 M Sodium ascorbate dilution solution 18.0 ± 2 ml. Description of the Drawings

[0096] Other advantages and features of the present invention are given based on the description of the exemplary embodiments and with the aid of the drawings.

[0097] The drawings show:[[]]

[0098] Figure 1 shows a scheme for providing a radiopharmaceutical by a manufacturer at each application time over at least 5 drug batches in one working week. A) Daily production. B) Consolidated production. ART = Activity reference time (calibration time);

[0099] Figure 2 shows a scheme for providing a radiopharmaceutical by a manufacturer at a specific application time in one working week from one large drug batch;

[0100] Figure 3 shows a filling scheme according to Alternative 1;

[0101] Figure 4 shows a filling scheme according to a method of the present invention (Alternative 2);

[0102] Figure 5 shows a scheme for providing a radiopharmaceutical at multiple application times in one working week by a single synthetic charge according to the present invention;

[0103] Figure 6 shows a schematic layout of a synthesis device for implementing the method according to the present invention and a schematic construction of the Fluidik of the device;

[0104] Figure 7 shows according to Figure 6 the construction in

[0105] Figure 8 a flowchart of the filling for producing a specific ART; Detailed Description of the Invention

[0106] For example, the present invention is described by taking the method of ITM Isotopen Technologies München AG (registered trademark), but the present invention is not limited thereto. Pharmaceutical preparations The active ingredient is [n.c.a. Lu-177] Lu-DOTATOC.

[0107] Of course, the principle of the present invention can also be applied to other radiolabeled drugs, such as [Lu-177] Lu-PSMA. This also applies to the use of other short-lived radionuclides.

[0108] For clarity, Figure 1 schematically shows that a manufacturer provides a radiopharmaceutical according to the prior art through at least 5 drug batches at each application time within a working week. Figure 1A ) shows the daily production situation, while Figure 1B ) shows the combined production situation. ART is the "active reference time", i.e., the calibration time.

[0109] Figure 2 The production situation is shown in the schematic diagram when the manufacturer provides the radiopharmaceutical only at a specific application time (here Wednesday) within a working week.

[0110] Compared with the prior art procedures, the method according to the present invention allows ensuring the consistent composition of the required radionuclide-labeled drug at all use times within the shelf life through a single production process (Table 1). The filling scheme according to the present invention is as Figure 4 shown, and the supply situation of the radiopharmaceutical at multiple application times within a working week through a single synthesis charge according to the present invention is as Figure 5 shown.

[0111] Table 1: Exemplary specifications of the calibration time (ART).

[0112]

[0113] The special configuration of the process fluid logic and the composition of the reagents used ensure a compact, easily expandable and transferable synthesis. This makes it possible to reduce the production to a single batch charge and ensure the advantage of daily availability.

[0114] Figure 6 shows a schematic construction of the fluid logic, as well as other devices and arrangements for synthesis, which have:

[0115] an adjustable temperature element 1 for heating to 100 °C within 5 minutes;

[0116] an adjustable vacuum pump 2 with a pneumatic device and an exhaust valve, up to 200 mbar;

[0117] an adjustable nitrogen pneumatic device 3 providing a pressure of up to 6 bar;

[0118] A reactor 4 made of glass or plastic, having 2 - 3 interfaces;

[0119] A container 5 or bag for formulating a solution;

[0120] A container 6 or bag for diluting a solution;

[0121] A reaction buffer in a syringe 7, vial or container;

[0122] A receiver 8 for a radiochemical precursor (Lu - 177 in the example);

[0123] A filling syringe, 1 - 20 ml;

[0124] A batch storage and mixing container 10;

[0125] A venting sterile filter of 0.22 μm, or a multi - layer filter of 0.45 μm, 0.22 μm;

[0126] An air filter of 0.22 μm;

[0127] A bypass line 13 with a sterile connector;

[0128] An open or closed vial filling station 14;

[0129] An air filter of 0.22 μm;

[0130] A first joint group 16 with a 2 - 3 - way valve; and

[0131] A second joint group 17 with a 2 - 3 - way valve.

[0132] With the said structure, liquids can be leak - proof transported by means of negative pressure. The injection pump 9 is only used for filling purposes and diluting the batch charge to the corresponding ART. The production of a batch solution of a specific ART can be carried out as follows:

[0133] 1. Produce a radiolabeled concentrate by adding a buffer solution to the radiochemical and chemical precursors and heating in a suitable reactor. The temperature and time vary depending on the product and can range from room temperature to 100 °C and from 5 minutes to several hours.

[0134] 2. Produce the latest ART (e.g., 4 days after ART + production) by adding the formulated solution and mixing in the batch container 10 to form the drug to be filled. In this case, ART + 4 means that the drug at the calibration time (ART) meets the specifications in Table 1 in the case of this example.

[0135] 3. Carry out a non - destructive flushing of the filling line and the sterile filter 11 (non - sterile side) via the bypass line 13 back to the batch container 10 for preparation of filling.

[0136] 4. Fill ART + 4 days and / or sample for quality control.

[0137] 5. After filling, another sample can be optionally taken, or the filter integrity test can also be performed using the injection pump 7 or the N2 pneumatic device 3.

[0138] 6. Use the filling syringe 9 to dilute the batch ART + 4 days to ART + 3 days (or ART + 4 - X days) using the dilution solution (filling solution).

[0139] 7. Then, similar to the process described in point 3, homogenize the batch charge and flush the bypass line 13.

[0140] 8. Then fill the batch charge ART + 3 days, etc. in the same manner as above.

[0141] According to Figure 7 the flowchart gives a schematic overview of the production process of a specific ART filling using the fluid logic according to Figure 6 the present invention.

[0142] The composition of the dilution solution and the addition amount of each ART can be easily calculated according to the specifications of the radiopharmaceutical. For the example in Table 1 ([n.c.a.177Lu]Lu - DOTATOC), the data are shown in Tables 2 and 3:

[0143] Table 2: Composition of the final radiopharmaceutical and the dilution solution.

[0144] Ingredient At the specified concentration of ART Concentration of the dilution solution <![CDATA[Lutetium ( 177 Lu)]]> 0.64 GBq / mL ± 10% - Edotreotide Maximum 8.33 μg / mL Maximum 8.33 μg / mL Sodium ascorbate 0.1M 0.1M

[0145] Table 3: Ratio of Art + 4 - day formulation to the corresponding ART + 4 - X - day formulation.

[0146]

[0147] Using the method according to the present invention, the production plan can be easily implemented through appropriate order planning and through an easily verifiable spreadsheet.

[0148] Very crucial for the implementation of the present invention is the bypass via the bypass line 13 from the sterile filter 11 back to the batch container 10. By circulating the solution between the filling line / sterile filter and the batch container, it is possible to implement the lossless filling of all specific ARTs in a facility in an economically and waste-economically meaningful way. In order to prepare a specific ART in a filling, either two filling lines are required as in alternative 1, or the filling line must be emptied and rinsed again after each ART, so that in the case of long pipelines (which is to be expected, since due to new regulations, the cleanroom class is changed from C to A), high losses and additional radioactive waste occur. Therefore, the bypass has particular advantages for the technical solution to the problem posed.

[0149] Figure 8 The circulation of the batch solution and the rinsing process through the pipeline shown by the dashed line are shown. By this rinsing process, it is ensured that lossless filling and a homogeneous filling solution are achieved after setting a specific ART. For this exemplary method, in particular by means of the bypass line 13 leading back to the batch container 10 before the sterile filter 11, it is possible to also rinse the pipeline and fill it with a homogeneous solution. The bypass line 13 is opened by the valve of the first joint group 16 during rinsing and closed during filling. When the bypass line 13 is open, the natural resistance of the sterile filter 11 prevents the liquid from escaping via the sterile filter 11 and guides the medium into the batch container 10.

Claims

1. A method for producing a product containing a radionuclide, the product having a required radioactivity at different application times that is the same as a given calibration time, characterized in that: - converting a concentrate containing a radionuclide into the required product labeled with the radionuclide, wherein the radionuclide is converted into the labeled product using a buffer solution, and a stock solution is thereby obtained, which, in addition to the product labeled with the radionuclide, contains all other components required for the intended use, wherein all other components contain at least one chelating agent component and at least one target molecule component, the target molecule component being capable of binding to a specific target within or on a target cell and the chelating agent component being covalently bound to the target molecule component to form a chelating agent - target molecule unit, and the radionuclide being coordinated to the chelating agent component, and wherein the radionuclide is selected from the group consisting of gallium - 68, yttrium - 90, molybdenum - 99, indium - 111, gadolinium - 146, gadolinium - 147, holmium - 166, lutetium - 177, tungsten - 188, rhenium - 188, bismuth - 205, bismuth - 206, and thorium - 227; - the required radionuclide contained in the stock solution has an activity such that a plurality of required batches can be obtained from the stock solution at the time of filling, each having a defined number of partial fills, and the partial fills of each batch each have the same radioactivity of the radionuclide at different application times as the given calibration time; - setting the activity of the product labeled with the radionuclide in the stock solution to be the same as the activity at the latest desired application time; - obtaining a partial fill of the first batch from the stock solution containing the product labeled with the radionuclide at a first filling time before the application time, wherein the first batch has an activity set to be the same as the activity at the latest application time, which corresponds to the activity at the calibration time at the actual application time; - providing a dilution solution, which contains all other components required for the intended use in addition to the product labeled with the radionuclide; - diluting the remaining stock solution after obtaining the first batch with the dilution solution such that at the filling time, compared with the latest application time, a reduced activity is achieved, so as to obtain a partial fill of the second batch for use at the previous application time, wherein the second batch has an activity set to be the same as the activity at the calibration time at an earlier application time; - gradually further diluting the remaining stock solution after obtaining the second batch with the dilution solution such that compared with the previous application time, a reduced activity is achieved, so that - at each further application time, partial fills of more batches are respectively obtained, wherein the more batches have an activity set to be the same as the activity at the calibration time at the corresponding application time.

2. The method according to claim 1, wherein Using the product labeled with the radionuclide, wherein a cyclic polyaza system having 4 to 8 N atoms is used as the chelating agent component.

3. The method according to claim 1, characterized in that Using 1,4,7,10 - tetraazacyclododecane - 1,4,7,10 - tetraacetic acid [DOTA] or one of its ionic forms as the chelating agent component.

4. The method according to any one of claims 1-3, characterized in that, The target molecule component is selected from the group consisting of: peptides and proteins.

5. The method according to claim 4, wherein A somatostatin analogue compound is used as the target molecule.

6. The method according to any one of claims 1 to 3, characterized in that, Edotreotide (DOTATOC) or a pharmaceutically acceptable salt thereof is used as the chelating agent target molecule unit.

7. The method according to any one of claims 1-3, characterized in that [Lu-177]Lu-DOTATOC or [Lu-177]Lu-PSMA is used as the product containing a radionuclide.

8. The method according to any one of claims 1 to 3, characterized in that, An auxiliary agent and / or a buffer system are also used in the stock solution and the dilution solution.

9. The method according to claim 8, characterized in that, An ascorbic acid / ascorbate buffer is used as the buffer system.

10. The method according to any one of claims 1-3, characterized in that, A leak-free fluid logic system under negative pressure is used to perform the method, and the buffer solution is mixed with the radionuclide-containing concentrate by circulating into a temperature-controlled reactor (4) in the fluid logic system.

11. The method according to any one of claims 1-3, characterized in that, The transformation carried out in the reactor (4) depends on the product being carried out at a temperature of 20 °C to 100 °C for a time of 5 minutes to several hours.

12. The method according to claim 10, characterized in that, Each partial fill passes through a sterile filter (11) before entering the manual fill vial (14).

13. The method according to claim 12, wherein A vented sterile filter with a pore diameter of 220 nm or a multi-layer filter with a first layer pore diameter of 450 nm and a second layer pore diameter of 220 nm is used as the sterile filter (11).

14. The method according to claim 13, wherein A bypass line (13) that returns to the batch vial (10) is used on the non-sterile side of the sterile filter (11) to prepare for the next batch fill and / or partial fill.

15. The method according to any one of claims 1 to 3, characterized in that Samples are taken from each batch for quality control.

16. An apparatus for performing the method according to any one of claims 1 to 15, having a fluid logic system connected with the following components: At least one reactor (4) An adjustable heating element (1) for heating the reactor (4); An adjustable vacuum pump (2) with a pneumatic device and an exhaust valve; An adjustable inert gas pneumatic device (3); A container (5) for formulating a solution fluidly connected to the reactor (4); A container (6) for diluting a solution; A reaction buffer container (7); A receiving container (8) for a radiochemical precursor; A filling metering device (9); A batch vial (10); A vented sterile filter (11); Air filters (12, 15); A bypass line (13) between the non-sterile side of the sterile filter (11) and the batch vial (10) fluidly connected thereto through a three-way joint; A manual fill vial (14); and A first joint group (16) with a multi-way valve; and A second joint group (17) with a multi-way valve; wherein the first joint group (16) is fluidly connected to the air filter (15), the batch vial (10), the inert gas pneumatic device (3), the container (6), the sterile filter (11), and the filling metering device (9); and wherein the second joint group (17) is fluidly connected to the reactor (4), the receiving container (8), the reaction buffer container (7), the bypass line (13), the batch vial (10), and the air filter (12), and the batch vial (10) is fluidly connected to the vacuum pump (2).

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