Collection system for the recovery of a separated radioactive fraction

Abstract

Collection system for the recovery of a separated radioactive fraction, comprising: a collection inlet point configured to receive a fraction from a separation system, a radio detector configured to determine a radioactivity of the fraction and to generate a radio detection signal based on the determined radioactivity, a collection valve system in fluidic communication with the collection inlet point, in which the collection valve system comprises at least one or several collection flask outlet points and a waste outlet point, and a control unit configured to control the collection valve system in order to guide the fraction towards one of the collection flask outlet points or a waste outlet point.

Description

[0001] Collection system for the recovery of a separated radioactive fraction

[0002] The subject of the present invention is the field of separation of radioactive fractions, for example for use as a radioactive or radiopharmaceutical marker, for example in positron emission tomography (PET).

[0003] Several systems are known for producing radioactive labels or radiopharmaceuticals in general. Generally, the radioactive substance is first produced in a reaction, resulting in a sample containing several substances, including the radioactive substance. To isolate the radioactive substance, the sample may be subjected to a separation process in which the radioactive substance is isolated. The isolated radioactive substance is then reformulated into a solution that can be injected into a human or animal.

[0004] Since a radiopharmaceutical is radioactive and often has a relatively short half-life, time is an important factor in the production of such a product. At the same time, hygiene and quality must meet very strict requirements in the pharmaceutical industry.

[0005] Thus, an object of the invention is to provide a system and / or method enabling faster production of radiopharmaceuticals, and / or higher quality, and / or at least to provide an alternative to the state of the art.

[0006] This objective is achieved with a collection system for the recovery of a separated radioactive fraction, comprising:

[0007] • a collection inlet configured to receive a fraction from a separation system,

[0008] • a radiodetector configured to determine the radioactivity of the fraction and to generate a radiodetection signal based on the determined radioactivity,

[0009] • a collection valve system in fluid communication with the collection inlet, wherein the collection valve system comprises at least one or more outlets to a collection bottle and a waste outlet,

[0010] • a control unit configured to control the collection valve system to guide the fraction to one of the outlets to a collection bottle or to the waste outlet.

[0011] The invention therefore relates to a collection system. The collection system may be used for the recovery of a separated radioactive fraction. In this context, "separated" means that the radioactive fraction is a fraction separated from a sample comprising a plurality of substances. At least one of said substances present in the sample is a radioactive substance. The radioactive fraction comprises a high level of the radioactive substance. It will be understood, however, that in practice it is possible that the radioactive fraction does not consist of 100% of the radioactive substance, i.e. the radioactive fraction may comprise other substances than the radioactive substance. These other substances may, for example, include a non-radioactive substance and / or another radioactive substance. The radioactive fraction may, for example, comprise a mobile phase.

[0012] For example, the ratio of radioactivity from the radioactive substance in the fraction, also defined as radiochemical purity, may be at least 80%, e.g. at least 85%, e.g. at least 90%, e.g. at least 95%, e.g. at least 99%.

[0013] The radioactive substance can, for example, be an organic molecule, such as glucose or an amino acid, carrying a radioisotope such as carbon-11, fluorine-18, iodine-131. The radioactive substance can, for example, be a peptide, for example a small peptide. The radioactive substance can, for example, be aromatic or polyaromatic.

[0014] According to the invention, the collection system for the recovery of a separated radioactive fraction comprises:

[0015] • a collection inlet configured to receive a fraction from a separation system,

[0016] • a radiodetector configured to determine the radioactivity of the fraction and to generate a radiodetection signal based on the determined radioactivity,

[0017] • a collection valve system in fluid communication with the collection inlet, wherein the collection valve system comprises at least one or more outlets to a collection bottle and a waste outlet,

[0018] • a control unit configured to control the collection valve system to guide the fraction to one of the outlets to a collection bottle or to the waste outlet.

[0019] The collection system comprises a collection inlet. Via the collection inlet, a fraction may be received from a separation system. The separation system may, for example, be a chromatography system, for example, a supercritical fluid chromatography system or a high-performance liquid chromatography system. The separation system may, for example, be configured to separate the fraction of a sample comprising a plurality of substances. The separation system may, for example, be a purification system. The collection inlet may, for example, be a portion of tubing in fluid communication with an outlet of the separation system, wherein additional components are optionally provided between said outlet and the collection inlet.

[0020] The collection system further comprises a radio detector. The fraction may be subjected to a measurement by the radio detector to determine the radioactivity of the fraction. Based on this measurement, a radio detection signal may be generated by the radio detector. The radio detector may be one of the known types of radioactivity detection or measurement devices, for example a semiconductor detector such as a PIN diode radiation detector.

[0021] The collection system further comprises a collection valve system. The collection valve system may comprise one or more valves that can be fluidly connected to each other. Said valve may for example be 4-port, 6-port or 8-port. Said valve may for example be switching valves. 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 arranged between the collection inlet and the collection valve system.

[0022] The collection valve system comprises a plurality of outlets, including at least one waste outlet. The waste outlet may, for example, be used when the fraction from the collection valve is not usable, for example, because it does not contain sufficient radioactive substance or because it is used to clean the collection system. The collection valve system also comprises at least one outlet to a collection bottle. The outlet to a collection bottle may be configured to be in fluid communication with a collection bottle. The collection bottle may, for example, be configured to receive the fraction when it meets certain requirements, for example, regarding composition and / or radioactivity.More than one collection bottle outlet may, for example, be desired when the separation system is configured to supply several mutually different fractions, which need to be stored separately in different collection bottles. This may, for example, be of interest for R&D purposes. In production applications, having multiple collection bottles may also have safety advantages in situations where the collection of a fraction into a collection bottle is started at an incorrect time. It is also possible that the radioactive fraction is supplied by the separation system in relatively large quantities, so that more than one collection bottle needs to be supplied with the radioactive fraction.

[0023] The collection system further comprises a control unit configured to control the collection valve system. By controlling the collection valve system, the control unit can control which outlet the fraction is guided to. This ensures that the fraction is guided to a collection bottle when the radioactivity determined by the radiodetector is desirable, and otherwise to the waste disposal site.

[0024] In some embodiments, the control unit is configured to receive the radiodetection signal from the radiodetector and control the collection valve system based on the radiodetection signal. Based on the detection signal, the control unit can determine whether the fraction comprises sufficient radioactive substance. In this case, the fraction is guided to the appropriate collection bottle outlet, and otherwise the fraction can, for example, be guided to the waste outlet. Thus, in these embodiments, the collection system is automated.

[0025] In some embodiments, the collection system further includes an operator interaction system configured to: receive the radiodetection signal and generate an output for the operator based on the radiodetection signal; receive an input from the operator and generate an operator control signal based on the operator input. The control unit may be configured to control the collection valve system based on the operator control signal.

[0026] In these embodiments, an operator may control the collection system using the operator interaction system. The operator output generated based on the radiodetection signal may be configured to inform the operator of the radioactivity determined by the radiodetector. The operator interaction system may, for example, include a display configured to display the operator output to the operator. If the operator determines from the operator output that the radioactivity meets the desired specifications, it may provide operator input. The operator interaction system may, for example, include a keypad, touchscreen, button, or the like, to receive operator input from the operator.The operator input is translated into an operator control signal, based on which the control unit controls the collection valve system, so that the fraction is guided as desired by the operator. Optionally, the control unit is also configured to control the system for interaction with an operator.

[0027] The control unit may, for example, comprise one or more input terminals, output terminals or communication terminals configured to be in communication with one or more input terminals, output terminals or communication terminals of other components such as the radio detector, the operator interaction system or the collection valve system. This communication may be in accordance with one of the known suitable communication methods or protocols, including wired or wireless communication. The control unit may, for example, be or comprise a processing unit. The control unit may, for example, comprise 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 equipment device such as a smartphone or a tablet.

[0028] In some embodiments, the separation system is a supercritical fluid chromatography system. Supercritical fluid chromatography (SPC) allows for a rapid separation process, which is beneficial given the relatively short half-lives of radioactive substances used for contemplated radiopharmaceuticals. The separation system may, for example, be configured to use a mobile phase to dissolve the radioactive substance. The mobile phase may, for example, be a supercritical fluid, e.g., a compressed gas near, around, 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, e.g., to change the polarity or strength of the supercritical fluid. The modifier may, for example, be methanol or ethanol.In particular, the use of ethanol as a modifier can be advantageous because it can reduce the time required for reformulation, as the fraction now only needs to be diluted with a biocompatible aqueous solution. In some embodiments, the collection system includes a backpressure regulator between the separation system and the collection valve system. The backpressure regulator can be configured to maintain an upstream pressure located upstream of the backpressure regulator, wherein the upstream pressure is higher than a downstream pressure located downstream of the backpressure regulator. Particularly when SPC-type chromatography is used, the pressure in the separation system will be high and must be kept high, for example at least 70 bar or at least 80 bar.Downstream of the backpressure regulator, the pressure can be lowered, which can cause rapid decompression of the mobile phase. For example, a supercritical fluid component, e.g., carbon dioxide, of the mobile phase can convert to the gaseous state while the modifier remains in the liquid phase. Optionally, the backpressure regulator is arranged downstream of the radio detector and upstream of the collection valve system. Thus, the radio detector is configured to determine the radioactivity of the high-pressure fraction.

[0029] In some embodiments, the collection system comprises a gas / liquid separation unit, wherein the gas / liquid separation unit is configured to separate the gas from the fluid in the fraction, possibly after leaving the collection valve system, for example upon entering one of the collection bottles. This embodiment may be particularly advantageous when using SEC-type chromatography, since the mobile phase may be partially converted to the gaseous state after decompression. The gas / liquid separation unit allows the remaining fraction to be made more concentrated, since a gaseous portion of the mobile phase may be removed. This may also reduce the time required for reformulation, particularly if the radioactive substance is dissolved in the modifier only, for example when the modifier is ethanol.

[0030] In some embodiments, the gas / liquid separation unit is a cyclone. The use of a cyclone may be advantageous in particular because it allows the separation of gas and liquid at atmospheric pressures. The cyclone may for example be disposed at the outlet of the collection bottle of the collection valve system or at the inlet of a collection bottle. In embodiments in which the collection system comprises a plurality of collection bottle outlets and / or a plurality of collection valves, it is possible for the collection system to comprise a corresponding plurality of cyclones.

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

[0032] In some embodiments, the collection system further includes a detection enhancer for the radio detector. The detection enhancer may be configured to enhance the determination of radioactivity by the radio detector. For example, the detection enhancer may be a stainless steel loop. The stainless steel loop may be disposed in front of the radio detector to enhance the sensitivity of the radio detector.

[0033] In some embodiments, the collection system further comprises a UV detector configured to determine the UV value of the fraction and to generate a UV detection signal based on the determined UV value. The UV value may, for example, represent the amount of ultraviolet or visible light absorbed by the fraction. Determining the UV value identifies a property of the fraction in addition to the radioactivity determined with the radio detector. This allows the content of the fraction, i.e., which substances it comprises and / or in what quantity, to be determined more precisely. It also allows non-radioactive substances to be assessed. 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 radiodetection signal, the operator and / or the control unit can control the collection valve system to guide the fraction to one of the collection bottle outlets or the waste outlet.

[0034] In some embodiments, the collection system comprises or may be connected to a reformulation system for reformulating the fraction into an injectable radiopharmaceutical. Typically, the fraction collected in the separation system cannot be injected into a human in this form. Therefore, it may be reformulated. The reformulation may, for example, comprise diluting the fraction, for example, using water or a biocompatible aqueous buffer such as saline.

[0035] In some embodiments, the collection system further includes a cleaning valve configured to be in fluid communication with a cleaning solvent source to introduce a cleaning solvent into the collection system, wherein the control unit is configured to control the cleaning valve. The cleaning solvent may be used to clean the collection system, for example, between different samples supplied to the separation system. The cleaning solvent source may, for example, be a cleaning solvent reservoir or a cleaning solvent container. The cleaning solvent may, for example, comprise water, ethanol, or isopropanol.

[0036] In some embodiments, the collection valve system includes a single valve. The valve may, for example, have a valve inlet for receiving the fraction. The valve inlet may, for example, be in fluid communication with the collection inlet and / or a backpressure regulator when the SEC is in use. The valve may further have at least the waste outlet and the outlet to a collection bottle for guiding the fraction to a collection bottle. The valve may, for example, be a switching valve. The valve may, for example, be a 4-port valve, a 6-port valve, or an 8-port valve. In some embodiments, the collection valve system includes a first valve and a second valve, wherein the first valve includes at least one outlet in fluid communication with a valve inlet of the second valve, wherein the second valve includes one or more collection bottle outlets.Optionally, the second valve comprises two or more collection valve outlets. Optionally, the first valve comprises the waste outlet. The first valve may for example have a valve inlet for receiving the fraction. This valve inlet may for example be in fluid communication with the collection inlet and / or to a backpressure regulator when the SEC is in use. The first and second valves may for example be switching valves. The first and second valves may for example be 4-port valves, 6-port valves or 8-port valves. Certain embodiments comprising the first and second valve may be advantageous in particular when a plurality of fractions are to be collected, since more collection bottle outlets may be provided, each of which may be connected to a different collection bottle.

[0037] In some embodiments, the collection system further comprises a separation system. The separation system may be in accordance with one of the embodiments explained herein. Generally, the separation system is configured to receive a sample comprising a plurality of substances and is configured to divide this sample into different fractions having said 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, for example, comprise a compressed gas near, around, or above its critical temperature and pressure. In practice, it has been found that advantageous results can be achieved even if the compressed gas is below but close to its critical temperature, for example, by a few degrees Celsius. Said compressed gas may, for example, be carbon dioxide or nitrous oxide. Carbon dioxide is preferred. The mobile phase may also comprise a modifier, for example, to modify the polarity or strength of the supercritical fluid. The modifier may, for example, be methanol or ethanol. In particular, the use of ethanol as a modifier is advantageous. It can indeed reduce the time required for reformulation, since the fraction now only needs to be diluted with a biocompatible aqueous solution.

[0038] In some embodiments, the collection system includes a housing. Optionally, one or more of the following are disposed within the housing: the collection valve system; the radio detector; the detection enhancer; an injection valve. Optionally, a collection bottle and the gas / liquid separation unit are disposed outside the housing.

[0039] The invention further relates to a method for recovering a separated radioactive fraction. Although the method can be carried out with the collection system according to the invention; neither the collection system nor the method are limited thereto. The features explained here with reference to the collection system have the same meaning with respect to the method, unless explicitly defined otherwise. The features explained with reference to the collection system can be applied mutatis mutandis to the method to achieve similar advantages.

[0040] In embodiments, the invention provides a method for recovering a separated radioactive fraction, comprising the step of using a collection system according to any of the embodiments explained herein.

[0041] In some embodiments, the invention provides a method for recovering a separated radioactive fraction, comprising the steps of: receiving a fraction from a separation system; determining the radioactivity of the fraction; controlling a collection valve system based on the determined radioactivity to guide the fraction to one or more outlets to a collection bottle or a waste outlet.

[0042] Optionally, the method is carried out 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 may for example be a high-performance liquid chromatography system or a supercritical fluid chromatogram system.

[0043] In some embodiments, the step of controlling the collection valve system is performed by a control unit, wherein the control unit receives a radiodetection signal based on the determined radioactivity.

[0044] In some embodiments, the method includes providing an operator output to an operator, wherein the output to the operator is based on the determined radioactivity, wherein the step of controlling the collection valve system is performed based on an input from the operator.

[0045] In some embodiments, the method further comprises providing a sample comprising a plurality of substances to the separation system, wherein the separation system is a supercritical fluid chromatography system. The separation system may, for example, comprise a chromatography column. Potentially, the sample comprises at least one radioactive substance and a mobile phase. The mobile phase may, for example, be a supercritical fluid, for example, a compressed gas near, around, or above its critical temperature and pressure, such as carbon dioxide or nitrous oxide. Carbon dioxide is preferred. The mobile phase may also comprise a modifier, for example, to modify the polarity or strength of the supercritical fluid. The modifier may, for example, be methanol or ethanol.The method may further comprise the step of subjecting the sample to a chromatographic separation in the separation system, wherein the fraction is separated from the sample at least before the radioactivity is determined. During said chromatographic separation, the sample having a plurality of substances may be divided into different fractions having said substances in different relative amounts. The method may further comprise the step of separating the gas from the liquid in the fraction in a gas / liquid separation unit, said gas / liquid separation unit may for example be a cyclone.

[0046] In some embodiments, the method further comprises a step of guiding the fraction into a collection vial. The collection vial may be in fluid communication with one of the collection vial outlets of the collection valve system. When the collection valve system comprises more than one collection vial outlet, each of those collection vial outlets may be in fluid communication with another collection vial. The collection valve system may be controlled to guide the fraction to an appropriate collection vial based on the determined radioactivity. Optionally, the step of separating the gas from the liquid in the fraction in a gas / liquid separation unit is performed after the fraction leaves the collection valve system and before or while the fraction enters the collection vial.

[0047] In some embodiments, the method further comprises determining a UV value of the fraction and controlling the collection valve system based on the determined UV value. For example, the collection valve system may be controlled to guide the fraction to an appropriate collection bottle or waste outlet based on the determined UV value, for example in addition to the determined radioactivity.

[0048] In embodiments, the method further comprises a reformulation step, wherein the fraction is reformulated into an injectable radiopharmaceutical.

[0049] 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 the waste outlet; allowing the cleaning solvent to flow out of the collection system through the waste outlet, for example to a waste container.

[0050] The invention further provides computer-readable instructions configured to, when executed, cause a control unit of a collection system to perform the method according to any of the embodiments described herein. The collection system may, for example, be in accordance with one of the embodiments described herein.

[0051] Exemplary embodiments of the invention are described with the aid of the figures. It should be understood that these figures serve only as examples of how the invention may be implemented and are in no way intended to be construed as limiting the scope of the invention and the claims. Similar features are indicated by similar reference numerals along the figures. In the figures: Fig. 1a: schematically shows a process for producing a pharmaceutical product;

[0052] Fig. 2a: shows schematically the exterior of a collection system;

[0053] Fig. 2b-2c: shows schematically the collection system of Fig. 2a, in which one wall is omitted for illustration purposes;

[0054] Fig. 2d: shows schematically the collection system of Fig. 2a-2c, in which one wall is also omitted for illustration purposes;

[0055] Fig. 2e-2f: shows schematically the collection system of Fig. 2a-2d, in which one collection bottle is omitted for illustration purposes;

[0056] Fig. 3a: shows schematically a collection valve system comprising a single valve;

[0057] Fig. 3b: Schematically shows a collection valve system having a first valve and a second valve.

[0058] Fig. 1a schematically shows a method 100 for purifying a radiopharmaceutical. The injection valve 102 is connected to a modifier source 101a and an initial sample source 101b. From the modifier source 101a a modifier may be provided, said modifier comprising, for example, ethanol or methanol. From the initial sample source 101b an initial sample may be provided. This initial sample may comprise at least one radioactive substance for use in the radiopharmaceutical, for example as a PET marker. Said initial sample may have been previously manufactured in a preparatory reaction (not shown) to produce the radioactive substance. The objective of the method 100 is to obtain the radioactive substance with sufficient radiopurity and chemical purity from said sample, and to reformulate it into an injectable radiopharmaceutical.

[0059] The injection valve 102 guides 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 the initial sample, the modifier, and the supercritical fluid is made. The supercritical fluid and the modifier together form a mobile phase.

[0060] The sample is then supplied to a separation apparatus 105. In this case, the separation apparatus is a supercritical fluid chromatography system having a chromatography column. However, other separation systems may also be used, for example, a high-pressure liquid chromatography system. In the separation apparatus, the sample comprising a plurality of substances is subjected to a process that divides this sample into different fractions having said substances in different relative amounts. Typically, these different fractions remain in the chromatography column for different lengths of time. When a fraction leaves the separation apparatus 105, a UV detector determines a UV value of said fraction. The UV detector 106 generates a UV detection signal 106.1 on this basis, which is transmitted to a control unit 1 1 1 , for example via an output terminal of the UV detector 106 to an input terminal of the control unit 1 1 1.

[0061] Then, a radio detector 107 determines the radioactivity of the fraction. On this basis, the radio detector 107 generates a radio detection signal 107.1 which is transmitted to the control unit 1 1 1 , for example via an output terminal of the radio detector 107 to an input terminal of the control unit 1 1 1 . The radio detector 107 can for example be a gamma detector.

[0062] A back pressure regulator 108 is arranged behind the radio detector 107. The back pressure regulator 108 is particularly advantageous when the separation apparatus is a supercritical fluid chromatography system, since the pressure upstream of the back pressure regulator 108 is high to ensure the supercritical state, while downstream of the back pressure regulator 108, the pressure can be lowered. The back pressure regulator 108 is configured to ensure that the pressure difference is maintained.

[0063] Downstream of the backpressure regulator 108, the fraction enters a collection module 109. The collection module 109 is controlled by the control unit 1 1 1 by means of a control signal 1 1 1.1 , which may in particular be configured to control a collection valve system of the collection module 109. For example, the control signal 1 1 1.1 may be sent from an output terminal of the control unit 1 1 1 to an input terminal of the collection module 109 or the collection valve system. In the collection module 109, the fraction is collected in one or more collection bottles or in a waste container. The way in which the fraction is collected is based on the UV detection signal 106.1 and the radiodetection signal 107.1 .

[0064] One or more fractions comprising a sufficient amount of the radioactive substance to be used as a radiopharmaceutical are reformulated by a reformulation system 109 into the radiopharmaceutical. The reformulation system 109 is configured to transform the fraction into an injectable solution, for example by diluting it.

[0065] It is noted that the term "collection system" as used herein may for example be reflected in the collection module 109, but may also include one or more of the other components schematically illustrated in FIG. 1 a.

[0066] It should be noted that Figure 1a shows only one example, but other embodiments are also possible. For example, mixed flow injection can also be applied. For example, the supercritical fluid source 104 for supplying the supercritical fluid can also be connected to the injection valve 102, wherein the injection valve 102 can be directly connected to the separation apparatus 105.

[0067] Fig. 1 b shows a second embodiment of the method 100 for purifying a radiopharmaceutical. The difference with the process illustrated in Fig. 1 a is that in Fig. 1 b an operator interaction system 120 is present. The operator interaction system 120 receives the radiodetection signal 107.1 and the UV detection signal 106.1. In this example, the operator interaction system 120 is directly in contact with the radiodetector 107 and the UV detector 106, but it is also possible for the control unit 1 1 1 to receive the radiodetection signal 107.1 and the UV detection signal 106.1 and then communicate this information to the operator interaction system 120.

[0068] The operator interaction system 120 generates an operator output 120.1 that is made visible to an operator by a display 121. The operator can determine based on the operator output 120.1 whether the radioactivity and / or UV value are within desired specifications or not. When they are, the operator can provide operator input 120.2, for example via a keypad 122 or a touchscreen. 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 unit 111, which controls the collection module 109 based on said operator control signal 120.3.

[0069] Figs. 2a-2f illustrate one possible embodiment of a collection system 20 according to the invention. Fig. 2a shows the exterior of the collection system 20, while in Figs. 2b-2f several components have been omitted from the figures to illustrate interior features that would not otherwise be visible. A housing 11 is provided for organizing several components of the collection system 20. The housing 11 may be arranged in a hot cell.

[0070] Fig. 2a illustrates a top wall 11a, a front wall 11b and a side wall 11c of the housing 11. First fastening elements 14 are provided on the front wall 11b, and a second fastening element 15 is provided on the side wall 11e. The first and second fastening elements 14, 15 allow the collection system 50 to be physically arranged at the desired location, for example a hot cell.

[0071] Fig. 2a illustrates a plurality of connection elements 16 for connecting to a collection valve within the housing 11, for example to provide a separate fraction, cleaning solvent, etc.

[0072] In Figs. 2b and 2c, the top wall 11a of the housing 11 has been removed from the figure, and in Fig. 2d, the front wall 11b as well, to make the components inside the housing 11 visible.

[0073] In the illustrated embodiment, an injection valve 7 is also provided in the housing 11. The injection valve 7 is a switching valve that has a plurality of ports 7.1 to allow different connections between the inlets and outlets. This allows a sample having a plurality of substances, a modifier, and a supercritical fluid to be supplied to a mixing chamber (not shown) for mixing. At least one of said substances in the sample is a radioactive substance that is intended for use in a radiopharmaceutical. As can be seen in Fig. 2a, the ports 7.1 extend outside the housing 11. This allows the sample, modifier, and supercritical fluid to be supplied to the injection valve 7 from outside the housing 11.After leaving said mixing chamber, the sample is supplied to a separation system (not shown), which in this case is a supercritical fluid chromatography system. In said separation system, the sample is divided into fractions which leave the separation system at different times. After first potentially passing a UV detector (not shown), a fraction is guided to the housing 11 via a collection inlet 16.1.

[0074] Fig. 2c further shows a radio detector 6. The radio detector 6 is configured to determine the radioactivity of the fraction. In this case, the radio detector 6 is capable of measuring the emissions of y. Based on the determined radioactivity, the radio detector 6 generates a radio detection signal which is transmitted to a control unit (not shown). Optionally, a stainless steel loop 4 can be placed in front of the radio detector 6. It has been found that this improves the sensitivity of the radio detector 6.

[0075] Then, the fraction can then be guided out of the housing 11 again, for example via one of the connecting elements 16, to pass a backpressure regulator (not shown). Since the fraction has been separated using SFC, it is at a relatively high pressure. By using the backpressure regulator, the pressure can be reduced downstream of the backpressure regulator while maintaining a high pressure upstream of it.

[0076] The fraction is then guided to a collection valve system 1 in the housing 11 via one of the connection elements 16. The collection valve system 1 is a switching valve which has a plurality of ports 1.1. One of these ports 1.1 is a collection valve inlet 1.1a which is in fluid communication with the collection inlet 16.1, in this case via intermediate components such as the backpressure regulator. The other ports 1.1 comprise at least one waste outlet 1.1b and one or more outlets to a collection bottle 1.1c. The collection valve system 1 is controlled by the control unit, which is configured to guide the fraction to one of the one or more outlets to a collection bottle 1.1c and the waste outlet 1.1b, based on the measurement of the radio detector 6 and / or the UV detector. The control unit can, for example, do this automatically or based on the operator's control signal.

[0077] In the illustrated embodiment, an optional heating sleeve 2 is provided on a portion of the collection valve 1. When rapid adiabatic decompression of carbon dioxide occurs downstream of the backpressure regulator, the temperature may drop locally, e.g. below -70°C. This could lead to the formation of dry ice, e.g. in the collection valve system. The heating sheet 2 compensates for the temperature drop.

[0078] Fig. 2a-2f further illustrates a collection bottle 8. The collection bottle 8 is in fluid communication with the outlet of the collection bottle 11 of the collection valve system 1. When the control unit determines that the fraction is to be collected, the collection valve system 1 is controlled such that said fraction is guided to the collection bottle 8 via the outlet to a collection bottle 11. In the embodiment shown, the collection bottle 8 has a cap 5 that comprises PEEK. In Fig. 2e-2f, the collection bottle is omitted from the figure. This makes visible the presence of a gas / liquid separation unit 9 at the inlet of the collection bottle 8, which in this case is a cyclone 9. This can be advantageous in particular when a supercritical fluid chromatography system is used as the separation system. Usually, a mobile phase is used in the supercritical state when separating such a system.The mobile phase may, for example, comprise a supercritical fluid and a modifier. Once the fraction passes the backpressure regulator, the pressure is reduced and the supercritical fluid, in this example carbon dioxide, converts to a gaseous state. By applying a gas / liquid separation unit 9, the gaseous carbon dioxide can be removed from the fraction. The fraction collected in the collection bottle 8 thus comprises a higher portion of the radioactive substance. In addition, this allows for faster reformulation into an injectable radiopharmaceutical, as the carbon dioxide no longer needs to be removed. This reformulation can be even faster if ethanol is used as a modifier of the mobile phase.

[0079] It can be seen that the collection bottle 8 is arranged outside the housing 11. This advantageously allows visual inspection, for example through the window of the hot cell if the collection system is used in a hot cell. It also allows the collection bottle 8 to be replaced with a new one during the cleaning operation.

[0080] In the illustrated embodiment, the collection bottle 8 comprises at least a first outlet 10.1 and a second outlet 10.2, in this case in the head 5. The first outlet 10.1 can for example be used as an exhaust gas for the separated gas in a gas / liquid separator. The second outlet 10.2 can for example be used to connect the collection bottle 8 to a reformulation system for reformulating the fraction into an injectable solution.

[0081] Fig. 2b-2d further show the valves 3. The valves 3 are connected to a pneumatic circuit to actuate the switching valves, e.g. in the collection valve system 1 and the injection valve 7.

[0082] Fig. 3a schematically shows a first possible embodiment of a collection valve system 50. In this embodiment, the collection valve system 50 comprises a single valve, indicated as valve 51. Valve 51 is a switching valve that has a valve inlet 52, an outlet to a collection bottle 53 and a waste outlet 54. In this example, valve 50 is a 4-port valve further having a fourth port 55 that is not used. Valve inlet 52 is in fluid communication with the collection inlet via a backpressure regulator and is configured to receive the fraction. The outlet to a collection bottle 53 is fluidly connected to the collection bottle. The waste outlet 54 is fluidly connected to a waste container. The illustrated embodiment may be suitable if only one collection bottle is to be filled, for example when there is only one type of fraction to be collected.

[0083] Fig. 3b schematically shows a second possible embodiment of a collection valve system 60. In this example, the collection valve system 60 comprises a first valve 61 and a second valve 71. The first valve 61 is a 4-port switching valve having a valve inlet 62. The valve inlet 62 is fluidly connected to the collection inlet via a backpressure regulator and is configured to receive the fraction. The first valve 61 further comprises a waste outlet 64 that is fluidly collected in a waste container and a fourth port 65 that is not used in the illustrated embodiment. The first valve 61 further comprises a valve outlet 63 that is fluidly connected to an inlet 72 of the second valve 71 by means of a connection 66.

[0084] The second valve 71 is in this embodiment a 5-port switching valve and comprises 4 outlets: an outlet to a first collection bottle 73 fluidly connected to a first collection bottle; a second outlet to a collection bottle 74 fluidly connected to a second collection bottle; a third outlet to a collection bottle 75 fluidly connected to a third collection bottle; and a fourth outlet to a collection bottle 76 fluidly connected to a fourth collection bottle. The embodiment shown thus makes it possible to collect the fractions in four different collection bottles. It will be understood, however, that depending on the number of different fractions to be collected, different configurations are possible. For example, the second valve 71 may comprise more outlets to a collection bottle and / or the collection valve system may comprise more valves.

[0085] 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 invention, which may be incorporated in various ways. Accordingly, the specific structural and functional details disclosed herein should not be construed as limiting, but merely as a basis for the claims and as a representative basis for teaching those skilled in the art to practice the present invention in various ways in virtually any suitable detailed structure. Not all of the objectives described need be achieved with particular embodiments.

[0086] Furthermore, the terms and expressions used herein are not intended to limit the invention, but to provide a comprehensible description of the invention. The words "a" or "an" used herein mean one or more, unless otherwise indicated. The terms "a multiple of", "a plurality" or "several" mean two or more. The words "comprise", "include", "contain" and "have" have an open meaning and do not exclude the presence of additional elements. Reference numerals in the claims should not be construed as limiting the invention.

[0087] The mere fact that certain technical features are described in different dependent claims always allows the possibility that a combination of these technical measures can be used advantageously.

[0088] A single processor or other unit may perform the functions of various components mentioned in the description and claims, for example processing units or control units, or the functionality of a single processing unit or control unit described herein may in practice be distributed over several components, possibly physically separated from each other. Any communication between components may be wired or wireless by known methods.

[0089] The actions performed by the control unit may be implemented in program form, for example, a computer program, a software application, or the like. The program may be executed using computer-readable instructions. The program may include a subroutine, a function, a procedure, an object method, an object implementation, an executable application, source code, object code, a shared library / dynamic load library, and / or another set of instructions designed for execution on a computer system.

[0090] A 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 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

CLAIMS A collection system for the recovery of a separate radioactive fraction, comprising: • a collection inlet configured to receive a fraction from a separation system, • a radiodetector configured to determine the radioactivity of the fraction and to generate a radiodetection signal based on the determined radioactivity, • a collection valve system in fluidic communication with the collection inlet, wherein the collection valve system comprises at least one or more outlets to a collection bottle and a waste outlet, • a control unit configured to control the collection valve system to guide the fraction to one of the outlets, either to a collection bottle or to the waste outlet. A collection system according to claim 1, further comprising the separation system, wherein said separation system is a supercritical fluid chromatography system, wherein the collection system further comprises: • a backpressure regulator between the separation system and the collection valve system • A gas / liquid separation unit, wherein the gas / liquid separation unit is configured to separate the gas from the fluid fraction after it exits the collection valve system, for example, by entering a collection flask. A collection system according to claim 2, wherein the gas / liquid separation unit is a cyclone. A collection system according to any one of the preceding claims, wherein the control unit is configured to receive the radio-sensing signal from the radio detector and control the collection valve system based on the radio-sensing signal. A collection system according to any one of the preceding claims, further comprising an operator interaction system configured to: • receive the radio detection signal and generate an output for the operator based on the radio detection signal, • receive an input from the operator and generate an operator control signal based on the operator input, in which the control unit is configured to control the collection valve system based on the operator control signal.

6. A collection system according to any one of the preceding claims, further comprising at least one first collection bottle configured to be in fluidic communication with the first outlet to a collection bottle of the collection valve system.

7. A collection system according to any one of the preceding claims, further comprising a detection enhancer for the radio detector, for example a stainless steel loop.

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

9. A collection system according to any one of the preceding claims, further comprising a reformulation system for reformulating the fraction into an injectable radiopharmaceutical.

10. A collection system according to any one of the preceding claims, further comprising a diluent valve configured to be in fluidic communication with a diluent source for the introduction of diluent into the collection system, wherein the control unit is configured to command the diluent valve to dilute the fraction. 1 1. A collection system according to any one of the preceding claims, further comprising a cleaning valve configured to be in fluidic communication with a cleaning solvent source for the introduction of a cleaning solvent into the collection system, wherein the control unit is configured to control the cleaning valve.

12. A collection system according to any one 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 in fluidic communication with an inlet of the second valve, wherein the second valve comprises at least one outlet to a collection bottle.

13. Method for recovering a separated radioactive fraction, comprising the step of using a collection system according to any one of the preceding claims.

14. A process for recovering a separated radioactive fraction, comprising the following steps: • receive a fraction of a separation system; • determine the radioactivity of the fraction; • control a collection valve system based on the determined radioactivity to guide the fraction to one or more outlets to a collection bottle or waste outlet.

15. A method according to the preceding claim, further comprising the following steps: • provide 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, • subject the sample to chromatographic separation in the separation system, in which the fraction is separated from the sample at least before the radioactivity is determined, • separate the gas from the liquid in the fraction in a gas / liquid separation unit.

16. A method according to any one of claims 14-15, further comprising a step of guiding the fraction into a collection bottle.

17. A method according to any one of claims 14-16, further comprising a step of determining a UV value of the fraction and of checking the collection valve system on the basis of the determined UV value.

18. A method according to any one of claims 14-18, further comprising a reformulation step, wherein the fraction is reformulated into an injectable radiopharmaceutical.

19. A process according to claim 18, wherein the fraction comprises ethanol, wherein the reformulation step comprises diluting the fraction with a saline solution.

0. A process according to any one of claims 14-1, further comprising a cleaning step comprising • open a cleaning valve • allow a cleaning solvent to enter the collection system through the cleaning valve • Check the collection valve system to open the waste outlet, • allow the cleaning solvent to flow from the collection system through the waste disposal.

1. Computer-readable instructions configured to, when executed, cause a control unit of a collection system to perform the process according to any one of claims 15-20.

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