Collection system for recovering separated radioactive fractions

Abstract

A collection system for recovering a separated radioactive fraction, comprising: a collection inlet configured to receive a fraction from a separation system; a radioactivity detector configured to measure radioactivity of the fraction and generate a radioactivity detection signal based on the measured radioactivity; a collection valve system in fluid communication with the collection inlet, wherein the collection valve system comprises at least one or several outlets leading to the collection container and a waste outlet; and a control device configured to control the collection valve system to direct the fraction to one of the outlets leading to the collection container or to the waste outlet.

Description

[0001] The present invention relates to the field of separation of radioactive fractions, for example for use as radiolabels or radiopharmaceutical markers, for example in positron emission tomography (PET).

[0002] Several systems are known and commonly used for producing radiolabeled or radiopharmaceuticals. Generally, a radioactive substance is first produced in a reaction, resulting in a sample having several substances including the radioactive substance. In order to separate the radioactive substance, the sample can be subjected to a separation process, in which the radioactive substance is separated. The separated radioactive substance is then reconstituted into a solution that can be injected into a human or animal body.

[0003] Since radiopharmaceuticals are radioactive and are characterized by a generally relatively short "half-life", time is an important factor when producing such products. At the same time, hygiene and quality must meet very stringent requirements in the pharmaceutical industry.

[0004] It is therefore an object of the present invention to provide a system and / or a method that allows for faster production of radiopharmaceutical products, and / or higher quality, and / or at least provides an alternative to the prior art.

[0005] This object is achieved by a collection system for recovering a separated radioactive fraction, the collection system comprising:

[0006] a collection inlet configured to receive the fraction from the separation system,

[0007] a radioactivity detector configured to measure the radioactivity of the fraction and generate a radioactivity detection signal based on the measured radioactivity,

[0008] a collection valve system in fluid communication with the collection inlet, wherein the collection valve system comprises at least one or more outlets leading to a collection container and a waste outlet,

[0009] - A control device configured to control the collection valve system to direct the fraction to an outlet leading to a collection container or a waste outlet.

[0010] Therefore, the present invention relates to a collection system. The collection system can be used to recover a separated radioactive fraction. In this case, "separated" means that the radioactive fraction is a separated fraction of a sample comprising multiple substances. At least one of the substances present in the sample is a radioactive substance. The radioactive fraction includes a high level of radioactive substance. However, it should be understood that in practice, the radioactive fraction may not be composed of 100% radioactive substance, that is, the radioactive fraction may include substances other than radioactive substances. These other substances may, for example, include non-radioactive substances and / or another radioactive substance. The radioactive fraction may, for example, include a mobile phase.

[0011] For example, the radioactivity ratio of the radioactive material in the fraction, also referred to as radiochemical purity, may be at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as at least 99%.

[0012] 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. The radioactive substance may be, for example, a peptide, such as a small peptide. The radioactive substance may be, for example, aromatic or polyaromatic.

[0013] According to the present invention, the collection system for recovering the separated radioactive fraction comprises:

[0014] a collection inlet configured to receive the fraction from the separation system,

[0015] a radioactivity detector configured to measure the radioactivity of the fraction and generate a radioactivity detection signal based on the measured radioactivity,

[0016] a collection valve system in fluid communication with the collection inlet, wherein the collection valve system comprises at least one or more outlets leading to a collection container and a waste outlet,

[0017] - A control device configured to control the collection valve system to direct the fraction to an outlet leading to a collection container or a waste outlet.

[0018] The collection system comprises a collection inlet. Through the collection inlet, fractions can be received from the separation system. The separation system can be, for example, a chromatography system, such as a supercritical fluid chromatography system or a high performance liquid chromatography system. The separation system can, for example, be configured to separate fractions of a sample comprising a plurality of substances. The separation system can, for example, be a purification system. The collection inlet can, for example, be a pipe section that is in fluid communication with an outlet of the separation system, wherein additional components are optionally provided between the outlet and the collection inlet.

[0019] The collection system also includes a radioactive detector. The fraction can be measured by the radioactive detector to determine the radioactivity of the fraction. Based on the measurement, the radioactive detector can generate a radioactive detection signal. The radioactive detector can be any known type of radioactive detection or measurement device, such as a semiconductor detector, such as a PIN diode radiation detector.

[0020] The collection system also includes a collection valve system. The collection valve system may include one or more valves that can be fluidically connected to each other. The valve may be, for example, a 4-way, 6-way or 8-way valve. The valve may be, for example, a switching valve. The collection valve system is in fluid communication with the collection inlet, thereby transferring 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.

[0021] The collection valve system includes multiple outlets, including at least one waste outlet. For example, when the fraction from the collection valve cannot be used, the waste outlet can be used, for example because it does not contain enough radioactive material or because it has been used to clean the collection system. The collection valve system also includes at least one outlet leading to a collection container. The outlet leading to the collection container can be configured to be in fluid communication with the collection container. The collection container can, for example, be configured to receive the fraction when the fraction meets certain requirements (for example, in terms of composition and / or radioactivity). For example, when the separation system is configured to provide several different fractions that will be stored separately in different collection containers, more than one outlet leading to the collection container may be ideal. For example, this may be meaningful for R&D purposes. In production applications, having multiple collection containers may also have safety advantages in the case where the collection of the fraction in the collection container starts at the wrong time. It is also possible that a relatively large amount of radioactive fractions are provided by the separation system, thereby requiring more than one collection container to provide radioactive fractions.

[0022] The collection system also includes a control device configured to control the collection valve system. By controlling the collection valve system, the control device can control which outlet the fraction is directed to. Thus, it can be ensured that when the radioactivity measured by the radioactivity detector is desirable, the fraction is directed to the collection container, and if it is undesirable, it is directed to waste treatment.

[0023] In some embodiments, the control device is configured to receive a radioactive detection signal from a radioactive detector and control the collection valve system based on the radioactive detection signal. Based on the detection signal, the control device can determine whether the fraction includes enough radioactive material. In this case, the fraction is directed to a suitable outlet leading to a collection container, and if not, the fraction can be directed to a waste outlet, for example. Therefore, in these embodiments, the collection system is automated.

[0024] In some embodiments, the collection system further comprises an operator interaction system configured to: receive a radioactivity detection signal and generate an operator output based on the radioactivity detection signal; receive an operator input and generate an operator control signal based on the operator input. The control device may be configured to control the collection valve system based on the operator control signal.

[0025] In these embodiments, the operator can use the operator interaction system to control the collection system. The operator output generated based on the radioactivity detection signal can be configured to inform the operator of the radioactivity measured by the radioactivity detector. For example, the operator interaction system can include a display configured to display the operator output to the operator. If the operator determines that the radioactivity meets the desired specifications based on the operator output, the operator interaction system can provide operator input. The operator interaction system can, for example, include a keyboard, a touch screen, a button, etc., for receiving operator input from the operator. The operator input is converted into an operator control signal, based on which the control device controls the collection valve system so that the fraction is guided according to the operator's expectations. Optionally, the control device is also configured to control the operator interaction system.

[0026] The control device may, for example, include one or more input terminals, output terminals, or communication terminals, which are configured to communicate with one or more input terminals, output terminals, or communication terminals of other components (such as radioactivity detectors, operator interaction systems, or collection valve systems). This communication may correspond to any known suitable communication method or procedure, including wired or wireless communication. The control unit may, for example, be or include a processing device. The control device may, for example, include a memory for storing received signals and / or computer-readable instructions. The control device may, for example, be implemented in a PLC, a computer, or a user device (such as a smart phone or tablet).

[0027] In some embodiments, the separation system is a supercritical fluid chromatography system. Supercritical fluid chromatography (SFC) allows a rapid separation process, which is very beneficial considering that the half-life of the radioactive material used in the envisioned radiopharmaceutical is relatively short. The separation system can, for example, be configured to use a mobile phase to dissolve the radioactive material. The mobile phase can, for example, be a supercritical fluid, such as a compressed gas close to, about or above its critical temperature and pressure, such as carbon dioxide or nitrous oxide. Carbon dioxide is preferred. The mobile phase can also include a modifier, such as for changing the polarity or intensity of the supercritical fluid. The modifier can be, for example, methanol or ethanol. In particular, using ethanol as a modifier may be advantageous because it can reduce the time required for re-formulation because the fraction can now only be diluted with a biocompatible aqueous solution.

[0028] In some embodiments, the collection system comprises a back pressure regulator between the separation system and the collection valve system. The back pressure regulator can be configured to maintain the upstream pressure upstream of the back pressure regulator, wherein the upstream pressure is greater than the downstream pressure downstream of the back pressure regulator. Particularly when using SFC type chromatograms, the pressure in the separation system will be very high, and must be kept very high, such as at least 70 bar or at least 80 bar. Downstream of the back pressure regulator, pressure can be reduced, which can cause the rapid decompression of mobile phase. For example, the supercritical fluid composition of mobile phase, such as carbon dioxide, can be converted into a gaseous state, and modifiers are retained in liquid phase. Optionally, the back pressure regulator is arranged on the downstream of a radioactive detector and the upstream of a collection valve system. Therefore, the radioactive detector is configured to measure the radioactivity of high pressure fractions.

[0029] In some embodiments, the collection system includes a gas / liquid separation device, wherein the gas / liquid separation device is configured to separate the gas from the liquid in the fraction, optionally after leaving the collection valve system, such as when entering one of the collection containers. When using SFC-type chromatography, this embodiment may be particularly advantageous because the mobile phase can be partially converted into a gaseous state after decompression. The gas / liquid separation device can be used to make the retained fraction more concentrated because the gaseous portion of the mobile phase can be removed. This can also reduce the time required for re-formulation, especially if the radioactive material is only dissolved in a modifier, such as when the modifier is ethanol.

[0030] In some embodiments, the gas / liquid separation device is a cyclone separator. The use of a cyclone separator is particularly advantageous because it allows separation of gas and liquid at atmospheric pressure. The cyclone separator can be arranged, for example, at the outlet of the collection container of the collection valve system or at the inlet of the collection container. In embodiments where the collection system includes multiple outlets to the collection container and / or multiple collection valves, the collection system can include corresponding multiple cyclone separators.

[0031] In some embodiments, the collection system further comprises at least a first collection container configured to be in fluid communication with a first outlet of the collection container of the collection valve system. The collection container can advantageously be used to collect fractions. Optionally, the first collection container comprises a cap made of PEEK, polypropylene, PTFE or stainless steel.

[0032] In some embodiments, the collection system also includes a detection enhancer for the radioactivity detector. The detection enhancer can be configured to enhance the radioactivity determination performed by the radioactivity detector. For example, the detection enhancer can be a stainless steel ring. The stainless steel ring can be arranged in front of the radioactivity detector to increase the sensitivity of the radioactivity detector.

[0033] In some embodiments, the collection system also includes a UV detector, which is configured to measure the UV value of the fraction and generate a UV detection signal based on the measured UV value. For example, the UV value can represent the amount of ultraviolet light or visible light absorbed by the fraction. In addition to the radioactivity measured with the radioactivity detector, the UV value can also measure the properties of the fraction. This allows the content of the fraction to be measured more accurately, i.e., which substances and / or their quantities the fraction includes. It also allows non-radioactive substances to 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 device is configured to receive the UV detection signal. Optionally, the control device 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 radioactivity detection signal, the operator and / or the control device can control the collection valve system to guide the fraction to one of the outlets or waste outlets leading to the collection container.

[0034] In some embodiments, the collection system includes or can be connected to a reconstitution system for reconstituting the fraction into an injectable radiopharmaceutical. Typically, the fraction collected in the separation system cannot be injected into the human body in this form. Therefore, it can be reconstituted. Reconstitution can, for example, include diluting the fraction, for example using water or a biocompatible aqueous buffer, such as saline.

[0035] In some embodiments, the collection system further comprises a cleaning valve configured to be in fluid communication with a cleaning solvent source so as to introduce a cleaning solvent into the collection system, wherein the control device is configured to control the cleaning valve. The cleaning solvent can be used to clean the collection system, for example, between different samples provided to the separation system. The cleaning solvent source can be, for example, a cleaning solvent reservoir or a cleaning solvent container. The cleaning solvent can, for example, include water, ethanol, or isopropanol.

[0036] In some embodiments, the collection valve system includes a single valve. For example, the valve can have a valve inlet for receiving the fraction. When using SFC, the valve inlet can be, for example, in fluid communication with the collection inlet and / or the back pressure regulator. The valve can also have at least a waste outlet and an outlet leading to a collection container so that the fraction is directed to the collection container. The valve can, for example, be a switching valve. The valve can, for example, be a 4-way valve, a 6-way valve, or an 8-way valve.

[0037] In some embodiments, the collection valve system includes a first valve and a second valve, wherein the first valve includes at least one outlet fluidly connected to the valve inlet of the second valve, wherein the second valve includes one or more outlets leading to a collection container. Optionally, the second valve includes two or more collection valve outlets. Optionally, the first valve includes a waste outlet. For example, the first valve can have a valve inlet for receiving a fraction. When using SFC, the valve inlet can be, for example, connected to a collection inlet and / or a back pressure regulator fluid. For example, the first valve and the second valve can be a conversion valve. For example, the first valve and the second valve can be a 4-way valve, a 6-way valve or an 8-way valve. When a variety of fractions are to be collected, some embodiments including the first valve and the second valve may be particularly advantageous because more outlets leading to a collection container can be provided, and each outlet can be connected to a different collection container.

[0038] In some embodiments, the collection system also includes a separation system. The separation system may correspond to one of the embodiments explained herein. Typically, the separation system is configured to receive a sample including a plurality of substances, and is configured to separate the sample into different fractions of the substances having different relative amounts. For example, the separation system may be a chromatographic system, for example, including a chromatographic 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. For example, the mobile phase may include a compressed gas close to, about, or above its critical temperature and pressure. In practice, it has been found that even if the compressed gas is lower than but close to its critical temperature, for example, a few degrees Celsius lower, favorable results may be obtained. The compressed gas may, for example, be carbon dioxide or nitrous oxide. Carbon dioxide is preferred. The mobile phase may also include a modifier, for example, for changing 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 a modifier. In fact, it may reduce the time required for re-formulation, because the fraction can now only be diluted with a biocompatible aqueous solution.

[0039] In some embodiments, the collection system includes a housing. Optionally, one or more of the following elements are disposed within the housing: a collection valve system; a radioactivity detector; a detection enhancer; an injection valve. Optionally, the collection container and the gas / liquid separation device are disposed outside the housing.

[0040] The present invention also relates to a method for recovering a separated radioactive fraction. Although the method can be performed with a collection system according to the present invention; neither the collection system nor the method is limited thereto. Unless expressly provided otherwise, the features explained herein with reference to the collection system have the same meaning for the method. The features explained with reference to the collection system can be applied mutatis mutandis to the method to obtain similar advantages.

[0041] In these embodiments, the object of the invention is a method for recovering a separated radioactive fraction comprising the step of using a collection system according to any of the embodiments explained herein.

[0042] In some embodiments, the present invention is directed to a method for recovering a separated radioactive fraction comprising the following steps:

[0043] - receiving fractions from a separation system;

[0044] - Determine the radioactivity of the fractions;

[0045] - Controlling the collection valve system based on the measured radioactivity to direct the fractions to one or more outlets leading to a collection container or to a waste outlet.

[0046] Optionally, the method is performed using a collection system according to one of the embodiments explained herein. Optionally, the separation system is a chromatography system, for example comprising a chromatography column. The chromatography system can be, for example, a high performance liquid chromatography system or a supercritical fluid chromatography system.

[0047] In some embodiments, the step of controlling the collection valve system is performed by a control device, wherein the control device receives a radioactivity detection signal based on the measured radioactivity.

[0048] In some embodiments, the method includes the step of providing an operator input to an operator, wherein the operator output is based on the determined radioactivity, and wherein the step of controlling the collection valve system is performed based on the operator input.

[0049] In some embodiments, the method also includes providing a sample including multiple substances to a separation system, wherein the separation system is a supercritical fluid chromatography system. The separation system may, for example, include a chromatographic column. The sample may include at least one radioactive substance and a mobile phase. The mobile phase may, for example, be a supercritical fluid, such as a compressed gas close to, approximately or above its critical temperature and pressure, such as carbon dioxide or nitrous oxide. Carbon dioxide is preferred. The mobile phase may also include a modifier, such as for example, for changing the polarity or intensity of the supercritical fluid. The modifier may be, for example, methanol or ethanol. The method may also include a step of chromatographically separating the sample in the separation system, wherein at least a fraction is separated from the sample before determining the radioactivity. In the chromatographic separation process, a sample with multiple substances may be divided into different fractions of the substances with different relative amounts. The method may also include a step of separating the gas from the liquid in the fraction in a gas / liquid separation device, which may, for example, be a cyclone separator.

[0050] In some embodiments, the method also includes the step of directing the fraction to a collection container. The collection container can be in fluid communication with an outlet fluid of the collection valve system leading to the collection container. When the collection valve system includes a plurality of outlets leading to the collection container, each of these outlets leading to the collection container can be in fluid communication with another collection container. The collection valve system can be controlled to direct the fraction to a suitable collection container based on the measured radioactivity. Optionally, after the fraction leaves the collection valve system, before or at the same time as the fraction enters the collection container, a step of separating the gas from the liquid in the fraction is performed in a gas / liquid separation device.

[0051] In some embodiments, the method further comprises the step of determining the UV value of the fraction and controlling the collection valve system based on the determined UV value. For example, in addition to the determined radioactivity, the collection valve system can also be controlled based on the determined UV value to direct the fraction to a suitable collection container or waste outlet.

[0052] In embodiments, the method further comprises a reconstitution step, wherein the fraction is reconstituted into an injectable radiopharmaceutical.

[0053] In some embodiments, the method further comprises a cleaning step. The cleaning step may, for example, comprise: opening a cleaning valve; allowing a cleaning solvent to enter the system through the cleaning valve; controlling the collection valve system to open a waste outlet; allowing the cleaning agent to flow out of the collection system through the waste outlet, for example, into a waste container.

[0054] The present invention also provides computer readable instructions, which are configured to, when executed, cause a control device of a collection system to perform a method according to any embodiment described herein. The collection system may, for example, correspond to one of the embodiments described herein.

[0055] Exemplary embodiments of the present invention are described with reference to the accompanying drawings. It should be understood that these drawings serve only as examples of how the present invention may be implemented and are in no way intended to be interpreted as limiting the scope of the present invention and the claims. In all drawings, similar features are represented by similar reference numerals. In the drawings:

[0056] Figure 1a : Schematically illustrates a process for producing a pharmaceutical product;

[0057] Figure 2a : Schematically shows the exterior of the collection system;

[0058] Figure 2b-2c : Schematically shows Figure 2a A collection system of, wherein the walls are omitted for purposes of illustration;

[0059] Figure 2d : Schematically shows Figure 2a-2cof a collection system, wherein the walls are also omitted for purposes of illustration;

[0060] Figure 2e-2f : Schematically shows Figure 2a-2d A collection system, wherein the collection container is omitted for illustration purposes;

[0061] Figure 3a : schematically shows a collection valve system including a single valve;

[0062] Figure 3b : Schematically shows a collection valve system having a first valve and a second valve.

[0063] Figure 1a A method 100 for purifying a radiopharmaceutical is schematically shown. An injection valve 102 is connected to a modifier source 101a and an initial sample source 101b. A modifier may be provided by the modifier source 101a, the modifier comprising, for example, ethanol or methanol. An initial sample may be provided by the initial sample source 101b. The initial sample may include at least one radioactive substance for a radiopharmaceutical, for example as a PET marker. The initial sample may have been pre-produced in a preliminary reaction (not shown) for producing a radioactive substance. The purpose of method 100 is to obtain a radioactive substance having sufficient radioactivity purity and chemical purity from the sample and to reconstitute it into an injectable radiopharmaceutical.

[0064] Injection valve 102 directs the modifier and sample to a mixing chamber 103, which is also connected to a supercritical fluid source 104 to provide a supercritical fluid, in this case carbon dioxide. In the mixing chamber 102, a sample comprising an initial sample, a modifier and a supercritical fluid is generated. The supercritical fluid and the modifier together form a mobile phase.

[0065] The sample is then provided to a separation device 105. In this case, the separation device is a supercritical fluid chromatography system having a chromatographic column. However, other separation systems, such as a high pressure liquid chromatography system, may also be used. In the separation device, a sample comprising a plurality of substances is subjected to a process of separating the sample into different fractions having different relative amounts of the substances. Typically, these different fractions stay in the chromatographic column for different periods of time.

[0066] The UV detector measures the UV value of the fraction when it leaves the separation device 105. The UV detector 106 generates a UV detection signal 106.1 on this basis, which is transmitted to the input terminal of the control device 111 via the output terminal of the UV detector 106, for example.

[0067] Then, the radioactivity detector 107 measures the radioactivity of the fraction. Based on this, the radioactivity detector 107 generates a radioactivity detection signal 107.1, which is transmitted to an input terminal of the control device 111 via an output terminal of the radioactivity detector 107, for example. The radioactivity detector 107 may be a gamma detector, for example.

[0068] The back pressure regulator 108 is disposed after the radioactivity detector 107. The back pressure regulator 108 is particularly advantageous when the separation device is a supercritical fluid chromatography system, because the pressure upstream of the back pressure regulator 106 is high to ensure the supercritical state, while the pressure downstream of the back pressure regulator 107 can be reduced. The back pressure regulator 108 is configured to ensure that the pressure difference is maintained.

[0069] Downstream of the back pressure regulator 108, the fraction enters a collection module 109. The collection module 109 is controlled by a control device 111 via a control signal 111.1, which can be particularly configured to control a collection valve system of the collection module 109. For example, the control signal 111.1 can be sent from an output terminal of the control device 111 to an input terminal of the collection module 109 or to an input terminal of the collection valve system. In the collection module 109, the fraction is collected in one or more collection containers or waste containers. The way of collecting the fraction is based on the UV detection signal 106.1 and the radioactivity detection signal 107.1.

[0070] One or more fractions comprising a sufficient amount of radioactive material for use as a radiopharmaceutical are reconstituted by a reconstitution system 109 in the radiopharmaceutical. The reconstitution system 109 is configured to convert the fractions into an injectable solution, for example by dilution.

[0071] It is worth noting that the term "collection system" used herein may be reflected in the collection module 109, for example, but may also include Figure 1a One or more other components schematically shown in FIG.

[0072] It is worth noting that Figure 1a Only one example is shown, but other embodiments are possible. For example, mixed flow injection can also be applied. For example, a supercritical fluid source 104 for providing a supercritical fluid can also be connected to the injection valve 102, wherein the injection valve 102 can be directly connected to the separation device 105.

[0073] Figure 1b A second embodiment of a method 100 for purifying a radiopharmaceutical is shown. Figure 1a The difference between the shown process is that Figure 1bThere is an operator interaction system 120. The operator interaction system 120 receives the radioactivity detection signal 107.1 and the UV detection signal 106.1. In this example, the operator interaction system 120 is directly in contact with the radioactivity detector 107 and the UV detector 106, but the control device 111 can also receive the radioactivity detection signal 107.1 and the UV detection signal 106.1 and then transmit the information to the operator interaction system 120.

[0074] The operator interaction system 120 generates an operator output 120.1, which is visible to the operator via a display 121. The operator can determine whether the radioactivity and / or UV values ​​are within the desired specifications based on the operator output 120.1. When they are within the desired specifications, the operator can provide an operator input 120.2, for example via a keyboard 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 transmitted to the control device 111, which controls the collection module 109 based on the operator control signal 120.3.

[0075] Figure 2a-2f A possible embodiment of a collecting system 20 according to the invention is shown. Figure 2a The exterior of the collection system 20 is shown, while Figure 2b-2f In order to illustrate internal features that would otherwise not be visible, several components have been omitted from the figure. A housing 11 is provided for several components of the tissue collection system 20. The housing 11 may be disposed in a thermal chamber.

[0076] Figure 2a Shown are top wall 11a, front wall 11b and side walls 11c of housing 11. First fastener 14 is provided on front wall 11b and second fastener 15 is provided on side wall 11c. First and second fasteners 14, 15 allow collection system 50 to be physically organized in a desired location, such as a hot room.

[0077] Figure 2a A plurality of connection elements 16 are shown which allow connection to a collecting valve within the housing 11 , for example to provide separated fractions, cleaning solvents or the like.

[0078] exist Figure 2b and 2c In the figure, the top wall 11a of the housing 11 has been removed from the figure, and in Figure 2d In the embodiment shown in FIG. 1 , the front wall 11 b is also removed so that the components inside the housing 11 are visible.

[0079] In the embodiment shown, an injection valve 7 is also arranged in the housing 11. The injection valve 7 is a switching valve with multiple ports 7.1 to allow different connections between the inlet and outlet. This results in a sample with multiple substances, modifiers and supercritical fluids being provided to a mixing chamber (not shown) for mixing. At least one of the substances in the sample is a radioactive substance for radiopharmaceuticals. Figure 2a As can be seen in FIG. 1 , the port 7 . 1 extends to the outside of the housing 11 . This results in the sample, the modifier and the supercritical fluid being provided to the injection valve 7 from outside the housing 11 .

[0080] After leaving the mixing chamber, the sample is provided to a separation system (not shown), in this case a supercritical fluid chromatography system. In the separation system, the sample is divided into fractions that leave the separation system at different times. After possibly first passing a UV detector (not shown), a fraction is directed to the housing 11 through a collection inlet 16.1.

[0081] Figure 2c A radioactivity detector 6 is further shown. The radioactivity detector 6 is configured to determine the radioactivity of the fraction. In this case, the radioactivity detector 6 is capable of measuring gamma radiation. Based on the determined radioactivity, the radioactivity detector 6 generates a radioactivity detection signal, which is transmitted to a control device (not shown). Optionally, a stainless steel ring 4 can be placed in front of the radioactivity detector 6. It has been found that this improves the sensitivity of the radioactivity detector 6.

[0082] The fraction can then be directed out of the housing 11 again, for example through one of the connecting elements 16, to pass through a back pressure regulator (not shown). Since the fraction has been separated using SFC, it is at a relatively high pressure. By using a back pressure regulator, the pressure downstream of the back pressure regulator can be reduced while maintaining a high pressure upstream thereof.

[0083] The fraction is then directed to the collection valve system 1 in the housing 11 through one of the connecting elements 16. The collection valve system 1 is a conversion valve having a plurality of ports 1.1. One of these ports 1.1 is a collection valve inlet 1.1a, which is fluidically connected to the collection inlet 16.1, in this case, through an intermediate component, such as a back pressure regulator. The other ports 1.1 include at least one waste outlet 1.1b and one or more outlets 11c leading to a collection container. The collection valve system 1 is controlled by a control device, which is configured to direct the fraction to one of the one or more outlets 1.1c leading to a collection container and the waste outlet 1.1b based on measurements of the radioactivity detector 6 and / or the UV detector. For example, the control device can perform this operation automatically or based on an operator control signal.

[0084] In the embodiment shown, an optional heating sleeve 2 is provided on a portion of the collecting valve 1. When the carbon dioxide undergoes a rapid adiabatic decompression downstream of the back pressure regulator, the temperature drops locally, for example below -70°C. This can lead to the formation of dry ice, for example in the collecting valve system. The heating foil 2 compensates for the temperature drop.

[0085] Figure 2a-2f A collecting container 8 is further shown. The collecting container 8 is in fluid communication with the outlet 1.1c to the collecting container of the collecting valve system 1. When the control device determines that a fraction is to be collected, the collecting valve system 1 is controlled in such a way that the fraction is directed to the collecting container 8 via the outlet 1.1c to the collecting container. In the embodiment shown, the collecting container 8 has a cover 5 comprising PEEK.

[0086] exist Figure 2e-2f In the figure, the collecting container is omitted. This makes it possible to see the presence of a gas / liquid separation device 9a at the inlet of the collecting container 8, in which case the gas / liquid separation device 9a is a cyclone separator 9. This is particularly advantageous when a supercritical fluid chromatography system is used as a separation system. Typically, when separating such a system, the mobile phase is used in a supercritical state. The mobile phase may, for example, include a supercritical fluid and a modifier. Once the fraction passes through the back pressure regulator, the pressure is reduced and the supercritical fluid (carbon dioxide in this example) is converted into a gaseous state. By applying the gas / liquid separation device 9, gaseous carbon dioxide can be removed from the fraction. Therefore, the fraction collected in the collecting container 8 includes a higher portion of radioactive material. In addition, this allows for faster reconstitution of injectable radiopharmaceuticals because there is no need to remove carbon dioxide. If ethanol is used as a modifier for the mobile phase, this reconstitution will be even faster.

[0087] It can be seen that the collection container 8 is arranged outside the housing 11. This advantageously allows a visual inspection, for example through a window of a hot chamber if the collection system is used in the hot chamber. It also allows the collection container 8 to be replaced with a new one during a cleaning operation.

[0088] In the embodiment shown, the collecting container 8 comprises at least a first outlet 10.1 and a second outlet 10.2, in this case at the head 5. The first outlet 10.1 can be used, for example, as waste gas for separating gases in a gas / liquid separator. The second outlet 10.2 can be used, for example, to connect the collecting container 8 to a reconstitution system to reconstitute the fraction into an injectable solution.

[0089] Figure 2b-2d Further shown is a valve 3. The valve 3 is connected to the pneumatic circuit in order to operate, for example, the switching valves in the collecting valve system 1 and the injection valve 7.

[0090] Figure 3a A first possible embodiment of a collection valve system 50 is schematically shown. In this embodiment, the collection valve system 50 includes a single valve, indicated as valve 51. Valve 51 is a switching valve having a valve inlet 52, an outlet 53 leading to a collection container, and a waste outlet 54. In this example, valve 50 is a 4-way valve and also has an unused fourth port 55. The valve inlet 52 is connected to the collection inlet fluid via a back pressure regulator and is configured to receive a fraction. The outlet 53 leading to the collection container is connected to the collection container fluid. The waste outlet 54 is connected to the waste container fluid. The embodiment shown may be suitable if only one collection container is filled, for example when only one fraction is collected.

[0091] Figure 3b A second possible embodiment of a collection valve system 60 is schematically shown. In this example, the collection valve system 60 includes a first valve 61 and a second valve 71. The first valve 61 is a 4-way switching valve having a valve inlet 62. The valve inlet 62 is fluidly connected to the collection inlet via a back pressure regulator and is configured to receive the fraction. The first valve 61 also includes a waste outlet 64 where the fluid is collected in a waste container and a fourth port 65 that is not used in the illustrated embodiment. The first valve 61 also includes a valve outlet 63, which is fluidly connected to an inlet 72 of a second valve 71 via a connector 66.

[0092] In this embodiment, the second valve 71 is a 5-way switching valve and includes 4 outlets: an outlet 73 of the first collecting container connected to the fluid of the first collecting container; a second outlet 74 of the collecting container connected to the fluid of the second collecting container; a third outlet 75 of the collecting container connected to the fluid of the third collecting container; and a fourth outlet 76 of the collecting container connected to the fluid of the fourth collecting container. Thus, the embodiment shown allows fractions to be collected in four different collection containers. However, it should be understood that different configurations are possible depending on the number of different fractions to be collected. For example, the second valve 71 may include outlets of more collection containers and / or collection valve systems, and may include more valves.

[0093] Where appropriate, detailed embodiments of the present invention are described herein; however, it should be understood that the disclosed embodiments are merely examples of the present invention, which can be combined in various ways. Therefore, the specific structural and functional details disclosed herein should not be interpreted as limiting, but should only be interpreted as a basis for the claims, and a representative basis for teaching those skilled in the art to implement the present invention in various ways in almost any suitable detailed structure. Not all described purposes need to be achieved by a specific embodiment.

[0094] In addition, the terms and expressions used herein are not intended to limit the present invention, but to provide an understandable description of the present invention. Unless otherwise specified, the words "a" or "an" used herein refer to one or more. The terms "a multiple of", "a plurality" or "several" mean two or more than two. The words "comprise", "include", "contain" and "have" have open meanings and do not exclude the presence of other elements. The reference numerals in the claims should not be interpreted as limiting the present invention.

[0095] The fact that certain technical features are described in different dependent claims always allows the possibility to advantageously use a combination of these technical measures.

[0096] A single processor or other device may perform the functions of the various components mentioned in the specification and claims, such as a processing device or a control device, or the functions of a single processing device or a control device described herein may actually be distributed over several components, which may be physically separated from each other. Any connectivity between components may be wired or wireless using known methods.

[0097] The actions performed by the control device may be implemented in the form of a program, such as a computer program, software application, etc. The program may be executed using computer-readable instructions. The program may include subroutines, functions, procedures, object methods, object implementations, executable applications, source code, object code, shared libraries / dynamically loaded libraries, and / or other instruction sets designed to be executed on a computer system.

[0098] Computer programs or computer readable instructions may be stored and / or distributed on suitable media, such as optical storage media or solid-state media provided 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 telecommunications systems.

Claims

1. A collection system for recovering separated radioactive fractions, comprising: a collecting inlet configured to receive the fraction from the separation system, a radioactivity detector configured to measure the radioactivity of the fraction and generate a radioactivity detection signal based on the measured radioactivity, a collection valve system in fluid communication with the collection inlet, wherein the collection valve system comprises at least one or more outlets leading to a collection container and a waste outlet, - A control device configured to control the collection valve system to direct the fraction to one of the outlets leading to a collection container or to the waste outlet.

2. The collection system according to claim 1, further comprising a separation system, wherein the separation system is a supercritical fluid chromatography system, wherein the collection system further comprises: A back pressure regulator between the separation system and the collection valve system; - A gas / liquid separation device, wherein the gas / liquid separation device is configured to separate gas from liquid in the fraction after the fluid of the fraction leaves the collection valve system, for example by entering a collection container.

3. The collection system of claim 2, wherein the gas / liquid separation device is a cyclone separator.

4. The collection system according to any one of the preceding claims, wherein the control device is configured to receive the radioactivity detection signal from the radioactivity detector and control the collection valve system based on the radioactivity detection signal.

5. The collection system according to any one of the preceding claims, further comprising an operator interaction system, the operator interaction system being configured to: receiving the radioactivity detection signal and generating an operator output based on the radioactivity detection signal, receiving operator input and generating operator control signals based on the operator input, in, The control device is configured to control the collection valve system based on the operator control signal.

6. The collection system according to any of the preceding claims, further comprising at least one first collection container, the first collection container being configured to be in fluid communication with a first outlet of a collection container of the collection valve system.

7. A collection system according to any of the preceding claims, further comprising a detection enhancer, such as a stainless steel ring, for the radioactivity detector.

8. The collection system according to any one of the preceding claims, further comprising a UV detector configured to measure a UV value of the fraction and generate a UV detection signal based on the measured UV value.

9. The collection system according to any one of the preceding claims, further comprising a reconstitution system for reconstituting the fraction into an injectable radiopharmaceutical.

10. The collection system according to any one of the preceding claims, further comprising a diluent valve configured to be in fluid communication with a diluent source for introducing a diluent into the collection system, wherein the control device is configured to control the diluent valve to dilute the fraction.

11. The collection system according to any one of the preceding claims, further comprising a cleaning valve configured to be in fluid communication with a cleaning solvent source for introducing a cleaning solvent into the collection system, wherein the control device is configured to control the cleaning valve.

12. A collection system according to any of the preceding claims, wherein the collection valve system comprises a first valve and a second valve, wherein the first valve comprises at least one outlet fluidly connected to an inlet of the second valve, and wherein the second valve comprises at least one outlet leading to a collection container.

13. A method of recovering a separated radioactive fraction comprising the step of using a collection system according to any preceding claim.

14. A method for recovering a separated radioactive fraction, comprising the steps of: · receiving fractions from the separation system; Determining the radioactivity of the fraction; - Controlling the collection valve system based on the measured radioactivity to direct the fractions to one or more outlets leading to a collection container or to a waste outlet.

15. The method according to the preceding claim further comprises the following steps: providing a sample comprising a plurality of substances to the separation system, wherein the separation system is a supercritical fluid chromatography system, wherein the sample comprises at least one radioactive substance and a mobile phase, subjecting the sample to a chromatographic separation in the separation system, wherein the fraction is separated from the sample at least before the determination of the radioactivity, - Separating the gas from the liquid in the fraction in a gas / liquid separation unit.

16. The method according to any one of claims 14-15, further comprising the step of directing the fraction to a collection vessel.

17. The method according to any one of claims 14 to 16, further comprising the step of determining a UV value of the fraction and controlling the collection valve system based on the determined UV value.

18. The method of any one of claims 14-18, further comprising a reconstitution step, wherein the fraction is reconstituted into an injectable radiopharmaceutical.

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

20. The method according to any one of claims 14 to 19, further comprising a cleaning step, the cleaning step comprising: Open the cleaning valve; Allow cleaning solvent to enter the collection system through the cleaning valve; 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.

21. Computer readable instructions configured, when executed, to cause a control device of a collection system to perform a method according to any one of claims 15-20.

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