Radiopharmaceuticals at Different Activity Reference Times

Abstract

A method and an apparatus for producing radionuclide-containing products having substantially the identical desired activity of radioactivity at different times of application, with respect to a given calibration time. The method according to the invention allows to ensure a consistent composition of the desired radionuclide-labeled pharmaceutical at all times of application within the shelf life through a single manufacturing process. With the present invention it is possible, for example, to provide [n.c.a. Lu-177]Lu-DOTATOC on each working day of the week with constant activity at the respective time of application in a single manufacturing step.

Claims

1.-19. (canceled)

20. 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; 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 (ART+3) 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 application time 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).

21. The method of claim 20, 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.

22. The method of claim 20, 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.

23. The method according to claim 22, 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.

24. The method of claim 23, 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.

25. The method of claim 20, 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.

26. The method of claim 25, characterized in that as the target molecule, a somatostatin analog compound, in particular an octreotide or an octreotide analog, in particular TOC, is used.

27. The method of claim 20, characterized in that as chelator target molecule unit edotreotide (DOTATOC) or a pharmaceutically acceptable salt thereof, is used.

28. The method of claim 20, characterized in that as the radionuclide-containing product an [Lu-177]Lu-DOTATOC or an [Lu-177]Lu-PSMA is used.

29. The method of claim 20, 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.

30. The method of claim 29, characterized in that as a buffer system an ascorbic acid/ascorbate buffer is used.

31. The method of claim 20, characterized in that for carrying out the method, a leakage-free fluidic system under negative pressure is used.

32. The method of claim 31, 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.

33. The method of claim 32, characterized in that the conversion is carried out in the reactor 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.

34. The method of claim 20, characterized in that each partial filling is guided through a sterile filter before entering a pharmaceutically acceptable vial.

35. The method of claim 34, characterized in that as sterile filter, 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.

36. The method of claim 35, characterized in that on the sterile filter, on the non-sterile side thereof, a by-pass line back into a bulk vessel is utilized in preparation for the next batch filling and/or partial filling.

37. The method of claim 20, characterized in that samples are taken from each batch for quality control.

38. An apparatus for carrying out the method of claim 20 comprising a fluidic system to which the following components are connected: at least one reactor; an adjustable heating element serving for heating the reactor; an adjustable vacuum pump with pneumatics and bleed valves; adjustable inert gas pneumatics; a vessel for a formulation solution, which is connected to the reactor in a fluidic manner; a vessel for a diluting solution; a reaction buffer vessel; a receiver vessel for a radiochemical precursor; a filling dosing device; a bulk storage and mixing vessel; a ventilated sterile filter; an air filter; a by-pass line between the non-sterile side of the sterile filter and the bulk storage and mixing vessel connected thereto in a fluidic manner via a three-way valve; a filling device; a first cock bank having multi-port valves; and a second cock bank having multi-port valves; wherein the first cock bank is in fluidic communication with the air filter, the bulk storage and mixing vessel, the inert gas pneumatics, the vessel, the sterile filter and the filling dosing device; and wherein the second cock bank is in fluidic communication with the reactor, the receiver vessel, the reaction buffer vessel, the by-pass line, the bulk storage and mixing vessel and the air filter, the bulk storage and mixing vessel being in fluidic communication with the vacuum pump.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0136] Further advantages and features of the present invention will become apparent on the basis of the description of embodiments as well as by way of the drawing:

[0137] FIG. 1A) and FIG. 1B) are a scheme for providing for a radiopharmaceutical at each time of application within a working week by at least 5 batches of pharmaceuticals by a manufacturer. A) Manufacture on a daily basis. B) Manufacturing pooled. ART=Activity Reference Time (calibration time);

[0138] FIG. 2 is a scheme for the provision of a radiopharmaceutical at a specific time of application within a working week by way of a large batch of pharmaceuticals by a manufacturer;

[0139] FIG. 3 is a filling scheme according to alternative 1;

[0140] FIG. 4 is a filling scheme according to a method according to the invention (alternative 2);

[0141] FIG. 5 is a scheme for providing a radiopharmaceutical at several times of application within a working week by a single synthesis approach according to the invention;

[0142] FIG. 6 is a schematic arrangement of a synthesis apparatus and structure of the fluidic system of an apparatus for carrying out the method according to the invention;

[0143] FIG. 7 is a flow diagram for the manufacture of ART-specific fillings according to the structure in FIG. 6; and

[0144] FIG. 8 is a scheme of the purging process of a filling line and a sterile filter via a by-pass.

EXAMPLE OF EMBODIMENT

[0145] The present invention is described without restriction hereto by the example of a method for the manufacture of Solucin? (registered trademark of ITM Isotopen Technologien M?nchen AG). Active ingredient of the pharmaceutical preparation Solucin? is [n.c.a. Lu-177]Lu-DOTATOC.

[0146] Naturally, the principles of the present invention can also be transferred to other radiolabeled pharmaceuticals such as [Lu-177]Lu-PSMA. The same applies to the use with other short-lived radionuclides.

[0147] FIG. 1A) and FIG. 1B) schematically illustrate the provision of a radiopharmaceutical according to the prior art at any time of application within a working week by at least 5 batches of pharmaceuticals by one manufacturer. FIG. 1A) shows the situation in case of daily manufacture, while FIG. 1B) shows the situation with pooled production. ART is the Activity Reference Time, i.e. the calibration time.

[0148] FIG. 2 shows a schematic representation of the manufacturing situation when a radiopharmaceutical is only provided by a manufacturer at a specific time within a working weekin this case Wednesdays.

[0149] In contrast to the methods of the prior art, the method according to the invention allows for safeguarding a consistent composition of the desired radionuclide-labeled pharmaceutical at all times of application within the shelf life (Table 1) by a single manufacturing process. The filling scheme according to the present invention is shown in FIG. 4, and the situation of providing a radiopharmaceutical at several times of application within a working week by a single synthesis approach according to the present invention is shown in FIG. 5.

TABLE-US-00002 TABLE 1 Exemplary specification of Solucin? at the calibration time point (ART) Amount per vessel (vial)/ Component Value on ART Lutetium (.sup.177Lu) 7.5 ? 0.7 GBq Edotreotide 150 ? 15 ?g Ascorbic acid 20 ? 2 mg Sodium ascorbate 80 ? 8 mg Ultrapure water 1.00 ? 0.01 ml Formulation, 0.1M of sodium ascorbate 18 ? 2 ml

[0150] The special configuration of the process fluidics and the composition of the reagents used ensure a compact, easily scalable and transferable synthesis. This makes it possible to reduce manufacture to a single bulk batch and guarantee the advantages of daily availability.

[0151] FIG. 6 shows the schematic structure of the fluidic system, as well as the further devices and arrangements for synthesis, including: [0152] A controllable temperature element 1 for heating up to 100? C. within 5 min; [0153] A controllable vacuum pump of 2 to up to 200 mbar with pneumatics and bleed valves; [0154] An adjustable nitrogen pneumatic system 3, which supplies a pressure of up to 6 bar; [0155] A reactor 4 made of glass or plastics with 2-3 connections; [0156] A vessel 5 or bag for the formulation solution; [0157] A vessel 6 or bag for the diluting solution; [0158] A reaction buffer in a syringe 7, vial or vessel; [0159] A template 8 for a radiochemical precursor, in the example case Lu-177; [0160] A filling syringe of 1-20 ml; [0161] A bulk storage and mixing vessel 10; [0162] A vented sterile filter of 0.22 ?m or multilayer filter of 0.45 ?m, 0.22 ?m; [0163] An air filter of 0.22 ?m; [0164] A by-pass line 13 with aseptic connector; [0165] An open- or closed-vial filling station 14; [0166] An air filter of 0.22 ?m; [0167] A first cock bank 16 with 2-3 port valves; and [0168] A second cock bank 17 with 2-3 port valves.

[0169] Due to the layout, the transfer of fluids can be performed in a leak-proof manner by means of negative pressure. The syringe pump 9 is used solely for filling purposes and for diluting the bulk preparation to the corresponding ARTs. The preparation of the ART-specific bulk solutions can be carried out as follows: [0170] 1. Preparation of the radiolabeled concentrate by adding buffer solution to the radiochemical and chemical precursor and heating in an appropriate reactor. Temperature and time are product specific and can vary from room temperature to 100? C. and from 5 minutes to several hours. [0171] 2. Preparation of the latest ART (e.g. ART+4 days after manufacture) through addition of the formulation solution and mixing in the bulk vessel 10 to the ready-to-fill pharmaceutical. ART+4 in this case means that the pharmaceutical at the calibration time (ART) in the example case meets the specification according to Table 1. [0172] 3. Loss-free purging of the filling line and the sterile filter 11 (non-sterile side) via the bypass line 13 back into the bulk vessel 10 in preparation for filling. [0173] 4. Filling ART+4 days and/or sampling for quality control. [0174] 5. After completion of the filling, further sampling can optionally be performed or else a filter integrity test can be performed with the aid of the syringe pump 7 or the N2 pneumatic system 3. [0175] 6. The filling syringe 9 is used to dilute the bulk Art+4 days to the ART+3 days (or ART+4-X days) using the diluting solution (fill-up solution). [0176] 7. Subsequently, homogenization of the bulk preparation and purging of the by-pass line 13 are carried out analogous to the process described in point 3. [0177] 8. Filling of the ART+3 days bulk batch etc. is then carried out in the same way as described above.

[0178] The flow chart according to FIG. 7 provides a schematic overview of the manufacturing process of ART-specific fillings according to the invention with a fluidic system according to FIG. 6.

[0179] The composition of the diluting solution and the addition quantities to the individual ARTs can be easily calculated by way of the specification of the radiopharmaceutical. For the example Solucin? ([n.c.a. .sup.177Lu]Lu-DOTATOC) in Table 1, the data are obtained as shown in Tables 2 and 3:

TABLE-US-00003 TABLE 2 Composition of the final radiopharmaceutical and the diluting solution. Specified Concentration Concentration of the Content on the ART Diluting solution Lutetium (.sup.177Lu) 0.64 GBq/mL ? 10% Edotreotide max. 8.33 ?g/mL max. 8.33 ?g/mL Sodium ascorbate 0.1M 0.1M

TABLE-US-00004 TABLE 3 Proportion of ART + 4 days formulation on the corresponding ART + 4 ? X days Formulations. Activity Diluting At time Vol. solution Concen- Activity of of the from tration ART on ART filling ART + 4 Table 2 on ART DOTATOC Days [GBq] [GBq] [mL] [mL] [GBq/mL] [?g] 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

[0180] With appropriate job scheduling and an easily validatable spreadsheet, production planning with the method according to the invention is easy to implement.

[0181] Crucial to the implementation of the present invention is a by-pass via a by-pass line 13 from the sterile filter 11 back to the bulk vessel 10. Through the circulation of the solutions between the filling line/sterile filter and the bulk vessel, loss-free filling of all specific ARTs in one plant can be created in an economical and waste management manner. In order to represent the specific ARTs in one approach, either two filling lines are necessary as in alternative 1, or else the filling line would have to be emptied and purged again after each ART, whereby in the case of very long lines (to be expected, as the cleanroom classes change from C to A due to new regulations), thus high losses and additional radioactive waste would occur. For this reason, especially the by-pass has a particular advantage for the technical solution of the object.

[0182] FIG. 8 shows the circulation of the bulk solution and the purging process via the line paths shown in dashed form. This purging process guarantees loss-free filling and a homogeneous filling solution after setting the specific ARTs. In the present exemplary method, it can be achieved, in particular by means of the by-pass line 13 upstream of the sterile filter 11 back into the bulk vessel 10, that also the line paths are purged and filled with homogeneous solution. The by-pass line 13 is opened by a valve of the first cock bank 16 during purging, and closed during filling. When the by-pass line 13 is open, the natural resistance of the sterile filter 11 prevents liquid from escaping via sterile filter 11 and directs the flow direction of the medium into the bulk vessel 10.