A collection system for recovering the separated radioactive fraction

Abstract

A collection system for recovering the separated radioactive fractions comprises a collection inlet configured to receive the fractions from the separation system, a radiation detector configured to determine a radioactivity of the fraction and generate a radiation detection signal based on the determined radioactivity, a collection valve system in fluid communication with the collection inlet, the collection valve system having at least one or more outlets to a collection container and a waste outlet, and a control unit configured to control the collection valve system to direct the fractions to one of the outlets to the collection container or to the waste outlet.

Description

[Technical field]

[0001] The present invention relates to the field of isolating radioactive fractions for use as, for example, radioactive or radiopharmaceutical markers, for example in Positron Emission Tomography (PET). [Background technology]

[0002] In general, there are several known systems for producing radioactive labels and radiopharmaceuticals. In general, a radioactive substance is first produced by a reaction, resulting in a sample having a plurality of substances including the radioactive substance. In order to isolate the radioactive substance, the sample is subjected to a separation process to isolate the radioactive substance. The isolated radioactive substance is prepared into a solution that can be injected into humans or animals.

[0003] Radiopharmaceuticals are characterized by their radioactivity and relatively short "half-life", making time a critical factor when producing such products. At the same time, the pharmaceutical industry has very strict hygiene and quality requirements. Summary of the Invention [Problem to be solved by the invention]

[0004] Therefore, the present invention aims to provide a system and / or method for producing radiopharmaceuticals more quickly, and / or with higher quality, and / or at least an alternative to the prior art. [Means for solving the problem]

[0005] This object is achieved by a collection system for recovering the separated radioactive fraction, comprising a collection inlet configured to receive the fraction from the separation system, a radiation detector configured to determine a radioactivity of the fraction and to generate a radiation detection signal based on the determined radioactivity, a collection valve system in fluid communication with the collection inlet, the collection valve system comprising at least one or more outlets to a collection container and a waste outlet, and a control unit configured to control the collection valve system to direct the fraction to one of the outlets to the collection container or to the waste outlet.

[0006] The present invention relates to a collection system. The collection system is used to collect a separated radioactive fraction. In this context, "separated" means that the radioactive fraction is a fraction separated from a sample containing multiple substances. At least one of the substances contained in the sample is radioactive. The radioactive fraction contains high levels of radioactive substances. However, it should be understood that in practice, the radioactive fraction may not contain 100% radioactive substances, i.e. the radioactive fraction may contain substances other than the radioactive substance. The other substances include, for example, non-radioactive substances and / or other radioactive substances. The radioactive fraction may, for example, contain the mobile phase.

[0007] For example, the ratio of radioactivity from the radioactive material in the fraction (also defined as radiochemical purity) may be at least 80%, such as at least 85%, at least 90%, at least 95%, at least 99%.

[0008] The radioactive substance may be, for example, an organic molecule such as glucose or an amino acid carrying a radioactive isotope such as carbon-11, fluorine-18, iodine-131, etc. The radioactive substance may be a peptide, for example a small peptide. The radioactive substance may be, for example, aromatic or polyaromatic.

[0009] According to the present invention, a collection system for recovering a separated radioactive fraction comprises a collection inlet configured to receive the fraction from the separation system, a radiation detector configured to determine a radioactivity of the fraction and to generate a radiation detection signal based on the determined radioactivity, a collection valve system in fluid communication with the collection inlet, the collection valve system comprising at least one or more outlets to a collection container and a waste outlet, and a control unit configured to control the collection valve system to direct the fraction to one of the outlets to the collection container or to the waste outlet.

[0010] The collection system comprises a collection inlet. The collection inlet receives the fractions from the separation system. The separation system may be, for example, a chromatography system, such as a supercritical fluid chromatography system or a high performance liquid chromatography system. The separation system may be, for example, configured to separate fractions of a sample containing multiple substances. The separation system may be, for example, a purification system. The collection inlet may be, for example, a section of pipe in fluid communication with an outlet of the separation system. Optional further components may be provided between the outlet and the collection inlet.

[0011] The collection system further comprises a radiation detector. The fraction is measured by the radiation detector to determine the radioactivity of the fraction. Based on this measurement, the radiation detector generates a radiation detection signal. The radiation detector may be any known type of radiation detection or measurement device, for example a semiconductor detector such as a PIN diode radiation detector.

[0012] The collection system further comprises a collection valve system. The collection valve system comprises one or more valves capable of fluid communication with each other. The valves may be, for example, 4-port, 6-port or 8-port valves. The valves may be, for example, diverter valves. The collection valve system is in fluid communication with the collection inlet and directs the fraction from the collection inlet to the collection valve system. Optionally, one or more components are disposed between the collection inlet and the collection valve system.

[0013] The collection valve system comprises a number of outlets, including at least one waste outlet. The waste outlet is used when the fraction from the collection valve is not available, for example because the fraction does not contain enough radioactive material or because the fraction is used to clean the collection system. The collection valve system also comprises at least one outlet to a collection vessel. The outlet to the collection vessel is configured to be in fluid communication with the collection vessel. The collection vessel may be configured to receive the fraction, for example if the fraction meets certain requirements regarding composition and / or radioactivity. For example, it may be desirable to provide one or more collection vessel outlets when the separation system is configured to provide a number of different fractions that are separately contained in different collection vessels. This may be of interest, for example, for research and development purposes. In production applications, having multiple collection vessels is of safety benefit in case the collection of fractions in the collection vessels is started at the wrong time. Also, the separation system may provide a relatively large amount of radioactive fractions, which may require the radioactive fractions to be provided to one or more collection vessels.

[0014] The collection system further comprises a control unit configured to control the collection valve system such that the control unit controls the directing of the fraction to an appropriate outlet, thus ensuring that the fraction is directed to a collection vessel if the radioactivity determined by the radiation detector is desirable, or to waste treatment if the determined radioactivity is undesirable.

[0015] In some embodiments, the control unit is configured to receive a radiation detection signal from the radiation detector and to control the collection valve system based on the radiation detection signal. Based on the detection signal, the control unit determines whether the fraction contains sufficient radioactive material. If the fraction contains sufficient radioactive material, the fraction is directed to an appropriate collection container outlet, otherwise the fraction is directed, for example, to a waste outlet. Thus, in these embodiments, the collection system is automated.

[0016] In some embodiments, the collection system further comprises an operator interaction system configured to receive the radiation detection signal, generate an operator output based on the radiation detection signal, receive an operator input, and generate an operator control signal based on the operator input, and the control unit configured to control the collection valve system based on the operator control signal.

[0017] In these examples, an operator can control the collection system using an operator interaction system. An operator output generated based on the radiation detection signal informs the operator of the radioactivity determined by the radiation detector. For example, the operator interaction system may comprise a display that displays the operator output to the operator. If the operator determines based on the operator output that the radioactivity meets the desired specifications, the operator interaction system provides an operator input. The operator interaction system may comprise, for example, a keypad, touch screen, buttons, etc., that receives operator input from the operator. The operator input is converted into an operator control signal, and based thereon, the control unit controls the collection valve system to direct the fractions as desired by the operator. Optionally, the control unit may be configured to control the operator interaction system.

[0018] The control unit comprises, for example, one or more input terminals, output terminals or communication terminals arranged to communicate with one or more input terminals, output terminals or communication terminals of other components such as a radiation detector, an operator interaction system or a collection valve system. Such communication corresponds to any known suitable communication method or protocol, including wired communication or wireless communication. The control unit may, for example, be or comprise a process unit. The control unit may comprise, for example, a memory for storing received signals and / or computer readable instructions. The control unit may, for example, be implemented in a PLC, a computer or a user device such as a smartphone or tablet.

[0019] In some embodiments, the separation system is a supercritical fluid chromatography system. Supercritical fluid chromatography (SFC) allows for a rapid separation process. A rapid separation process is beneficial due to the relatively short half-life of the radioactive substances used in the envisaged radiopharmaceuticals. The separation system may be configured to use, for example, a mobile phase that dissolves the radioactive substances. The mobile phase may be, for example, a supercritical fluid, e.g., a compressed gas close to (around) or above its critical temperature and pressure, such as carbon dioxide or nitrous oxide, with carbon dioxide being preferred. The mobile phase may include, for example, a modifier that changes the polarity or strength of the supercritical fluid. The modifier may be, for example, methanol or ethanol. In particular, the use of ethanol as a modifier is advantageous in that the time required for preparation can be reduced, since the fractions only need to be diluted with a biocompatible aqueous solution.

[0020] In some embodiments, the collection system comprises a back pressure regulator between the separation system and the collection valve system. The back pressure regulator is configured to maintain an upstream pressure upstream of the back pressure regulator. The upstream pressure is greater than the downstream pressure downstream of the back pressure regulator. The pressure in the separation system must be kept relatively high, for example at least 70 bar or at least 80 bar, especially when SFC type chromatography is used. The pressure may be lower downstream of the back pressure regulator, but this may cause a rapid decompression of the mobile phase. For example, a supercritical fluid component of the mobile phase, for example carbon dioxide, may turn into a gas while the modifier is in the liquid phase. Optionally, the back pressure regulator is located downstream of the radiation detector and upstream of the collection valve system. The radiation detector is thus configured to determine the radioactivity of the high pressure fraction.

[0021] In some embodiments, the collection system comprises a gas-liquid separation unit, which is configured to separate gas from the fluid in the fraction, optionally after exiting the collection valve system, e.g. when entering one of the collection vessels. This embodiment is particularly advantageous when using SFC type chromatography, since the mobile phase is partially converted to a gaseous state after decompression. The gas-liquid separation unit can be used to make the remaining fraction more concentrated, since the gaseous part of the mobile phase can be removed. This allows the preparation time to be reduced, especially if the radioactive material is only dissolved in the modifier, e.g. if the modifier is ethanol.

[0022] In some embodiments, the gas-liquid separation unit is a cyclone. The use of a cyclone is particularly advantageous since separation of gas and liquid is possible at atmospheric pressure. The cyclone may be located, for example, at the collection vessel outlet or collection vessel inlet of the collection valve system. In embodiments where the collection system includes multiple collection vessel outlets and / or multiple collection valves, the collection system may include a corresponding number of cyclones.

[0023] In some embodiments, the collection system further comprises at least a first collection vessel configured to be in fluid communication with a first outlet to the collection vessel of the collection valve system. The collection vessel is advantageously used to collect the fraction. Optionally, the first collection vessel comprises a cap formed from PEEK, polypropylene, PTFE or stainless steel.

[0024] In some embodiments, the collection system further comprises a detection facilitation device for the radiation detector. The detection facilitation device is configured to facilitate the determination of radioactivity by the radiation detector. For example, the detection facilitation device may be a stainless steel loop. The stainless steel loop may be placed in front of the radiation detector to increase the sensitivity of the radiation detector.

[0025] In some embodiments, the collection system further comprises a UV detector. The UV detector is configured to determine a UV value of the fraction and generate a UV detection signal based on the determined UV value. For example, the UV value represents the amount of ultraviolet or visible light absorbed by the fraction. By determining the UV value, a property of the fraction can be identified in addition to the radioactivity determined by the radiation detector. This allows a more accurate determination of the contents of the fraction, i.e. the substances it contains and / or their content. Also, non-radioactive substances can be evaluated. Optionally, the operator interaction system is configured to receive the UV detection signal and generate a UV output from the operator based on the UV detection signal. Optionally, the control unit is configured to receive the UV detection signal. Optionally, the control unit is configured to control the collection valve system based on the UV detection signal. For example, based on the UV detection signal, possibly in combination with the radiation detection signal, the operator and / or the control unit may control the collection valve system to direct the fraction to one of the waste outlets or the collection container outlets.

[0026] In some embodiments, the collection system comprises or is connected to a preparation system for preparing the fraction into an injectable radiopharmaceutical. Usually, the fraction collected in the separation system cannot be injected into a human in this form. Therefore, the collected fraction is prepared. Preparation may include, for example, diluting the fraction using a biocompatible aqueous buffer, such as saline, or water.

[0027] In some embodiments, the collection system further comprises a wash valve. The wash valve is configured to be in fluid communication with a wash solvent source for introducing a wash solvent into the collection system. The control unit is configured to control the wash valve. The wash solvent may be used, for example, to wash the collection system between different samples provided to the separation system. The wash solvent source may be, for example, a wash solvent reservoir or a wash solvent container. The wash solvent may include, for example, water, ethanol, or isopropanol.

[0028] In some embodiments, the collection valve system comprises a single valve. For example, the valve may have a valve inlet for receiving the fraction. The valve inlet may be in fluid communication with, for example, a collection inlet and / or with a back pressure regulator if SFC is used. The valve may further have at least a waste outlet and an outlet to a collection vessel for directing the fraction to the collection vessel. The valve may be, for example, a switching valve. The valve may be, for example, a 4-port valve, a 6-port valve, or an 8-port valve.

[0029] In some embodiments, the collection valve system comprises a first valve and a second valve. The first valve comprises at least one outlet in fluid communication with a valve inlet of the second valve. The second valve comprises one or more collection vessel outlets. Optionally, the second valve comprises two or more collection vessel outlets. Optionally, the first valve comprises a waste outlet. For example, the first valve may have a valve inlet for receiving the fraction. The valve inlet may be in fluid communication with, for example, a collection inlet and / or with a back pressure regulator if SFC is used. For example, the first and second valves may be switching valves. For example, the first and second valves may be 4-port, 6-port or 8-port valves. An embodiment including a first and second valve is particularly advantageous when collecting multiple fractions, since more collection vessel outlets can be provided, each of which can be connected to a different collection vessel.

[0030] In some embodiments, the collection system further comprises a separation system. The separation system corresponds to one of the embodiments described herein. In general, the separation system is configured to receive a sample containing a plurality of substances and to divide the sample into different fractions containing the plurality of substances in different relative amounts. For example, the separation system may be a chromatography system, for example comprising a chromatography column. For example, the separation system may be a high performance liquid chromatography system. For example, the separation system may be a supercritical fluid chromatography system. For example, the separation system may be configured to add a mobile phase to the sample. The mobile phase may comprise, for example, a compressed gas close to (around) or above a critical temperature and pressure. In practice, it has been found that compressed gases below the critical temperature, but close to the critical temperature, for example by a few degrees Celsius, can provide advantageous results. The compressed gas may be, for example, carbon dioxide or nitrous oxide, with carbon dioxide being preferred. The mobile phase may also comprise a modifier, for example to modify the polarity or strength of the supercritical fluid. The modifier may be, for example, methanol or ethanol. In particular, it is advantageous to use ethanol as the modifier. In fact, the preparation time can be reduced since the fractions only need to be diluted with a biocompatible aqueous solution.

[0031] In some embodiments, the collection system comprises a housing. Optionally, one or more components of the collection valve system, the radiation detector, the detection facilitation device, and the injection valve are disposed in the housing. Optionally, the collection vessel and the gas-liquid separation unit are disposed outside the housing.

[0032] The invention further relates to a method for recovering the separated radioactive fraction, which can be carried out using a collection system according to the invention, but the collection system and the method are not limited thereto. In this specification, the features described with reference to the collection system have the same meaning with respect to the method, unless expressly stated otherwise. The features described with reference to the collection system apply to the method with similar advantages.

[0033] In an embodiment, it is an object of the present invention to provide a method for recovering a separated radioactive fraction, the method comprising using a collection system according to any embodiment described herein.

[0034] In some embodiments, it is an object of the present invention to provide a method for recovering a separated radioactive fraction, the method comprising the steps of receiving the fraction from a separation system, determining the radioactivity of the fraction, and controlling a collection valve system based on the determined radioactivity to direct the fraction to one or more outlets to a collection vessel or to waste outlet.

[0035] Optionally, the method is performed using a collection system according to one of the embodiments described herein. Optionally, the separation system is a chromatography system, for example comprising a chromatography column. The chromatography system may be, for example, a high performance liquid chromatography system or a supercritical fluid chromatography system.

[0036] In some embodiments, the step of controlling the collection valve system is performed by a control unit that receives a radiation detection signal based on the determined radioactivity.

[0037] In some embodiments, the method includes providing an operator output to an operator, the output for the operator being based on the determined radioactivity, and controlling the collection valve system is performed based on the operator input.

[0038] In some embodiments, the method further comprises providing the sample comprising the plurality of substances to a separation system. The separation system is a supercritical fluid chromatography system. The separation system may comprise, for example, a chromatography column. The sample may comprise at least one radioactive substance and a mobile phase. The mobile phase may be, for example, a supercritical fluid, e.g., a compressed gas at or near (around) its critical temperature and pressure, such as carbon dioxide or nitrous oxide, with carbon dioxide being preferred. The mobile phase may comprise, for example, a modifier for changing the polarity or strength of the supercritical fluid. The modifier is, for example, methanol or ethanol. The method further comprises subjecting the sample to chromatographic separation in the separation system. Fractions are separated from the sample at least prior to the determination of the radioactivity. During the chromatographic separation, the sample comprising the plurality of substances is divided into different fractions having different relative amounts of the plurality of substances. The method further comprises separating gas from liquid in the fractions in a gas-liquid separation unit. The gas-liquid separation unit may be, for example, a cyclone.

[0039] In some embodiments, the method further comprises directing the fraction to a collection vessel. The collection vessel is in fluid communication with one of the collection vessel outlets of the collection valve system. If the collection valve system comprises one or more collection vessel outlets, each of these collection vessel outlets is in fluid communication with a different collection vessel. The collection valve system is controlled to direct the fraction to an appropriate collection vessel based on the determined radioactivity. Optionally, in a gas-liquid separation unit, separating gas from liquid in the fraction is performed after the fraction has exited the collection valve system and before or while the fraction flows into the collection vessel.

[0040] In some embodiments, the method further comprises determining a UV value of the fraction and controlling a collection valve system based on the determined UV value, e.g., the collection valve system is controlled to direct the fraction to an appropriate collection container or waste outlet based on the determined UV value, e.g., in addition to the determined radioactivity.

[0041] In an embodiment, the method further comprises a preparation step of formulating the fraction into an injectable radiopharmaceutical.

[0042] In some embodiments, the method further includes a cleaning step, for example including opening a cleaning valve, flowing cleaning solvent through the cleaning valve into a collection system, controlling the collection valve system to open a waste outlet, and flowing cleaning solvent out of the collection system through the waste outlet, for example into a waste container.

[0043] The invention further provides computer readable instructions, which, when executed, are configured to cause a control unit of a collection system to perform a method according to any of the embodiments described herein, the collection system for example corresponding to one of the embodiments described herein.

[0044] Exemplary embodiments of the present invention will now be described with reference to the drawings, which are illustrative of how the invention may be implemented, and which are understood to be in no way intended to be construed as limiting the scope of the invention and the claims. Like features are designated with like reference numerals throughout the drawings. [Brief description of the drawings]

[0045] [Figure 1a] FIG. 1a shows a schematic diagram of the pharmaceutical manufacturing process. [Figure 2a] FIG. 2a shows a schematic view of the collection system. [Figure 2b]FIG. 2b shows a schematic representation of the collection system of FIG. 2a, with the walls omitted. [Figure 2c] FIG. 2c shows a schematic representation of the collection system of FIG. 2a, with the walls omitted. [Figure 2d] FIG. 2d shows a schematic representation of the collection system of FIGS. 2a-2c, with the walls omitted. [Figure 2e] FIG. 2e shows a schematic representation of the collection system of FIGS. 2a-2d, without the collection vessel. [Figure 2f] FIG. 2f shows a schematic representation of the collection system of FIGS. 2a-2d, without the collection vessel. [Figure 3a] FIG. 3a shows a schematic of a collection valve system with a single valve. [Figure 3b] FIG. 3b shows a schematic of a collection valve system having a first valve and a second valve. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0046] FIG. 1a shows a schematic diagram of a method 100 for purifying a radiopharmaceutical. An injection valve 102 is connected to a modifier source 101a and an initial sample source 101b. The modifier source 101a provides a modifier. The modifier comprises, for example, ethanol or methanol. The initial sample source 101b provides an initial sample. The initial sample comprises at least one radioactive substance used in the radiopharmaceutical, for example as a PET label. The initial sample may have been previously produced in a preparatory reaction (not shown) for producing the radioactive substance. The objective of the method 100 is to obtain a radioactive substance from the sample with sufficient radioactive and chemical purity to prepare it into an injectable radiopharmaceutical.

[0047] An injection valve 102 directs the modifier and sample into a mixing chamber 103. The mixing chamber 103 is connected to a supercritical fluid source 104 to provide the supercritical fluid, which in this embodiment is carbon dioxide. In the mixing chamber 102, a sample is generated that includes the initial sample, the modifier and the supercritical fluid. The supercritical fluid and the modifier together form the mobile phase.

[0048] The sample is then fed to a separation device 105. In this embodiment, the separation device is a supercritical fluid chromatography system having a chromatography column. However, other separation systems may be used, such as, for example, a high pressure liquid chromatography system. In the separation device, a sample containing multiple substances undergoes a process that divides the sample into different fractions containing different proportions of said substances. Typically, these different fractions remain in the chromatography column for different times.

[0049] When the fractions are discharged from the separation device 105, the UV detector detects the UV value of the fraction. Based on this, the UV detector 106 generates a UV detection signal 106.1. The UV detection signal 106.1 is transmitted to the control unit 111, for example via an output terminal of the UV detector 106 to an input terminal of the control unit 111.

[0050] The radiation detector 107 then detects the radiation level of the fraction. Based on this, the radiation detector 107 generates a radiation detection signal 107.1. The radiation detection signal 107.1 is transmitted to the control unit 111, for example via an output terminal of the radiation detector 107 to an input terminal of the control unit 111. The radiation detector 107 is, for example, a gamma ray detector.

[0051] A backpressure regulator 108 is positioned after the radiation detector 107. The backpressure regulator 108 is particularly advantageous when the separation apparatus is a supercritical fluid chromatography system because it allows for a higher pressure upstream of the backpressure regulator 108 and a lower pressure downstream of the backpressure regulator 108 to ensure supercritical conditions. The backpressure regulator 108 is configured to ensure that a pressure differential is maintained.

[0052] Downstream of the backpressure regulator 108, the fractions flow into the collection module 109. The control unit 111 controls the collection module 109 by means of a control signal 111.1. In particular, the control unit 111 may be configured to control a collection valve system of the collection module 109. For example, the control signal 111.1 is sent from an output of the control unit 111 to an input of the collection module 109 or the collection valve system. In the collection module 109, the fractions are collected in one or more collection or waste containers. The fractions are collected in response to the UV detection signal 106.1 and the radiation detection signal 107.1.

[0053] One or more of the fractions contain a sufficient amount of radioactive material to be used as a radiopharmaceutical and are prepared as a radiopharmaceutical by preparation system 109. Preparation system 109 is configured to convert the fractions into an injectable solution, for example by dilution.

[0054] As used herein, the term "acquisition system" may be reflected, for example, in acquisition module 109, and may include one or more other components shown generally in FIG. 1a.

[0055] It should be noted that Fig. 1a shows only one example and other embodiments are possible, for example a mixed flow may be injected, for example a supercritical fluid source 104 for supplying the supercritical fluid may be connected to the injection valve 102, which may be directly connected to the separation device 105.

[0056] Fig. 1b shows a second embodiment of the method 100 for purifying a radiopharmaceutical. The embodiment shown in Fig. 1b differs from the process shown in Fig. 1a in that it includes an operator interaction system 120, which receives the radiation detection signal 107.1 and the UV detection signal 106.1. In this example, the operator interaction system 120 is in direct contact with the radiation detector 107 and the UV detector 106. However, the control unit 111 may also transmit this information to the operator interaction system 120 after receiving the radiation detection signal 107.1 and the UV detection signal 106.1.

[0057] The operator interaction system 120 generates an operator output 120.1. The operator can view the operator output 120.1 via the display 121. The operator determines whether the radioactivity and / or UV values ​​are within the desired specifications based on the operator output 120.1. If the radioactivity and / or UV values ​​are within the desired specifications, the operator provides an operator input 120.2, for example via a keypad 122 or a touch screen. The operator interaction system 120 generates an operator control signal 120.3 based on the operator input 120.2. The operator control signal 120.3 is sent to the control unit 111, which controls the acquisition module 109 based on the operator control signal 120.3.

[0058] Figures 2a-2f show a possible embodiment of a collection system 20 according to the invention. Figure 2a shows the outside of the collection system 20. In figures 2b-2f some components have been omitted from the figures in order to illustrate internal features that are not otherwise visible. A housing 11 is provided to accommodate and arrange some components of the collection system 20. The housing 11 may be arranged in a hot cell.

[0059] 2a shows the top wall 11a, front wall 11b and side wall 11c of the housing 11. The front wall 11b is provided with a first fastener 14 and the side wall 11c is provided with a second fastener 15. The first fastener 14 and the second fastener 15 allow the collection system 50 to be positioned in a desired location, such as a hot cell.

[0060] Figure 2a shows a number of connection elements 16. The connection elements 16 allow for connection to collection valves within the housing 11, for example for the delivery of separate fractions, washing solvents, etc.

[0061] To show the components in the housing 11, the top wall 11a of the housing 11 has been removed in Figures 2b and 2c, and the front wall 11b has been removed in Figure 2d.

[0062] In the embodiment shown, the housing 11 is provided with an injection valve 7. The injection valve 7 is a switching valve having a number of ports 7.1 allowing different connections between the inlet and the outlet. As a result, a sample containing a number of substances, modifiers and a supercritical fluid is fed to a mixing chamber (not shown) for mixing. At least one substance in the sample is a radioactive substance intended for use in radiopharmaceuticals. As shown in FIG. 2a, the port 7.1 extends to the outside of the housing 11. As a result, the sample, modifiers and supercritical fluid are fed to the injection valve 7 from outside the housing 11.

[0063] After exiting the mixing chamber, the sample is fed into a separation system (not shown). In this example, the separation system is a supercritical fluid chromatography system. In the separation system, the sample is split into fractions which exit the separation system at different times. After passing, optionally, through a UV detector (not shown), one fraction is directed into the housing 11 via collection inlet 16.1.

[0064] Further, Fig. 2c shows a radiation detector 6. The radiation detector 6 is configured to determine the radioactivity of the fraction. In this embodiment, the radiation detector 6 measures gamma rays. Based on the determined radioactivity, the radiation detector 6 generates a radiation detection signal that is sent to a control unit (not shown). Optionally, a stainless steel loop 4 may be placed in front of the radiation detector 6. This increases the sensitivity of the radiation detector 6.

[0065] The fractions are then directed again out of the housing 11, for example via one of the connecting elements 16, to pass through a backpressure regulator (not shown). The fractions are at relatively high pressure since they have been separated using SFC. The use of a backpressure regulator allows the pressure to be reduced downstream while maintaining a high pressure upstream of the backpressure regulator.

[0066] The fractions are then directed to the collection valve system 1 in the housing 11 via one of the connection elements 16. The collection valve system 1 is a switching valve having a number of ports 1.1. One of the ports 1.1 is a collection valve inlet 1.1a in fluid communication with a collection inlet 16.1. In this embodiment, the collection valve inlet 1.1a is in fluid communication with the collection inlet 16.1 via an intermediate component such as a back pressure regulator. The other port 1.1 comprises at least one waste outlet 1.1b and one or more outlets 11c to a collection vessel. The collection valve system 1 is controlled by a control unit. The control unit is configured to direct the fractions to the one or more outlets 1.1c to the collection vessel and to the waste outlet 1.1b based on the measurements of the radiation detector 6 and / or the UV detector. The control unit directs the fractions, for example automatically or based on an operator control signal.

[0067] In the illustrated embodiment, an optional heating sleeve 2 is provided on a portion of the collection valve 1. Rapid adiabatic decompression of the carbon dioxide downstream of the back pressure regulator can cause a local drop in temperature, e.g., below -70°C. This can result in, e.g., dry ice formation in the collection valve system. The heating foil 2 compensates for this drop in temperature.

[0068] 2a-2f further show a collection vessel 8. The collection vessel 8 is in fluid communication with the collection vessel outlet 1.1c of the collection valve system 1. When the control unit decides to collect a fraction, the collection valve system 1 is controlled to direct the fraction via the collection vessel outlet 1.1c to the collection vessel 8. In the illustrated embodiment, the collection vessel 8 has a cap 5 which comprises PEEK.

[0069] In Fig. 2e-2f, the collection vessel is omitted. Therefore, the presence of the gas-liquid separation unit 9a can be visually confirmed at the inlet of the collection vessel 8. In this embodiment, the gas-liquid separation unit 9a is a cyclone 9. This is particularly advantageous when a supercritical fluid chromatography system is used as the separation system. Usually, when separating such systems, the mobile phase is used in the supercritical state. The mobile phase may, for example, include a supercritical fluid and a modifier. When the fraction passes through the back pressure regulator, the pressure is reduced and the supercritical fluid, which is carbon dioxide in this embodiment, changes to a gaseous state. By applying the gas-liquid separation unit 9, the gaseous carbon dioxide is removed from the fraction. Thus, the fraction collected in the collection vessel 8 contains a higher proportion of radioactive material. Furthermore, the preparation into an injectable radiopharmaceutical can be performed more quickly, since it is no longer necessary to remove carbon dioxide. The preparation can be performed even faster if ethanol is used as a modifier for the mobile phase.

[0070] The collection vessel 8 is arranged outside the housing 11. This is advantageous, for example, if the collection system is used in a hot cell, since it allows visual inspection through a window in the hot cell. It also allows the collection vessel 8 to be replaced with a new one during cleaning operations.

[0071] In the embodiment shown, the collection vessel 8 comprises at least a first outlet 10.1 and a second outlet 10.2, in this embodiment at the head 5. The first outlet 10.1 may be used, for example, to vent the gas separated in the gas-liquid separator. The second outlet 10.2 may be used, for example, to connect the collection vessel 8 to a preparation system for preparing the fraction into an injection liquid.

[0072] 2b-2d further show a valve 3. The valve 3 is connected to a pneumatic circuit for operating switching valves, for example in the collection valve system 1 and the injection valve 7.

[0073] FIG. 3a shows a schematic diagram of a first embodiment of a collection valve system 50. In this embodiment, the collection valve system 50 comprises a single valve, shown as valve 51. Valve 51 is a diverter valve, having a valve inlet 52, an outlet 53 to a collection vessel, and a waste outlet 54. In this embodiment, the valve 50 is a four-port valve, further having an unused fourth port 55. The valve inlet 52 is in fluid communication with the collection inlet via a back pressure regulator, and is configured to receive a fraction. The outlet 53 to the collection vessel is in fluid communication with the collection vessel. The waste outlet 54 is in fluid communication with a waste vessel. The illustrated embodiment is suitable for cases where only one collection vessel is filled, e.g., where only one type of fraction is collected.

[0074] 3b shows a schematic diagram of a second embodiment of the collection valve system 60. In this embodiment, the collection valve system 60 comprises a first valve 61 and a second valve 71. The first valve 61 is a four-port changeover valve having a valve inlet 62. The valve inlet 62 is in fluid communication with the collection inlet via a back pressure regulator and is configured to receive the fraction. The first valve 61 further comprises a waste outlet 64 for fluidly collecting in a waste container and a fourth port 65, which is not used in the embodiment shown. The first valve 61 further comprises a valve outlet 63, which is fluidly connected to an inlet 72 of a second valve 71 by a connection 66.

[0075] In this embodiment, the second valve 71 is a 5-port changeover valve and has four outlets: an outlet 73 to a first collection vessel fluidly connected to the first collection vessel, a second outlet 74 to a collection vessel fluidly connected to the second collection vessel, a third outlet 75 to a collection vessel fluidly connected to the third collection vessel, and a fourth outlet 76 to a collection vessel fluidly connected to the fourth collection vessel. Thus, in the illustrated embodiment, the fractions are collected in four different collection vessels. However, it should be understood that different configurations may be used depending on the number of different fractions to be collected. For example, the second valve 71 may have more outlets to the collection vessels and / or the collection valve system may have more valves.

[0076] Detailed embodiments of the present invention have been described herein. However, it should be understood that the disclosed embodiments are merely examples of the present invention, which may be incorporated in various ways. Therefore, the specific structural and functional details disclosed herein should not be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching those skilled in the art to implement the present invention in its various aspects in substantially any suitable detailed structure. It is not necessary that all of the described objectives be achieved by a particular embodiment.

[0077] Furthermore, the terms and expressions used in this specification are not intended to limit the present invention, but are intended to describe the present invention in an easily understandable manner. As used in this specification, the terms "a" or "an" mean one or more, unless otherwise specified. The terms "a multiple of", "a plurality" or "several" mean two or more. The terms "comprise", "include", "contain" and "have" are open-ended and do not exclude the presence of additional elements. Reference numerals in the claims should not be construed as limiting the present invention.

[0078] The mere fact that certain technical features are recited in different dependent claims always allows that a combination of these technical measures can be used to advantage.

[0079] A single processor or other unit may perform the functions of the various components described herein, e.g., a processing unit or control unit, or the functions of a single processing unit or control unit described herein may in fact be distributed among several components, possibly physically separated from each other. Communication between the components may be wired or wireless, using known methods.

[0080] The operations performed by the control unit are in the form of programs, e.g., computer programs, software applications, etc. Programs are implemented using computer readable instructions. Programs may include subroutines, functions, procedures, object methods, object implementations, executable applications, source code, object code, shared libraries / dynamic load libraries, and / or other sets of instructions designed to be executed on a computer system.

[0081] The computer program or computer readable instructions may be stored and / or distributed on a suitable medium, such as an optical storage medium or a solid-state medium provided together with or as part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless communication systems.

Claims

1. a collection system for recovering the separated radioactive fraction, comprising: a collection inlet configured to receive the fraction from the separation system; a radiation detector configured to determine a radioactivity of the fraction and to generate a radiation detection signal based on the determined radioactivity; a collection valve system in fluid communication with the collection inlet, the collection valve system including at least one or more outlets to a collection container and a waste outlet; a control unit configured to control the collection valve system to direct the fraction to one of the outlets to the collection vessel or to the waste outlet; A collection system comprising:

2. the separation system further comprising: the separation system is a supercritical fluid chromatography system; The collection system comprises: a backpressure regulator between the separation system and the collection valve system; a gas-liquid separation unit configured to separate gas from fluid of the fraction after it exits the collection valve system; The collection system of claim 1 further comprising:

3. 3. The collection system of claim 2, wherein the liquid-gas separation unit is a cyclone.

4. 4. The collection system of claim 1, wherein the control unit is configured to receive the radiation detection signal from the radiation detector and control the collection valve system based on the radiation detection signal.

5. further comprising an operator interaction system; The operator interaction system comprises: receiving the radiation detection signal and generating an output for an operator based on the radiation detection signal; configured to receive an operator input and generate an operator control signal based on the operator input; The collection system of any one of claims 1 to 3, wherein the control unit is configured to control the collection valve system based on the operator control signal.

6. 4. The collection system of claim 1, further comprising at least one first collection vessel configured to be in fluid communication with a first outlet to the collection vessel of the collection valve system.

7. 4. The collection system of claim 1, further comprising a detection facilitation device for the radiation detector.

8. 4. The collection system of claim 1, further comprising a UV detector configured to determine a UV value of the fraction and to generate a UV detection signal based on the determined UV value.

9. 4. A collection system according to any one of claims 1 to 3, further comprising a preparation system for preparing said fraction into an injectable radiopharmaceutical.

10. a diluent valve configured to be in fluid communication with a diluent source for introducing diluent into the collection system; 4. The collection system of claim 1, wherein the control unit is configured to control the diluent valve to dilute the fraction.

11. a wash valve configured to be in fluid communication with a wash solvent source that introduces a wash solvent into the collection system; The collection system according to any one of claims 1 to 3, characterized in that the control unit is configured to control the flushing valve.

12. the collection valve system comprises a first valve and a second valve; the first valve having at least one outlet in fluid communication with an inlet of the second valve; 4. The collection system of claim 1, wherein the second valve comprises at least one outlet to the collection vessel.

13. 1. A method for recovering a separated radioactive fraction, comprising: A method comprising the step of using a collection system according to any one of claims 1 to 3.

14. 1. A method for recovering a separated radioactive fraction, comprising: receiving a fraction from a separation system; determining the radioactivity of said fraction; controlling a collection valve system based on the determined radioactivity to direct the fraction to one or more outlets to a collection vessel or to a waste outlet; A method comprising:

15. providing a sample containing a plurality of substances to the separation system, the separation system being a supercritical fluid chromatography system, the sample comprising at least one radioactive substance and a mobile phase; subjecting the sample to chromatographic separation in the separation system, wherein the fraction is separated from the sample at least prior to determining radioactivity; separating gas from liquid in said fraction in a gas-liquid separation unit; 15. The method of claim 14, further comprising:

16. 15. The method of claim 14, further comprising the step of directing the fraction to the collection vessel.

17. 15. The method of claim 14, further comprising determining a UV value of the fraction and controlling the collection valve system based on the determined UV value.

18. The method according to any one of claims 14 to 17, further comprising a preparation step of preparing said fraction into an injectable radiopharmaceutical.

19. the fraction comprises ethanol; 20. The method of claim 18, wherein the preparing step comprises diluting the fraction with saline.

20. further comprising a washing step, The washing step comprises: opening a flush valve; allowing a cleaning solvent to flow through the cleaning valve into a collection system; controlling the collection valve system to open the waste outlet; allowing the cleaning solvent to flow out of the collection system through the waste outlet; The method according to any one of claims 14 to 17, comprising:

21. Computer readable instructions, which when executed are configured to cause a control unit of a collection system to carry out a method according to any of claims 15 to 17.

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