MANUFACTURE OF RADIOPHARMACEUTICALS FOR DIFFERENT TIMES OF APPLICATION

Description

[0001] The present invention relates to a method for producing radionuclide-containing products with the same desired radioactivity at different application times, based on a given calibration time, according to the preamble of claim 1, and to a device for carrying out the method according to claim 19. 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 pharmaceuticals are very often produced directly on site, which appears necessary due to their short half-life, or lifetime, particularly in the case of diagnostic compounds. Until a few years ago, complex therapeutic radiopharmaceuticals were also often produced locally in small quantities, depending on the patient.To date, only easily synthesized, less complex radiopharmaceuticals consisting either of a single radionuclide or a simple radionuclide formulation have been centrally manufactured and distributed to nuclear medicine users. Examples of such drugs include [I-131]NaI, [Ra-223]RaCl2, and [Sm-153]Sm-EDTMP.

[0002] A number of suitable radioactive isotopes are now available to the skilled person in sufficient quantities and of pharmaceutical quality. The recently important isotopes Lu-177 and Ga-68 are just a few examples: For example, the applicant of the present patent application describes in EP2546839B1 a patented process for the production of carrier-free, highly pure Lu-177 compounds (half-life = 6.64 days, ß-<-decay) for medical purposes.

[0003] In particular, a preparative column chromatography process for the production of such carrier-free, highly pure 177<Lu compounds is disclosed therein. A cation exchanger and a suitable complexing agent are used in the 177<Lu production process. This process makes it possible for the first time to produce carrier-free, highly pure 177<Lu compounds in milligram quantities for pharmaceutical and medical purposes in a highly pure form from 176<Yb compounds irradiated with thermal neutrons, with the radionuclides 177<Lu and 176<Yb being present for purification in a mass ratio of approximately 1:10 2< to 1:10 10<.

[0004] In addition, WO / 2018 / 122250A1 of the applicant of the present patent application discloses a 68<Ge / 68<Ga generator with which the positron emitter Ga-68 (half-life = 67.71 minutes) can be continuously generated on site, e.g. in the nuclear medicine laboratory of a clinic in pharmaceutical quality for the production of theranostics.

[0005] A general overview of stable concentrated radionuclide complex solutions of the state of the art is provided, for example, in US 10596278B2.

[0006] Chelator components for radionuclides and target components are described in detail in EP 1 289 571 B1, for example, and are thus well known to the person skilled in the art. This publication relates to prochelators and chelators of radiometal-labeled molecules in general.

[0007] There, macrocyclic polyaza compounds for labelling with radioactive metals are described, containing an N n system, where n stands for 4, 5 or 6, with different ring sizes, and where at least one of the N atoms is substituted by a free carboxyl group for coupling to an amino function in a biologically active effector molecule, where all N atoms carry a protected side chain for the synthesis of the final molecule.

[0008] In particular, EP 1 289 571 B1 describes a chelating agent for labelling biologically active molecules with a radioactive metal, having the general formula: where: the two Y groups can be arranged either trans or cis, 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 radiosensitizing agent such as doxorubicin; R represents hydrogen, C 1 -C 3 alkyl or an alcohol; X represents a spacer, in particular (CH 2 ) n -X', where n represents 1-10 and X' represents COOH, NH 2 , SH, OH or O-halogen, where the halogen is in particular Br, I or Cl, or a molecule of the formula or the formula Y stands for COO -< , CH 2 CONH 2 or CH 2 CH 2 OH, optionally complexed with a radioactive metal.

[0009] In addition, BREEMAN (2012) [Wouter AP 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] provides an overview of 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 radionuclide therapy in preclinical and clinical applications.

[0010] Heppeler et al. (1999) describe somatostatin analogues derivatized with radiometal-labeled macrocyclic chelator components [Heppeler et al.: "Radiometal-labelled 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].

[0011] Eisenwiener et al. (2001) disclose the synthesis and peptide coupling of a DOTA-based prochelator that 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. 694-696. PRINT. Meeting Info: 14th International symposium on Radiopharmaceutical chemistry, Interlaken, Switzerland, June 10-15, 2001].

[0012] ANDRÉ et al. (1998) describe 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA) as a bifunctional chelator for radiogallium-labeled biomolecules [André, J. et al.: "1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA): a new bifunctional chelator for radiogallium-labelling of biomolecules", Chem. Commun., 1998, 12, 1301-1302].

[0013] Rien et al. (2016) describe the radionuclide labeling of DOTA-TOC with Lu in a buffer solution [Rien et al.: "Synthesis of DOTA-TOC Conjugate as a Precursor of 177Lu-DOTA-TOC Radiopharmaceutical for Therapy and Diagnosis of Somatostatin Receptor Positive Cancer", Indonesian Polymer Journal, 2016, 19(1), 1-14].

[0014] Thus, a multitude of different radionuclides and suitable chelator components and target molecule components as well as labeling techniques and the use of the labeled molecules for medical purposes are available to the person skilled in the art.

[0015] For therapeutic radiopharmaceuticals, which – as described above – consist of extremely complex formulations and components, various challenges exist in their centralized manufacturing. For example, the decay of the generally short-lived radioactive component makes it difficult to ensure the same drug composition at all times of use with respect to a calibration time (Activity Reference Time, ART). This problem is currently emerging and has been solved in the past by so-called kit reconstitution at the point of use. In this case, the radioactive component of the drug is provided separately, and reconstitution or even a complex synthesis and quality control must be carried out on-site prior to use. Examples of this are Octreoscan ([In-111]In-pentetreotide) and Zevalin ([Y-90]Y-ibritumomab tiuxetan).

[0016] Another way to circumvent this difficulty is to produce the radiopharmaceutical for a fixed application time and make it available to the user. Depending on the design, this can result in disadvantages for either the manufacturer or the user. In order to make the drug available every day of the workweek (Monday to Friday), the manufacturer would have to announce at least five separate small batches per week for a fixed application time, with appropriate production planning and organizational lead time for the ordering process. This state-of-the-art production method is Fig. 1This process is complex and costly for the manufacturer, particularly for regulatory reasons related to drug approval, since each individual daily batch of drug – in addition to checking the correct amount of radioactivity used – requires intensive quality control and approval under pharmaceutical law. If such a concept were implemented, an existing production facility would be fully utilized and would be difficult to use for the production of other radiopharmaceuticals.

[0017] An alternative concept, based on the state of the art, is to produce a single large batch per week. This avoids the disadvantages mentioned above and would also result in more cost-effective production. The disadvantage of this procedure, however, is that the user only receives the radiopharmaceutical at predefined times determined by the manufacturer, and the user must subordinate their entire planning to the manufacturer. This situation is particularly disadvantageous for the clinical user, which can lead to, and experience shows, lower acceptance of the corresponding radiopharmaceutical product. Such a production regime is schematically illustrated in Fig. 2 shown.

[0018] Another alternative is the individualized production of radiopharmaceuticals at a defined time of use. Using decay calculations for the respective isotope used, a sufficiently small amount of solution can be withdrawn at a defined time before the time of use so that the activity corresponds to the activity at the target time. However, with this approach, neither the radioactivity concentration nor the concentration of the chemical compounds contained therein are constant, and the amount of the target biomolecule also varies. This can lead to suboptimal absorption of the drug in the patient.

[0019] Against this background, it is the object of the present invention to provide an exact and identical amount of radioactivity in radiopharmaceutical products at a specific time of use, based on a calibration time in a plurality of individual batches during the working week, without having to accept the disadvantages described above.

[0020] This problem is solved by a method having the characterizing features of claim 1.

[0021] In terms of device technology, the object is achieved by a device according to claim 19.

[0022] In particular, the present invention relates to a process for the preparation of radionuclide-containing products having the same desired activity of radioactivity at different application times (ART+1, ART+2, ART+3, ART+4), relative to a given calibration time (ART), wherein a radionuclide-containing concentrate is converted into a desired product labelled with the radionuclide, thus obtaining a stock solution which, in addition to the radionuclide-labelled product, contains all the other components required for the intended use, wherein the desired radionuclide is contained in the stock solution at an activity such that a plurality of desired batches, each with a defined number of partial fillings, can be obtained from the stock solution at a filling time, wherein each batch of partial fillings has the same activity of the radionuclide, relative to the calibration time (ART), at different application times (ART+1, ART+2, ART+3, ART+4); the activity of the radionuclide-labelled product in the stock solution is adjusted to a latest desired application time (ART+4);a first batch of partial fillings is taken from the stock solution containing the radionuclide-labelled product at a first filling time prior to the time of use, which;

[0023] has an activity set to the latest application time (ART+4) which, at its actual application time, corresponds to the activity at the calibration time (ART); a dilution solution is provided which, with the exception of the radionuclide-labelled product, contains all the other components required for the intended use; the remaining stock solution, which has been adjusted to the latest desired application time (ART+4), is diluted with the dilution solution in such a way that a desired reduced activity, relative to the latest application time (ART+4), is adjusted at the filling time, so that a second batch of partial fillings is taken for use at the previous application time, which has an activity adjusted to an earlier application time (ART+3) which, at its actual application time, corresponds to the activity at the calibration time (ART);the remaining stock solution, adjusted to the previous application time (ART+3), is gradually diluted with the dilution solution until the application time corresponds to the calibration time (ART); and further batches of partial fillings are taken at each subsequent application time (ART+2, ART+1), which have an activity adjusted to the respective application time (ART+2, ART+1), whereby the last batch has the activity of the calibration time (ART).

[0024] The invention enables the production of the pharmaceutical preparation Solucin® (registered trademark of ITM Isotopen Technologien München AG) in a single batch for all possible ARTs in a small and compact facility, including filling. This significantly reduces the number of batches required compared to the current state of the art (see Fig. 5). This saves the manufacturer manufacturing, testing, and release costs without limiting the availability of the drug. Furthermore, additional capacity is gained at the production facility for other products, which increases productivity and efficiency. There is no theoretical limit for the bulk batches. In contrast to alternative 1, alternative 2 according to the invention eliminates the need for a second filling unit, which in turn saves investment, maintenance, and qualification costs.

[0025] The present invention further relates to a device for carrying out the method according to the invention with a fluidic system to which the following components are connected: at least one reactor; an adjustable heating element for heating the reactor; an adjustable vacuum pump with pneumatics and vent valves; an adjustable inert gas pneumatics; a container for a formulation solution, which is fluidically connected to the reactor; a container for a dilution solution; a reaction buffer container; a storage container for a radiochemical precursor; a filling and dosing device; a bulk storage and mixing vessel; a vented sterile filter; an air filter; a bypass line between the non-sterile side of the sterile filter and the bulk storage and mixing vessel, which is fluidically connected to it via a three-way valve; a filling device; and a first valve bank with multi-way valves; and a second valve bank with multi-way valves;wherein the first valve bank is in fluidic connection with the air filter, the bulk storage and mixing vessel, the inert gas pneumatics, the container, the sterile filter, and the filling and dosing device; and wherein the second valve bank is in fluidic connection with the reactor, the feed vessel, the reaction buffer vessel, the bypass line, the bulk storage and mixing vessel, and the air filter, wherein the bulk storage and mixing vessel is in fluidic connection with the vacuum pump.

[0026] In principle, it would be possible to produce radiopharmaceuticals for different application times according to Alternative 1 as follows: A concentrate is produced for the latest calibration time (ART+4). The ART+4 is then filled directly from this concentrate at 100%. In addition, all other ARTs (ART1-3) can be prepared from this concentrate using a diluent. In this case, a correspondingly smaller amount of the concentrate is filled into the respective vials and then filled up to the specification-compliant volume with a diluent. However, this would require two corresponding filling units in the filling line, namely one filling line for the concentrate and one for the diluent. The disadvantage of this would be that each vial would have to be tested under pharmaceutical law and / orAccording to GMP, this would be unique, and this could result in a non-representative sample, particularly for the quality controls required in pharmaceutical practice. Furthermore, homogenization must be performed in the respective vial. This would entail a significant validation effort for the filling process and would be complex and rather impractical under the aforementioned pharmaceutical law aspects. The filling scheme according to Alternative 1 of the state of the art is shown in . Fig. 3 shown.

[0027] This is where the invention comes in (alternative 2): According to the invention, a concentrate is produced for the latest calibration time (ART+4). From this concentrate, the ART+4 is filled directly and at 100%. In addition, all other ARTs (ART1-3) can be prepared from this concentrate using a dilution solution. For this purpose, all ART+4 are first filled from the bulk vessel. Then - in contrast to the individual dilution fillings in vials mentioned above - the bulk batch is diluted to Art+3 and then filled. Finally, ART+2 and ART+1 etc. follow. The advantage of the inventive concept lies in the significantly smaller system, which consists of only a single filling unit in the filling line. Furthermore, the individual fillings are made from a homogeneous bulk batch. This results in a much more homogeneous sample for quality control sampling.A filling scheme of the process of the present invention according to alternative 2 is shown in . Fig. 4 shown.

[0028] Preferred embodiments of the present invention are described below: The method according to the invention can be carried out particularly advantageously with all currently relevant radionuclides. These include, for example, 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.

[0029] Theranostics produced on the basis of the aforementioned short-lived radionuclides - i.e. substances that can be used therapeutically and / or diagnostically - have already proven themselves in numerous applications in nuclear medicine and can be made available to clinical users using the method according to the invention with precisely calibrated activity, in sufficient quantity and consistently high quality for all application times within a working week.

[0030] Typically, within the scope of the present invention, a product labeled with the radionuclide is used, which contains 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 in or to a target cell, and wherein the chelator component and the target molecule component are covalently bonded to one another to form a chelator-target molecule unit, and the radionuclide is coordinately bound to the chelator component. This provides the optimal chemical structure for each radionuclide and target.

[0031] Preferably, a product is used in which a cyclic polyaza system with 4 to 8 nitrogen atoms serves as the chelator component. Such chelators have proven advantageous for a number of transition metals. They can also be easily reversibly protected with protective groups during the synthesis of the complex products to avoid undesirable side reactions.

[0032] A preferred pharmaceutically acceptable chelating component is the commercially available 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or one of its ionic forms or pharmaceutically acceptable salts.

[0033] The target molecule components used in the present invention are fundamentally based on the intended medical application.

[0034] For tumor therapy and diagnostics, for example, somatostatin-analogous peptides have proven useful. Particularly preferred are target molecule components selected from the group consisting of: peptides, in particular cyclic peptides with 4 to 20 amino acids, where at least one amino acid is a D-amino acid, in particular D-phenylalanine; and a protein, in particular a receptor protein, preferably PSMA.

[0035] The replacement of L-amino acids with D-amino acid enantiomers in the target molecule components is designed to reduce the exposure of the coupled target peptides to in vivo attacks by proteases or peptidases, as these typically degrade physiologically occurring L-amino acid peptides and proteins as natural substrates. The integration of D-amino acids into the target molecule component thus significantly extends the biological half-life because proteolytic degradation is significantly delayed.

[0036] An octreotide or an octreotide analogue, in particular TOC, has emerged as a target molecule for the somatostatin analogue compound.

[0037] A particularly preferred system is to use edotreotide (DOTATOC) or a pharmaceutically acceptable salt thereof as the chelator-target molecule unit. Within the scope of the present invention, it is particularly preferred to use a [nca Lu-177]Lu-DOTATOC as the radionuclide-containing product. This product, which can be prepared using the method according to the invention, binds selectively to the tumor tissue of so-called GEP-NETs and destroys them by delivering cytotoxic, ionizing doses of radiation. Neuroendocrine tumors (NETs) of the gastroenteropancreatic system (GEP) [GEP-NETs] comprise a group of tumors with significant differences in their growth and hormonal behavior.The spectrum of clinical courses is equally broad: on the one hand, there are benign tumors that are diagnosed as incidental findings in imaging or histological processing of surgical specimens; on the other hand, there are clinically unfavorable courses due to rapidly growing tumors.

[0038] The present invention is of particular clinical importance for this type of tumor.

[0039] The [nca Lu-177]Lu-DOTATOC provided by the method according to the 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-Nets in the so-called COMPETE study. The drug Solucin ®< consists of two molecular components: the targeting molecule edotreotide (DOTATOC), a somatostatin analogue, and the EMA-approved beta emitter EndolucinBeta ®< (no-carrier-added lutetium-177, registered trademark of ITM Isotopen Technologien München AG).

[0040] Other product-peptide combinations which can be used according to the invention include, for example, [Lu-177]Lu-PSMA for the treatment and diagnosis of prostate cancer.

[0041] In addition to the active pharmaceutical ingredients (API), excipients such as general excipients and / or buffer systems are preferably used in the stock solution and the diluent solution.

[0042] An ascorbic acid / ascorbate buffer can be used advantageously as a buffer system, which has proven itself many times in practice.

[0043] To carry out the method according to the invention, a leak-free fluidic system under negative pressure is advantageously used because this allows radioactive contamination to be completely avoided.

[0044] In a preferred embodiment, the conversion of the radionuclide to the labeled product takes place using precursors that are reacted with the radionuclide-containing concentrate in a temperature-controlled reactor integrated into the fluidic system. Temperature control allows for the implementation of different reaction conditions required for the respective chemical system. For example, a desired conversion can be carried out in the reactor at a temperature of 20°C to 100°C, depending on the product, and for a time of 5 minutes to several hours.

[0045] To meet GMP hygiene standards, each partial fill is passed through a sterile filter before being poured into a pharmaceutically acceptable vial. For this purpose, commercially available vented sterile filters with a pore diameter of 220 nm or a multilayer filter with a first layer pore diameter of 450 nm and a second layer pore diameter of 220 nm are advantageously used.

[0046] Typically, a by-pass line is provided on the non-sterile side of the sterile filter used, leading back into a bulk vessel. This prepares the next batch filling and / or partial filling and advantageously allows a substantially loss-free rinsing of a filling line and the sterile filter on its non-sterile side to be carried out between the individual batches via the by-pass line, so that no radioactivity is carried over uncontrolled into the next filling and the calibration to the ART is also correct for the subsequent filling.

[0047] To ensure quality, samples are taken from each batch for quality control in accordance with GMP standards. This has shown that the individual batches present a homogeneous picture.

[0048] The process according to the invention is preferably used to produce [Lutetium-177]Lu-DOTATOC (SOLUCIN ®< ) as a radionuclide-containing product, using a concentrate which contains the following activity and components based on the calibration time (ART): - Lutetium-177 7.5 ± 0.7 GBq - Edotreotide (DOTATOC) 150 ± 15 µm - Ascorbic acid 20 ± 2 mg - sodium ascorbate 80 ± 8 mg - Ultrapure water 1.00 ± 0.01 ml - 0.1 M Na-ascorbate diluent 18.0 ± 2 ml.

[0049] Further advantages and features of the present invention will become apparent from the description of embodiments and from the drawings.

[0050] It shows: Fig. 1 shows a scheme for providing a radiopharmaceutical at any application time within a working week using at least 5 drug batches by a manufacturer. A) Daily production. B) Pooled production. ART = Activity Reference Time (calibration time); Fig. 2 shows a scheme for providing a radiopharmaceutical at a specific application time within a working week using a large drug batch by a manufacturer; Fig. 3 shows a filling scheme according to alternative 1; Fig. 4 shows a filling scheme according to a method according to the invention (alternative 2); Fig. 5 shows a scheme for providing a radiopharmaceutical at multiple application times within a working week using a single synthesis approach according to the invention; Fig. 6 shows a schematic arrangement of a synthesis apparatus and the fluidics structure of a device for carrying out the method according to the invention; Fig.7a flow chart for the production of ART-specific fillings according to the setup in . Figure 6 ; and Fig. 8 a scheme of a rinsing process of a filling line and a sterile filter via a bypass. Example

[0051] The present invention is described, without limitation, using the example of a process for the production of Solucin® (a registered trademark of ITM Isotopen Technologien München AG). The active ingredient of the pharmaceutical preparation Solucin® is [nca Lu-177]Lu-DOTATOC.

[0052] Of course, the principles of the present invention can also be applied to other radiolabeled pharmaceuticals, such as [Lu-177]Lu-PSMA. The same applies to the use with other short-lived radionuclides.

[0053] In Fig. 1For the purpose of illustration, the provision of a radiopharmaceutical according to the state of the art at each application time within a working week by at least 5 drug batches by a manufacturer is shown schematically. Fig.1 A) shows the situation in daily production, while Fig. 1 B) reflects the situation with pooled production. ART is the "Activity Reference Time," i.e., the calibration time.

[0054] Fig. 2 shows a schematic representation of the manufacturing situation when a radiopharmaceutical is only made available by the manufacturer at a specific time of use within a working week - here on Wednesdays.

[0055] In contrast to the prior art processes, the process according to the invention allows the consistent composition of the desired radionuclide-labeled pharmaceutical to be ensured at all times of use within the shelf life through a single manufacturing process (Table 1). The filling scheme according to the present invention is shown in Fig. 4 shown and the supply situation of a radiopharmaceutical at several application times within a working week by a single synthesis approach according to the present invention is shown in Fig. 5 shown. Table 1: Example specification of Solucin ®< at the time of calibration (ART) ingredient Quantity per vial / value at ART Lutetium (177< Lu) 7.5 ± 0.7 GBq Edotreotide 150 ± 15 µg Ascorbic acid 20 ± 2 mg Sodium ascorbate 80 ± 8 mg Ultrapure water 1.00 ± 0.01 ml Formulation, 0.1 M sodium ascorbate 18 ± 2 ml

[0056] The unique configuration of the process fluidics and the composition of the reagents used ensure a compact, easily scalable, and transferable synthesis. This reduces production to a single bulk batch and ensures the benefits of daily availability.

[0057] Fig. 6 shows the schematic structure of the fluidics, as well as the other devices and arrangements for synthesis, with: An adjustable temperature element 1 for heating up to 100°C within 5 min; an adjustable vacuum pump 2 up to 200 mbar with pneumatics and vent valves; an adjustable nitrogen pneumatic 3, which delivers a pressure of up to 6 bar; a reactor 4 made of glass or plastic with 2-3 connections; a container 5 or bag for the formulation solution; a container 6 or bag for the dilution solution; a reaction buffer in a syringe 7, vial or container; a reservoir 8 for a radiochemical precursor, in the example case Lu-177; a 1-20 ml filling syringe; a bulk storage and mixing vessel 10; a vented sterile filter 0.22 µm or multi-layer filter 0.45 µm, 0.22 µm; an air filter 0.22 µm; a by-pass line 13 with aseptic connector; an open- or closed-vial filling station 14; a 0.22 µm air filter; a first valve bank 16 with 2-3 way valves; and a second valve bank 17 with 2-3 way valves.

[0058] The design allows for leak-proof transfer of liquids using negative pressure. Syringe pump 9 is used solely for filling and diluting the bulk solution to the corresponding ARTs. The preparation of the ART-specific bulk solutions can be carried out as follows: 1. Produce the radiolabeled concentrate by adding buffer solution to the radiochemical and chemical precursors and heating in an appropriate reactor. Temperature and time are product-specific and can vary between room temperature and 100°C and from 5 minutes to several hours. 2. Produce the latest ART (e.g. ART+4 days after production) by adding the formulation solution and mixing in the bulk vessel 10 to form the drug product ready for filling. ART+4 in this case means that the drug product meets the specification according to Table 1 at the calibration time (ART) in the example case. 3. Flush the filling line and the sterile filter 11 (unsterile side) loss-free via bypass line 13 back into the bulk vessel 10 in preparation for filling. 4. Fill ART+4 days and / or take samples for quality control. 5. After filling, another sample can optionally be taken orA filter integrity test can also be performed using the syringe pump 7 or N2 pneumatics 3. 6. The filling syringe 9 is used to dilute the bulk ART+4 days to ART+3 days (or ART+4-X days) using the dilution solution. 7. The bulk batch is then homogenized and the bypass line 13 is rinsed in a similar manner to the process described in point 3. 8. The bulk batch ART+3 days, etc., is then filled in a similar manner as described above.

[0059] The flowchart according to Fig. 7 gives a schematic overview of the inventive manufacturing process of ART-specific fillings with a fluidic system according to Fig. 6 .

[0060] The composition of the dilution solution and the addition amounts for the individual ARTs can be easily calculated based on the radiopharmaceutical specifications. For the example Solucin ®< ([nca 177< Lu]Lu-DOTATOC) in Table 1, the data are as shown in Tables 2 and 3: Table 2: Composition of the final radiopharmaceutical and diluent solution. Salary Specified concentration at ART Concentration of the dilution solution Lutetium (177< Lu) 0.64 GBq / mL ± 10% - Edotreotide max. 8.33 µg / mL max. 8.33 µg / mL Sodium ascorbate 0.1 M 0.1 M Table 3: Proportion of the Art+4 day formulation to the corresponding ART+4-X day formulations. ART Activity at ART Activity at filling time Vol. of ART+4 Dilution solution from Table 2 Concentration at ART DOTATOC days [GBq] [GBq] [mL] [mL] [GBq / mL] [µg] 0 7.7 7.7 12.1 5.9 0.64 150 1 7.7 8.5 13.3 4.7 0.64 150 2 7.6 9.4 14.7 3.3 0.64 150 3 7.7 10.5 16.4 1.6 0.64 150 4 7.6 11.5 18.0 0.0 0.64 150

[0061] Through appropriate order planning and an easily validated spreadsheet, production planning can be easily implemented using the method according to the invention.

[0062] Crucially crucial for the implementation of the present invention is a bypass via bypass line 13 from the sterile filter 11 back to the bulk vessel 10. By circulating the solutions between the filling line / sterile filter and the bulk vessel, loss-free filling of all specific ARTs in one plant can be designed in an economically and waste-management-friendly manner. To produce the specific ARTs in one batch, either two filling lines are necessary, as in Alternative 1, or the filling line would have to be emptied and re-flushed after each ART. This would result in high losses and additional radioactive waste in very long lines (as expected, as cleanroom classes are being changed from C to A due to new regulations). For this reason, the bypass, in particular, offers a particular advantage for the technical solution to the problem.

[0063] Fig. 8shows the circulation of the bulk solution and the rinsing process via the dashed-line lines. This rinsing process guarantees loss-free filling and a homogeneous filling solution after setting the specific ARTs. In the present exemplary process, the lines can also be rinsed and filled with a homogeneous solution, particularly through the bypass line 13 upstream of the sterile filter 11 back into the bulk vessel 10. The bypass line 13 is opened by a valve on the first valve bank 16 during rinsing and closed during filling. When the bypass line 13 is open, the natural resistance of the sterile filter 11 prevents liquid from escaping via the sterile filter 11 and directs the flow of the medium into the bulk vessel 10.

Claims

1. A method for the manufacture of radionuclide-containing products having an identical desired activity of radioactivity at different times of application (ART+1, ART+2, ART+3, ART+4), with respect to a given calibration time (ART), characterized in that - a radionuclide-containing concentrate is converted to a desired radionuclide-labeled product and thus a bulk solution is obtained which, in addition to the radionuclide-labeled product, contains all further components required for the intended use, wherein - the desired radionuclide is contained in the bulk solution in such an activity that a plurality of desired batches, each with a defined number of partial fillings, can be obtained from the bulk solution at a filling time, each batch of partial fillings at different times of application (ART+1, ART+2, ART+3, ART+4) in each case having an identical activity of the radionuclide, with respect to the calibration time (ART); - the activity of the radionuclide-labeled product in the bulk solution is set to a latest desired time of application (ART+4); - from the bulk solution containing the radionuclide-labeled product, a first batch of partial fillings is taken at a first filling time prior to the time of application, which has an activity set to the latest time of application (ART+4) which, at its actual time of application, corresponds to the activity at the calibration time (ART); - a diluting solution is provided, which, with the exception of the radionuclide-labeled product, includes all other components required for the intended use; - the remaining bulk solution set to the latest desired time of application (ART+4) is diluted with the diluting solution in such a way that, at the time of filling, a desired reduced activity based on the latest time of application (ART+4) is set, so that for use at the preceding time of application, a second batch of partial fillings is taken, which has an activity set to an earlier time of application (ART+3), which at its actual time of application, corresponds to the activity at the calibration time (ART); - the remaining bulk solution set to the earlier time of application (ART+3) is continued to be diluted stepwise with the diluting solution until the time of application corresponds to the calibration time (ART); and - further batches of partial fillings are respectively taken at each further time of application (ART+2, ART+1), which have an activity set to the respective time of application (ART+2, ART+1), the last batch having the activity of the calibration time (ART).

2. The method according to claim 1, characterized in that 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 claim 1 or 2, characterized in that a radionuclide-labeled product is used, which 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, and the chelator component and the target molecule component being bonded to each other covalently to form a chelator-target molecule unit, and the radionuclide being coordinately bound to the chelator component.

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

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

6. The method according to any of the preceding claims 1 to 5, characterized in that the target molecule component is selected from the group consisting of: peptides, in particular cyclic peptides with 4 to 20 amino acids, at least one amino acid being a D-amino acid, in particular D-phenylalanine; and a protein, in particular a receptor protein, preferably PSMA.

7. The method according to claim 6, characterized in that as the target molecule, a somatostatin analog compound, in particular an octreotide or an octreotide analog, in particular TOC, is used.

8. The method according to any of the preceding claims 1 to 7, characterized in that as chelator target molecule unit, edotreotide (DOTATOC) or a pharmaceutically acceptable salt thereof, is used.

9. The method according to any of the preceding claims 1 to 8, characterized in that as the radionuclide-containing product, an [Lu-177]Lu-DOTATOC or an [Lu-177]Lu-PSMA is used.

10. The method according to any of the preceding claims 1 to 9, characterized in that in addition to the active pharmaceutical ingredients (API), excipients such as general excipients and / or buffer systems are used in the bulk solution and the diluting solution.

11. The method according to claim 10, characterized in that as a buffer system, an ascorbic acid / ascorbate buffer is used.

12. The method according to any of the preceding claims 1 to 11, characterized in that for carrying out the method, a leakage-free fluidic system under negative pressure is used.

13. The method according to claim 12, characterized in that for conversion of the radionuclide to the labeled product, precursors are used, which are converted using the concentrate containing the radionuclide by means of a temperature-controlled reactor (4) introduced into the fluidic system.

14. The method according to claim 13, characterized in that the conversion is carried out in the reactor (4) in a product-specific manner at a temperature of 20°C to 100°C and for a time ranging from 5 min to several hours.

15. The method according to any of the preceding claims 1 to 14, characterized in that each partial filling is guided through a sterile filter (11) before entering a pharmaceutically acceptable vial (14).

16. The method according to claim 15, characterized in that as sterile filter (11), a ventilated sterile filter with a pore diameter of 220 nm or a multilayer filter having a pore diameter of 450 nm of a first layer and a pore diameter of a second layer of 220 nm is used.

17. The method according to claim 16, characterized in that on the sterile filter (11), on the non-sterile side thereof, a by-pass line (13) back into a bulk vessel (10) is used in preparation for the next batch filling and / or partial filling.

18. The method according to any of the preceding claims 1 to 17, characterized in that samples are taken from each batch for quality control.

19. An apparatus for carrying out the method according to at least one of claims 1 to 18 comprising a fluidic system to which the following components are connected: at least one reactor (4) an adjustable heating element (1) serving for heating the reactor (4); an adjustable vacuum pump (2) with pneumatics and bleed valves; adjustable inert gas pneumatics (3); a vessel (5) for a formulation solution, which is connected to the reactor (4) in a fluidic manner; a vessel (6) for a diluting solution; a reaction buffer vessel (7); a receiver vessel (8) for a radiochemical precursor; a filling dosing device (9); a bulk storage and mixing vessel (10); a ventilated sterile filter (11); an air filter (12, 15); a by-pass line (13) between the non-sterile side of the sterile filter (11) and the bulk storage and mixing vessel (10) connected thereto in a fluidic manner via a three-way valve; a filling device (14); as well as a first cock bank (16) having multi-port valves; and a second cock bank (17) having multi-port valves; wherein the first cock bank (16) is in fluidic communication with the air filter (15), the bulk storage and mixing vessel (10), the inert gas pneumatics (3), the vessel (6), the sterile filter (11) as well as the filling dosing device (9); and wherein the second cock bank (17) is in fluidic communication with the reactor (4), the receiver vessel (8), the reaction buffer vessel (7), the by-pass line (13), the bulk storage and mixing vessel (10) and the air filter (12), the bulk storage and mixing vessel (10) being in fluidic communication with the vacuum pump (2).