Radiopharmaceuticals for different ARTs

Abstract

The present invention relates to a method and an apparatus for producing a radionuclide-containing product having substantially the same desired activity of radioactivity in different applications for a given calibration time. In contrast to the procedures of the prior art, the method of the present invention makes it possible to ensure a consistent composition of the desired radionuclide-labeled pharmaceutical in all applications during its useful life by a single manufacturing process. According to the present invention, for example, a single manufacturing step can provide [nca Lu-177]Lu-DOTATOC with a constant activity in each application on each working day of the week.

Description

[Technical Field]

[0001] explanation The present invention relates to a method for producing radionuclide-containing products having substantially the same desired activity in different applications for a given calibration point in time according to the general terms of claim 1, as well as an apparatus according to claim 21 for carrying out this method. [Background technology]

[0002] Radiopharmaceuticals are radioactive compounds used in nuclear medicine. They are classified as diagnostic and therapeutic pharmaceuticals or so-called "theranotics," which can be used both therapeutically and diagnostically. They are often prepared directly on-site, which seems necessary, especially for diagnostic compounds, due to their short half-lives or shelf lives. Until a few years ago, complex therapeutic radiopharmaceuticals were often prepared locally in small quantities on a patient-oriented basis. Until now, simpler, less complex radiopharmaceuticals consisting of only a single radionuclide or simple radionuclide formulations have been centrally produced and distributed to nuclear medicine users. Examples of such pharmaceuticals include [I-131]NaI, [Ra-223]RaCl2, and [Sm-153]Sm-EDTMP. On the other hand, several suitable radioisotopes are available to those skilled in the art in sufficient quantities and pharmaceutical quality, notable examples being the isotopes Lu-177 and Ga-68, which have recently become important. For example, the applicant of the present patent application has already patented a carrier-free, highly pure Lu-177 compound (half-life = 6.64 days, β - This article describes a method for producing a cellulose acetate copolymer (cellulose acetate copolymer). In particular, the patent describes the carrier-free high purity 177 A preparative column chromatographic method for the preparation of Lu compounds is disclosed. 177 The Lu production method utilizes a cation exchanger and a suitable complexing agent. This method initially yields milligram quantities of carrier-free, highly pure Lu suitable for pharmaceutical and medical purposes. 177Lu compounds were irradiated with thermal neutrons. 176 This radionuclide can be produced from Yb compounds. 177 Lu and 176 Yb is provided at approximately 1:10 2 ~1:10 10 The mixture is refined to a mass ratio of

[0003] Furthermore, the present applicant's WO / 2018 / 122250A1 allows for the constant production of the positron emitter Ga-68 (half-life = 67.71 minutes) in pharmaceutical quality suitable for the manufacture of theranostics on-site, for example in a clinic's nuclear medicine laboratory. 68 Ge / 68 A Ga generator is disclosed. For example, US 10596278B2 provides a general overview of stable concentrated radionuclide complex solutions of the prior art. Chelator moieties and targeting moieties for radionuclides are well known to those skilled in the art, as they are described in detail, for example, in EP 1 289 571 B1. This document generally relates to prochelators and chelators of radiometal-labeled molecules. This document contains N n Macrocyclic polyaza compounds for labeling with radiometals containing systems have been described, in which n represents 4, 5 or 6 depending on the ring size, and at least one of the N atoms is substituted with a free carboxyl group for binding to the amino function of a biologically active effector molecule, and all of the N atoms carry protected side chains for the synthesis of the final molecule.

[0004] In particular, EP 1 289 571 B1 describes compounds of the general formula: [ka] (In the formula: The two Y groups may be in either the trans or cis configuration as shown; A represents an effector molecule, such as a peptide, in particular octreotide, CCK, substance P or gastrin, a protein, in particular an antibody or an enzyme, a sugar or a radiosensitizer, such as doxorubicin; R is hydrogen, C1-C3 alkyl or alcohol; X is a spacer, especially (CH2) n -X', where n is 1 to 10 and X' is COOH, NH2, SH, OH or O-halogen, which halogen is in particular Br, I or Cl, or a molecule of the formula [ka] or a molecule of the formula [ka] and Y is COO-, CH2CONH2 or CH2CH2OH describes a chelating agent for labeling biologically active molecules with radiometals, having the formula:

[0005] Furthermore, BREEMAN (2012) [Wouter AP BREEMAN; Practical Aspects of Labeling DTPA- and DOTA-Peptides with 90 Y, 111 In, 177 Lu, and 68 Ga for Peptide-Receptor Scintigraphy and Peptide-Receptor Radionucleide Therapy in Preclinical and Clinical Applications. The University of New Mexico Health Sciences Center, VOLUME 16, LESSON 5: 11 / 16 / 2012] describes the use of DTPA peptides and DOTA peptides for peptide-receptor scintigraphy and peptide-receptor radionucleide therapy in preclinical and clinical applications. 90Y, 111 In, 177 Lu, and 68 An overview of an embodiment of labeling with Ga is provided. Heppeler et al. (1999) disclosed a somatostatin analogue derivatized with a radiometal-labeled macrocyclic chelator moiety [Heppeler et al.: "Radiometal-labeled macrocyclic chelator-derivatized somatostatin analogue with superb tumor targeting properties and potential for receptor-mediated internal radiotherapy", Chem.-Eur. J., 1999, 5(7), 1974-1981]. Eisenwiener et al. (2001) disclosed the synthesis and peptide coupling of a DOTA-based prochelator, which forms 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. Meeting Info: 14th International symposium on Radiopharmaceutical chemistry Interlaken, Switzerland, June 10-15, 2001]. ANDRE et al. (1998) described 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA) as a bifunctional chelator for radioactive gallium-labeling of biomolecules [Andre, J. et al.: “1,4,7-Triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA): a new bifunctional chelator for radio gallium-labeling of biomolecules”, Chem. Commun., 1998, 12, 1301-1302].

[0006] Thus, as a result, a wide variety of suitable radionuclides and chelator and targeting moieties, as well as labeling techniques and labeling molecules for medical purposes, are available to those skilled in the art. As mentioned above, therapeutic radiopharmaceuticals, which consist of extremely complex formulations and components, present various challenges in their centralized production. The decay of radioactive components, which are generally short-lived, poses difficulties, for example, in maintaining the same composition of the pharmaceutical in all applications relative to the time of calibration (Activity Reference Time, ART). This problem has been solved, and has been solved until now, by so-called kit reconstitution at the time of application. Here, the radioactive components of the pharmaceutical are provided separately, and reconstitution, or even complex synthesis, and quality control must be performed on-site before application. Examples include Octreoscan ([In-111]In-pentetreotide) and Zevalin ([Y-90]Y-ibritumomab tiuxetan).

[0007] Another possibility to circumvent this difficulty is to manufacture radiopharmaceuticals for fixed-time application and make them available to users. Depending on the concept, this would result in disadvantages for either the manufacturer or the user. To make the drug available every day of the working week (Monday to Friday), the manufacturer would have to schedule at least five separate small batches per week for fixed-time application, with production plans and organizational lead times corresponding to the ordering process. A prior art production method is shown in Figure 1. This method is complex and costly, especially for regulatory reasons of drug approval, since each individual daily batch of drug requires intensive quality control and release by drug regulatory authorities, in addition to testing the exact amount of radioactivity used. When implementing this concept, existing production plants would be at maximum capacity and would be largely unavailable for radiopharmaceutical production.

[0008] An alternative concept of the prior art is to provide for the production of a single large batch per week. This would save the manufacturer from the above-mentioned disadvantages and would also allow the manufacturer to be more cost-effective. However, the disadvantage of this procedure is that the radiopharmaceutical is only available to the user at a predetermined time determined by the manufacturer, and the user must subordinate their overall schedule to the manufacturer. This situation is particularly disadvantageous for clinical users and, as experience has shown, results in a reduced acceptance of the corresponding radiopharmaceutical. The production system is shown diagrammatically in Figure 2. Another alternative is the personalized production of radiopharmaceuticals at the time of prescribed use. By calculating the decay of each isotope, a small amount of solution can be received at a predetermined time before use, whose activity matches the activity at the target time. However, with this approach, neither the radioactivity concentration nor the concentration of the compounds contained therein is constant, and the amount of target biomolecules also fluctuates. This can result in patients receiving suboptimal drug therapy. Summary of the Invention

[0009] Against this background, the object of the present invention is to provide radiopharmaceuticals with accurate and equal amounts of radioactivity at the time of calibration and at the time of specific application, in multiple individual batches, during a working week, without having to accept the above-mentioned disadvantages. This object is solved by a method comprising the features of claim 1. Regarding the device, the object is solved by a device according to claim 21. More particularly, the present invention relates to a method for producing a radionuclide-containing product having essentially the same desired activity at different application times (ART+1, ART+2, ART+3, ART+4) based on a given calibration time (ART), comprising: - a radionuclide-containing concentrate is provided, which concentrate contains the desired radionuclide in an activity such that a plurality of desired batches, each having a defined number of partial charges, can be obtained from the concentrate when filled, and each batch of partial charges at different application times (ART+1, ART+2, ART+3, ART+4) has a radionuclide of substantially the same activity relative to the calibration time (ART); - the radionuclides of the concentrate are converted into the desired radionuclide-labeled product, thus obtaining a bulk solution containing, in addition to the radionuclide-labeled product, all further components required for the intended use; - the activity of the radionuclide-labeled product in this bulk solution is set to the time of the last desired application (ART+4); - from the bulk solution containing the radionuclide-labeled product, a first batch of partial fills is withdrawn at the first fill before the time of application, which has an activity set at the time of the last application (ART+4) and which, at the time of its actual application, corresponds to the activity at the time of calibration (ART); - a dilute solution is supplied containing, except for the radionuclide-labeled product, all other components required for the intended use; - the remaining bulk solution set at the last desired application time (ART+4) is diluted with diluent solution at the time of filling so as to set a reduced desired activity based on the last application time (ART+4), so that a second batch of partial fill is drawn for use in the preceding application time, having an activity set at the earlier application time (ART+3), the actual application of which corresponds to the activity at the time of calibration (ART); The residual bulk solution, set at the earlier application time (ART+3), continues to be diluted stepwise with the dilution solution until the application time coincides with the calibration time (ART); and - further batches of partial fills, having the activity set at each application time (ART+2, ART+1), are drawn at each further application time (ART+2, ART+1), the last batch having the activity at the calibration time (ART).

[0010] The present invention allows the production of the pharmaceutical formulation Solucin® (registered trademark of ITM Isotopen Technologien Munchen AG) in a single manufacturing approach, including the filling of all possible ARTs, in a small and compact plant. Significantly fewer steps are required compared to the current prior art (see Figure 5). This allows manufacturers to save on production, testing, and release costs without limiting the effectiveness of the drug. Furthermore, additional capacity for other products is gained in the production plant, which means increased productivity and efficiency. This bulk approach has no theoretical limit. In contrast to Alternative 1, Alternative 2 of the present invention allows for the distribution of a second filling unit, which in turn saves on investment, maintenance, and qualification costs.

[0011] The present invention further provides an apparatus for carrying out the present invention, comprising the following components: adjustable heating element; Adjustable vacuum pump with pneumatics and bleed valve; Adjustable inert gas pneumatic pressure; at least one reactor; a container for the formulation solution fluidly connected to the reactor; Containers for diluted solutions; Reaction buffer container; receiving tanks for radiochemical precursors; filling / dispensing devices; bulk storage and mixing vessels; vented sterile filters; Air filter; a bypass line between the non-sterile side of the sterile filter and a bulk storage and mixing vessel fluidly connected thereto by a three-way valve; filling devices; and First stopcock with multi-port valve group and Second stopcock with multi-port valve group a fluid system in which First Cook group is in fluid communication with the inert gas pneumatic pressure, the container, the sterile filter, and the filling / dispensing device; and Second Cook group is in fluid communication with a reactor, a receiving vessel, a reaction buffer vessel, a bypass line, a bulk storage and mixing vessel, and an air filter, the bulk storage and mixing vessel being in fluid communication with a vacuum pump.

[0012] In principle, radiopharmaceuticals for different applications could be prepared according to Alternative 1 as follows: A concentrate is prepared at the last calibration (ART+4). From this concentrate, ART+4 is filled directly to 100%. Furthermore, all other ARTs (ART1-3) can be made equivalent by filling correspondingly smaller amounts of concentrate into their respective vials and then filling them with diluent to the required volume. However, this would require two corresponding filling units on the filling line: one for the concentrate and one for the diluent. The disadvantage of this is that, according to pharmaceutical legislation and GMP, each vial is a unique sample, which can lead to atypical sampling, especially in the quality control required by pharmaceutical practices. Furthermore, homogenization must be performed on each vial. This, according to pharmaceutical legislation, would impose significant validation efforts for the filling process, which would be costly and highly impractical. The filling scheme for prior art Alternative 1 is shown in Figure 3.

[0013] This is the advantage of the present invention (Alternative 2). According to the present invention, a concentrate is prepared at the last calibration (ART+4). From this concentrate, ART+4 is filled directly to 100%. Furthermore, from this concentrate, all other ARTs (ART1-3) can be equalized using dilution solutions. For this purpose, all ART+4 is first filled from the bulk container. Then, as opposed to the individual dilution fills in vials, the bulk batch is diluted to ART+3 in the same sequential fill. Finally, ART+2 and ART+1, etc., follow. The advantage of this inventive concept is the significantly smaller plant, consisting of only a single filling unit per filling line. Furthermore, the individual fills are prepared from a homogenous bulk batch. This results in a significantly more homogenous image for sampling from a quality control perspective. The filling scheme of the inventive method according to alternative 2 is shown in Figure 4. DETAILED DESCRIPTION OF THE INVENTION

[0014] In the following, preferred embodiments of the present invention are described. Particularly advantageously, the method of the invention can be carried out with all currently relevant radionuclides, such as those 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. Theranostics produced on the basis of the above-mentioned short-lived radionuclides, i.e. substances with therapeutic and / or diagnostic applications, are already well established in nuclear medicine and, using the method of the present invention, can be made available to clinical users in sufficient quantities and in consistently high quality, with precisely calibrated activity, respectively, over the entire application time within a working week.

[0015] Typically, within the scope of the present invention, radionuclide-labeled products are used that contain at least one chelator moiety and at least one targeting molecule moiety, where the targeting molecule moiety is capable of binding to a specific target in or on a target cell, the chelator moiety and the targeting molecule moiety are covalently linked to each other to form a chelator-targeting molecule unit, and the radionuclide is coordinately bound to the chelator moiety, which provides the optimal chemical structure for each radionuclide and target. Preferably, a cyclic polyaza system having 4 to 8 N atoms is used as the chelator component. This chelator has been proven to be advantageous for some transition metals. During the synthesis of the complex product, they can also be reversibly supplied without the need for protective groups to avoid undesired side reactions. A preferred pharmaceutically acceptable chelator moiety is 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. The target molecule components used within the scope of the present invention will in principle depend on the intended medical application. For example, somatostatin analog peptides have proven useful in the treatment and diagnosis of tumors. Particularly preferred are target molecule components selected from the group consisting of peptides, particularly cyclic peptides having 4 to 20 amino acids, at least one of which is a D-amino acid, particularly D-phenylalanine; and proteins, particularly receptor proteins, preferably PSMA. The substitution of D-amino acid enantiomers for L-amino acids in the targeting molecule moiety results in conjugated target peptides that are less exposed to in vivo attack by proteases or peptidases, which typically act as neutral substrates and degrade physiologically occurring L-amino acid peptides and proteins. By incorporating D-amino acids into the targeting molecule moiety, proteolytic degradation is significantly delayed, thereby significantly extending biological half-life.

[0016] As a somatostatin analogue compound, octreotide or octreotide analogues, particularly TOC, have emerged as target molecules. A particularly preferred system is the use of edotreotide (DOTATOC) or a pharmaceutically acceptable salt thereof as the chelator-targeting molecule unit. Within the context of the present invention, the use of [nca Lu-177]Lu-DOTATOC as the radionuclide-containing product is particularly preferred. This product, which can be produced by the method of the present invention, selectively binds to tumor tissue in so-called GEP-NETs and destroys it by delivering cytotoxic ionizing radiation doses. Neuroendocrine tumors (NETs) of the gastroenteropancreatic system (GEP) [GEP-NETs] comprise a group of tumors that vary widely in their growth and hormonal behavior. The spectrum of clinical course is similarly broad; on the one hand, there are benign tumors that can be diagnosed as incidental findings during imaging or histological review of surgical specimens; and on the other hand, there are rapidly growing tumors that have a clinically unfavorable course. The present invention has particular clinical significance for this type of tumor. The [nca Lu-177]Lu-DOTATOC provided by the method of the present invention is currently being tested by the applicant of the present invention in clinical phase III (as of February 2021) as Solucin® for the treatment of GEP-Net in a so-called competitive study. The formulation Solucin® consists of two molecular components: on the one hand, the target molecule edotreotide (DOTATOC), a somatostatin analogue, and, on the other hand, the EMA-approved beta-emitter EndolucinBeta® (carrier-free lutetium-177, registered trademark of ITM Isotopen Technologien München AG). Other product-peptide combinations that can be used in accordance with the present invention include, for example, [Lu-177]Lu-PSMA for the treatment and diagnosis of prostate cancer.

[0017] Preferably, in addition to the active pharmaceutical ingredient (API), excipients and / or buffer systems are utilized in the bulk and diluent solutions. Advantageously, ascorbic acid / ascorbate buffers, which have been frequently tested in practice, can be used as buffer systems. To carry out the method of the invention, a leak-free fluid system under negative pressure is used, as this completely avoids radioactive contamination. In a preferred embodiment, the conversion of radionuclides to labeled products is carried out via precursors, which are mixed with radionuclide-containing concentrates using temperature-controlled reactors looped through a fluid system. Temperature control allows for the realization of various reaction conditions required for each chemical system. For example, desired product-specific reactions can occur in reactors at temperatures ranging from 20°C to 100°C over times ranging from 5 minutes to several hours. To meet GMP hygiene standards, each partial fill is passed through a sterile filter before entering a pharmaceutically acceptable vial. For this purpose, commercially available ventilated sterile filters with a pore size of 220 nm or multi-layer filters with a pore size of 450 nm in the first layer and a pore size of 220 nm in the second layer are used. Typically, a bypass line returning to the bulk container is provided on the non-sterile side of the used sterile filter, whereby, on the one hand, the next batch fill and / or partial fill is prepared, and, on the other hand, substantially loss-free purging of the filling line and the sterile filter on the non-sterile side of the sterile filter can be carried out in an advantageous manner via the bypass line between individual batches, so that radioactivity is not carried over in an uncontrolled manner into the next fill and calibration to ART is also suitable for the subsequent fill.

[0018] To ensure quality, GMP-compliant samples are taken from each batch for quality control. Each individually taken batch was found to produce a homogenous image. Preferably, the method of the present invention is used to produce the radionuclide-containing product [Ruthenium-177]Lu-DOTATOC (SOLUCIN®), which contains the following activity and components relative to the time of calibration (ART): -Ruthenium-177 7.5±0.7GBq -Edotreotide (DOTATOC) 150±15μm -Ascorbic acid 20±2mg -Sodium ascorbate 80±8mg -Ultra pure water 1.00±0.01ml -0.1M sodium ascorbate diluted solution 18.0±2ml Further advantages and features of the present invention will become apparent on the basis of the description of the embodiments and from the following drawings. [Brief explanation of the drawings]

[0019] [Figure 1A] Schematic diagram for a manufacturer to provide a radiopharmaceutical at each application time within a working week, showing daily production, where ART = Activity Reference Time (calibration time). [Figure 1B] Schematic diagram for a manufacturer to provide a radiopharmaceutical for each application within a working week, showing pooled production, where ART = active reference time (calibration time). [Figure 2]FIG. 1 is a schematic diagram for the provision of radiopharmaceuticals as large batches of pharmaceuticals by manufacturers at specific times during the work week. [Figure 3] FIG. 1 is a filling schematic diagram according to Alternative 1. [Figure 4] FIG. 1 is a filling scheme according to the method of the present invention (Alternative 2). [Figure 5] FIG. 1 is a schematic diagram for providing radiopharmaceuticals for multiple applications within a one-week workweek via a monosynthetic approach of the present invention. [Figure 6] FIG. 1 shows a schematic layout of the structure of the fluid system of a synthesis apparatus and an apparatus for carrying out the method of the present invention. [Figure 7] 7 is a flow diagram for the manufacture of an ART-specific packing according to the structure of FIG. 6. [Figure 8] FIG. 1 is a schematic diagram of the purging process of the filling line and sterile filter via bypass. [Example]

[0020] Example of an embodiment The present invention is illustrated, without being limited thereto, by the example of the manufacturing method of Solucin® (registered trademark of ITM Isotopen Technologien München AG). The active ingredient of the pharmaceutical formulation Solucin® is [nca Lu-177]Lu-DOTATOC. Of course, the principles of the present invention can be transferred to other radiolabeled pharmaceuticals, such as [Lu-177]Lu-PSMA, and the same applies for use with other short-lived radionuclides. Figure 1 shows a schematic representation of the provision of radiopharmaceuticals by one manufacturer with at least five batches of pharmaceuticals at any given time within a working week according to the prior art. Figure 1A shows the situation in the case of daily production, while Figure 1B shows the situation with pooled production. ART is the "Activity Reference Time", i.e., the time of calibration. Figure 2 shows a schematic diagram of a production situation in which radiopharmaceuticals are provided by the manufacturer only once at a specific time during the working week, in this case on Wednesdays. In contrast to prior art methods, the method of the present invention allows for the preservation of a consistent composition (Table 1) of the desired radionuclide-labeled pharmaceutical for all applications within its shelf life through a single manufacturing process. The inventive loading scheme is shown in Figure 4, and the inventive monosynthetic approach to providing a radiopharmaceutical for multiple applications within a single work week is shown in Figure 5.

[0021] Table 1: Example standards for Solucin® at the time of calibration (ART) [Table 1]

[0022] The special configuration of the process fluidics used and the composition of the reagents ensure a compact, easily scalable and portable synthesis, which allows the production to be reduced to a single bulk batch, ensuring the advantage of daily availability. Figure 6 below: 1 controllable temperature element for heating up to 100°C in less than 5 minutes; 2 controllable vacuum pumps for raising the pressure to 200 mbar with air and bleed valves; 3 adjustable nitrogen pneumatic systems delivering pressures up to 6 bar; a glass or plastic reactor 4 with 2-3 connections; Container 5 or bag for formulation solution; Containers 6 or bags for diluted solutions; Syringe 7, reaction buffer in a vial or container; Template 8 for radiochemical precursors, in the example case Lu-177; 1-20 ml filling syringes; Bulk storage and mixing vessel 10; 0.22 μm vented sterile filter or 0.45 μm, 0.22 μm multi-layer filter; 0.22μm air filter; bypass line with sterile connector; Open or closed vial filling station14; 0.22μm air filter; First cock with 2-3 port valve group 16; Second cock with 2-3 port valve group 17 Schematic structures of fluidic systems, including:

[0023] This layout allows for the use of negative pressure to transfer fluids in a leak-proof manner. Syringe pump 9 is used solely for filling purposes and for diluting the bulk preparation to the corresponding ART. Preparation of the ART-specific bulk solution can be performed as follows: 1. Preparation of radiolabeled concentrate by adding a buffer solution to the radiochemical precursor and chemical precursor and heating in a suitable reactor. Temperature and time are product specific and can vary from room temperature to 100°C and from 5 minutes to several hours. 2. Preparation of the final ART (ART+, e.g., 4 days after manufacture) by adding the formulation solution and mixing until the ready-to-fill drug product is in the bulk container 10. ART+4 in this case means that the drug product at the time of calibration (ART) meets the specifications in Table 1 in this example. 3. Lossless purging of the filling line and sterile filter 11 (non-sterile side) via bypass line 13 back to the bulk container 10 in preparation for filling. 4. Filling ART+4 days and / or sampling for quality control 5. After filling is complete, optional further sampling or filter integrity testing can be performed with the aid of syringe pump 7 or N2 pneumatic system 3. 6. The filling syringe 9 is used to dilute the bulk Art+4 day to ART+3 day (or ART+4-X day) with the dilution solution (fill-up solution). 7. Thereafter, homogenization of the bulk preparation and purging of the bypass line 13 is carried out similar to the process described in item 3. 8. Next, fill the ART+3 day bulk batch etc. in the same manner as above.

[0024] The flow chart of FIG. 7 provides a schematic overview of the process for producing the ART specific packing of the present invention using the fluid system of FIG. The composition of the dilution solution and the amount to be added for each ART can be easily calculated based on the specifications of the radiopharmaceutical. Examples in Table 1 include Solucin® ([nca 177 For [Lu]Lu-DOTATOC), the data shown in Tables 2 and 3 below are obtained.

[0025] Table 2: Composition of final radiopharmaceutical and diluent solutions [Table 2]

[0026] Table 3: Ratio of ART+4 day formulation to corresponding ART+4-X day formulation [Table 3]

[0027] With proper job scheduling and easily verifiable spreadsheets, production planning according to the method of the present invention is easy to implement. The bypass from the sterile filter 11 back to the bulk container 10 via the bypass line 13 is crucial for the implementation of the present invention. Thanks to the circulation of the solution between the filling line / sterile filter and the bulk container, loss-free filling of all specific ARTs can be achieved in one plant in an economical and waste-management manner. To achieve the equivalent of a specific ART with one approach would require two filling lines, as in Alternative 1, or the filling line would have to be emptied and purged again after each ART, which would result in high losses and additional radioactive waste in the case of very long lines (expected as the clean room class changes from C to A due to new regulations). For this reason, the bypass in particular has a specific advantage in the targeted technical solution.

[0028] 8 shows the circulation and purging process of the bulk solution through the line path shown in wavy line format. This purging process ensures loss-free filling and a homogenous filled solution after a specific ART setting. In this exemplary method, this can be achieved, in particular, by using a bypass line 13 upstream of the sterile filter 11 that returns to the bulk container 10, and the line path is also purged and filled with homogenous solution. The bypass line 13 is connected to the first stopcock during purging. group The bypass line 13 is opened by the valve 16 and closed during filling. When the bypass line 13 is open, the natural resistance of the sterile filter 11 prevents the liquid from leaking through the sterile filter 11 and directs the flow direction of the medium into the bulk container 10. Another aspect of the present invention may be as follows. [1] A method for producing a radionuclide-containing product having essentially the same desired activity at different application times (ART+1, ART+2, ART+3, ART+4) for a given calibration time (ART), comprising: - a radionuclide-containing concentrate is provided, which concentrate contains the desired radionuclide in such an activity that a plurality of desired batches, each having a defined number of partial fills, can be obtained from said concentrate when filled, each batch of partial fills at different application times (ART+1, ART+2, ART+3, ART+4) having in each case substantially the same activity of said radionuclide relative to the calibration time (ART); - the radionuclides of the concentrate are converted into the desired radionuclide-labeled product, thus obtaining a bulk solution containing, in addition to the radionuclide-labeled product, all further components required for the intended use; - the activity of the radionuclide-labeled product in the bulk solution is set to the last desired application time (ART+4); - from the bulk solution containing the radionuclide-labeled product, a first batch of partial fills is drawn at the first fill before the time of application, which has an activity set at the time of the last application (ART+4) and which, at the time of its actual application, corresponds to the activity at the time of calibration (ART); - a dilute solution is provided which contains, except for the radionuclide-labeled product, all other components required for the intended use; - the residual bulk solution set at the last desired application time (ART+4) is diluted with the dilution solution at the time of filling to set a reduced desired activity based on the last application time (ART+4), so that a second batch of partial fills is drawn for use in the preceding application time, having an activity set at the earlier application time (ART+3), the actual application of which corresponds to the activity at the time of calibration (ART); The remaining bulk solution, set at an earlier application time (ART+3), continues to be diluted stepwise with the diluted solution until the application time coincides with the calibration time (ART); and - Further batches of partial fills, each with the activity set at the time of application (ART+2, ART+1), are drawn at each further application (ART+2, ART+1), with the final batch having the activity at the time of calibration (ART). The method, characterized in that [2] The method according to [1], 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. [3] The method according to [1] or [2], characterized in that a radionuclide-labeled product is used that contains at least one chelator component and at least one target molecule component, the target molecule component being capable of binding to a specific target in or on a target cell, the chelator component and the target molecule component being covalently bonded to each other to form a chelator-target molecule unit, and the radionuclide is coordinately bonded to the chelator component. [4] The method according to [3] above, characterized in that a product is used in which a cyclic polyaza system having 4 to 8 N atoms is used as a chelator component. [5] The method according to [4], wherein 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or one of its ionic forms is used as the chelator component. [6] The method according to any one of [1] to [5], wherein the target molecule component is selected from the group consisting of peptides, particularly cyclic peptides having 4 to 20 amino acids, at least one of which is a D-amino acid, particularly D-phenylalanine; and proteins, particularly receptor proteins, preferably PSMA. [7] The method according to [6], wherein a somatostatin analog compound, particularly octreotide or an octreotide analog, particularly TOC, is used as the target molecule. [8] The method according to any one of [1] to [7] above, wherein edotreotide (DOTATOC) or a pharmaceutically acceptable salt thereof is used as the chelator target molecule unit. [9] The method according to any one of [1] to [8], wherein [Lu-177]Lu-DOTATOC or [Lu-177]Lu-PSMA is used as the radionuclide-containing product.

[10] The method according to any one of [1] to [9], wherein in addition to the active pharmaceutical ingredient (API), excipients, such as common excipients and / or buffer systems, are used in the bulk solution and the diluted solution.

[11] The method according to

[10] , wherein an ascorbic acid / ascorbate buffer solution is used as the buffer system.

[12] The method according to any one of [1] to

[11] , wherein a leak-free fluid system under negative pressure is used to carry out the method.

[13] The method according to any one of [1] to

[12] , wherein a precursor is used for converting the radionuclide into a labeled product, and the precursor is converted in a temperature-controlled reactor (4) using a concentrate containing the radionuclide and introduced into the fluid system.

[14] The method according to

[13] , wherein the conversion is carried out in a reactor (4) at a temperature of 20°C to 100°C for a time period ranging from 5 minutes to several hours in a product-specific manner.

[15] The method according to any one of [1] to

[14] , wherein each partial fill is passed through a sterile filter (11) before entering a pharmaceutically acceptable vial (14).

[16] The method according to

[15] , characterized in that the sterile filter (11) is a ventilated sterile filter having a pore size of 220 nm or a multi-layer filter having a first layer with a pore size of 450 nm and a second layer with a pore size of 220 nm.

[17] The method according to

[16] , characterized in that in preparation for the next batch filling and / or partial filling, a bypass line (13) is used on the non-sterile side of the sterile filter (11) returning to the bulk container (10).

[18] The method according to

[17] , characterized in that between each batch via the bypass line (13) a substantially loss-free purging of the filling line and the non-sterile side of the inorganic filter (11) is carried out.

[19] The method according to any one of [1] to

[18] above, wherein samples are taken from each batch for quality control.

[20] [Lutetium-177]Lu-DOTATOC is produced as a radionuclide-containing product and the concentrate used has the following activity and composition relative to the calibration time (ART): - Lutetium-177 7.5±0.7GBq -Edotreotide (DOTATOC) 150±15μm -Ascorbic acid 20±2mg -Sodium ascorbate 80±8mg -Ultra pure water 1.00±0.01ml -0.1M sodium ascorbate diluted solution 18.0±2ml The method according to any one of [1] to

[19] above, comprising:

[21] An apparatus for carrying out the method according to at least one of [1] to

[20] , Contains: adjustable heating element (1); Adjustable vacuum pump (2) with air pressure and bleed valve; Adjustable inert gas pneumatic pressure (3); at least one reactor (4); a container (5) for the formulation solution fluidically connected to the reactor (4); Container for dilute solution (6); Reaction buffer container (7); Receptacle for radiochemical precursor (8); Filled medication dispensing devices (9); Bulk storage and mixing vessels (10); ventilated sterile filter (11); Air filters (12, 15); a bypass line (13) between the non-sterile side of the sterile filter (11) and a bulk storage and mixing vessel (10) fluidly connected thereto by a three-way valve; Filling device (14); and First stopcock with multi-port valve group (16); and Second stopcock with multi-port valve group (17) a fluid system in which First cock group (16) is in fluid communication with the inert gas air pressure (3), the container (6), the sterile filter (11), and the fill-and-dispense device (9); and The second cock group (17) is in fluid communication with the reactor (4), receiving vessel (8), reaction buffer vessel (7), bypass line (13), bulk storage and mixing vessel (10) and air filter (12), and the bulk storage and mixing vessel (10) is in fluid communication with the vacuum pump (2).

Claims

1. A method for producing multiple batches of a radionuclide-containing product, comprising: (a) obtaining a bulk solution containing (1) a radionuclide-labeled radionuclide-containing product and (2) any additional components required for the intended use; (b) obtaining a first batch from the bulk solution; (c) providing a dilution solution to the remaining bulk solution after obtaining the first batch to obtain a second batch; (d) supplying a dilution solution to the remaining bulk solution after obtaining the second batch to obtain a third batch; and (e) supplying a dilution solution to the remaining bulk solution after obtaining the third batch to obtain a fourth batch; Including, (i) wherein the first batch is to be applied at the time of application (ART+4), the third batch is to be applied at the time of application (ART+2), the second batch is to be applied at the time of application (ART+3), and the fourth batch is to be applied at the time of application (ART+1), and the order of application is at the time of application (ART+1), at the time of application (ART+2), at the time of application (ART+3), and at the time of application (ART+4); (ii) each batch is prepared so that the fourth batch at the time of application (ART+1), the third batch at the time of application (ART+2), the second batch at the time of application (ART+3), and the first batch at the time of application (ART+4) have the same radioactivity; and (iii) The diluted solution contains all the additional components required for the intended use of (2). The method, characterized in that

2. 2. The method of claim 1, 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.

3. 3. The method of claim 1 or 2, wherein a radionuclide-labeled product is used that contains at least one chelator moiety and at least one target molecule moiety, the target molecule moiety being capable of binding to a specific target in or on a target cell, the chelator moiety and the target molecule moiety being covalently linked to each other to form a chelator-target molecule unit, and the radionuclide is coordinately linked to the chelator moiety.

4. 4. The method according to claim 3, characterized in that a product is used in which a cyclic polyaza system having 4 to 8 N atoms is used as the chelator component.

5. 5. The method according to claim 4, wherein 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or one of its ionic forms is used as the chelator component.

6. The method according to any one of claims 1 to 5, wherein the target molecule component is selected from the group consisting of peptides and proteins.

7. 7. The method of claim 6, wherein the target molecule component is a cyclic peptide having 4 to 20 amino acids, at least one of which is a D-amino acid.

8. 8. The method of claim 7, wherein the D-amino acid is D-phenylalanine.

9. The method of claim 6 , wherein the target molecule component is a receptor protein.

10. 10. The method of claim 9, wherein the receptor protein is PSMA.

11. 7. The method of claim 6, wherein a somatostatin analog compound is used as the target molecule.

12. 12. The method of claim 11, wherein the somatostatin analog compound is octreotide or an octreotide analog.

13. 12. The method of claim 11, wherein the somatostatin analog compound is TOC.

14. 14. The method according to any one of claims 1 to 13, wherein edotreotide (DOTATOC) or a pharmaceutically acceptable salt thereof is used as the chelator targeting molecule unit.

15. 15. The method according to any one of claims 1 to 14, wherein as the radionuclide-containing product, [Lu-177]Lu-DOTATOC or [Lu-177]Lu-PSMA is used.

16. 16. The method according to any one of claims 1 to 15, characterized in that an excipient is used in the bulk solution and in the dilution solution.

17. 17. The method of claim 16, wherein the excipient is a common excipient and / or a buffer system.

18. 18. The method according to claim 17, characterized in that an ascorbic acid / ascorbate buffer is used as buffer system.

19. 19. The method according to any one of claims 1 to 18, characterized in that a leak-free fluid system under negative pressure is used to carry out the method.

20. A method according to claim 19, characterized in that the precursor used for the conversion of the radionuclide-labeled radionuclide-containing product is converted by a temperature-controlled reactor (4) using a concentrate containing the radionuclide and introduced into the fluid system.

21. 21. The process according to claim 20, characterized in that the conversion is carried out in a reactor (4) at a temperature between 20°C and 100°C for a time ranging from 5 minutes to several hours in a product-specific manner.

22. 22. The method according to any one of the preceding claims, characterized in that each batch is passed through a sterile filter (11) before being placed in a pharmaceutically acceptable vial (14).

23. 23. The method according to claim 22, characterized in that as sterile filter (11) a ventilated sterile filter with a pore size of 220 nm or a multi-layer filter with a pore size of 450 nm in the first layer and a pore size of 220 nm in the second layer is used.

24. 24. The method according to claim 23, characterized in that in preparation for the next batch filling, a bypass line (13) is used on the sterile filter (11) on its non-sterile side, returning to the bulk container (10).

25. 25. The method according to any one of claims 1 to 24, wherein samples are taken from each batch for quality control.

26. An apparatus for carrying out the method according to at least one of claims 1 to 25, comprising: The following ingredients: at least one reactor (4); an adjustable heating element (1) for heating the reactor (4); Adjustable vacuum pump (2) with air pressure and bleed valve; Adjustable inert gas pneumatic pressure (3); a container (5) for the formulation solution, fluidly connected to the reactor (4); Container for dilute solution (6); Reaction buffer container (7); a receiver for the radiochemical precursor (8); Filled medication device (9); Bulk storage and mixing vessel (10); ventilated sterile filter (11); Air filters (12, 15); a bypass line (13) between the non-sterile side of the sterile filter (11) and a bulk storage and mixing vessel (10) fluidly connected thereto by a three-way valve; a filling device (14); and a first group of cocks (16) having multi-port valves; and Second group of cocks (17) with multi-port valves a fluid system in which The first set of valves (16) are in fluid communication with an air filter (15), a bulk storage and mixing vessel (10), the inert gas pneumatic pressure (3), a vessel (6), a sterile filter (11), and a filling and dispensing device (9); and The apparatus, wherein the second set of cocks (17) is in fluid communication with the reactor (4), receiving vessel (8), reaction buffer vessel (7), bypass line (13), bulk storage and mixing vessel (10) and air filter (12), and the bulk storage and mixing vessel (10) is in fluid communication with the vacuum pump (2).

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