Methods for synthesizing radiopharmaceuticals

Abstract

To provide a method of monitoring an automated radiosynthesizer during a run.SOLUTION: The method comprises: a step S10 of recording radioactivity data from radioactivity detectors associated with the radiosynthesizer; a step S20 of accessing historic data from a data storage; a step S30 of detecting a precursor of a yield drop in the recorded radioactivity data based on the historic data; a step S40 of predicting a yield in synthesizing a tracer with the radiosynthesizer, based on the detected precursor of the yield drop; and a step S50 of initiating actions related to the level of the predicted yield.SELECTED DRAWING: Figure 11

Description

[Technical Field]

[0001] The present invention is directed to positron emission tomography (PET) and single photon emission computed tomography (SPC) imaging. Radioactive materials used in SPECT (radiopharmaceuticals) and other radiopharmaceuticals are used during synthesis. Related to the field of sexual medicines. [Background technology]

[0002] PET and SPECT imaging systems are increasingly being used to detect disease. and early detection of such diseases (e.g., disease states in the oncology and neurology range). and are useful in providing a definitive diagnosis. For example, currently, PET and SPECT studies A large proportion of these are related to cancer detection and early detection of Alzheimer's disease. Disease requires early diagnosis to allow timely and effective treatment.

[0003] PET and SPECT imaging systems each measure positron emissions within a patient's tissue. It produces images based on the distribution of radioactive and gamma-ray emitting isotopes. The body is usually exposed to positron-emitting isotopes, such as carbon-11, nitrogen-13, oxygen-15, or fluorine-1 8, or probe molecules with gamma-ray-emitting isotopes, e.g., technetium-99m. Radiopharmaceuticals are administered to patients by injection, containing radioactive materials that are easily metabolized and Radiopharmaceuticals are desired because they are localized in the body or chemically bound to receptor sites in the body. After localization at the site of interest (e.g., by chemical binding to receptor sites), PET or SPECT imaging is performed. An image is generated.

[0004] Examples of known radiopharmaceuticals are: 18 F-FLT([18 F]fluorothymidine), 18 F-FDDNP(2(1-{6[(2-[ 18 F]fluoroethyl)(methyl)amino (2-naphthyl)ethylidene)malonitrile), 18 F-FHBG(9-[4-[ 18 F]fluoro-3-(hydroxymethyl)butyl]guanine or [ 18 F]-pensik Robill), 18 F-FESP([ 18 F]-fluoroethylspiperone), 18 Fp- MPPF(4(2-methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-[1 8p]fluorobenzamido]ethylpiperazine) and 18 F-FDG([ 18 F]- 2-deoxy-2-fluoro-D-glucose).

[0005] The radioactive isotopes in radiopharmaceuticals are isotopes that exhibit radioactive decay, e.g., positron-emitting isotopes. Such isotopes are usually called radioisotopes or radionuclides. Exemplary radioisotopes include: 18 F, 124 l, 11 C. 13 N and 15 Contains O, Their half-lives are 110 minutes, 4.2 days, 20 minutes, 10 minutes, and 2 minutes, respectively. Because of the short half-lives of these isomers, the synthesis and purification of the corresponding radiopharmaceuticals is rapid and It must be efficient. Any quality control (QC) assessment of a radiopharmaceutical requires a short Preferably, these processes (i.e. synthesis, purification and and QC evaluation) must be completed in a time significantly shorter than the half-life of the radioisotope in the radiopharmaceutical. Currently, QC evaluation (e.g., chemical yield and Purity) are relatively time-consuming, mainly because they are performed manually. Therefore, in order to produce high-quality radiopharmaceuticals in the desired quantities, To ensure that the synthesis and purification of radiopharmaceuticals is proceeding efficiently, Systems, configurations and methods for collecting, analyzing and interpreting data obtained during the purification process From this analysis, elements and methods are sought that will allow for the synthesis and / or purification of radiopharmaceuticals. Any changes made before, during or after the synthesis of the radiopharmaceutical that resulted in any defects Sometimes they can be corrected.

[0006] The drawback of this solution is that when a "bad" batch (with a low yield) occurs, it It is detected using absolute plateau values. This prevents the user from initiating actions during a process run to prevent yield loss. . Summary of the Invention [Problem to be solved by the invention]

[0007] The object of the present disclosure is to overcome one or more of the above-identified deficiencies and shortcomings of the art. Methods and computers that seek to reduce, mitigate or eliminate, singly or in any combination The present invention provides a method and apparatus configured to execute a computer program. [Means for solving the problem]

[0008] The purpose is to monitor the automated radiosynthesizer while it is running. This is achieved by a method of making the radio synthesizer operable. The method has several separate radioactivity detectors associated with each radiation. recording radioactivity data from the radioactivity detector; and recording historical data from the data storage device. and detecting precursors of yield decline in the recorded radioactivity data based on historical data. and a step of detecting the tracer based on the yield when the tracer is synthesized using a radiosynthesizer. and predicting the level of yield based on the detected precursors of yield decline. and initiating an action related to the

[0009] The advantage is that it provides higher yield levels by avoiding unexpected yield losses. This is what can be done.

[0010] This objective is further achieved by providing a control system for monitoring the automatic radio synthesizer during run-time. The radio synthesizer is operatively associated with the radio synthesizer. The control system controls the temperature of each of the radiation detectors. The radioactivity data from the reactor is recorded, and the precursors of yield decline in the recorded radioactivity data are detected by the data. Detection is based on historical data accessible from a storage device and using a radio synthesizer. The yield of the tracer synthesis was predicted based on the detected precursors of yield decline. The system is configured to recommend an action related to the level of yield achieved.

[0011] Further objects and advantages will be apparent to those skilled in the art from the following detailed description. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 illustrates a method for generating and using a PET or SPECT imaging agent and extracting data collection file data according to an exemplary embodiment of the present invention. [Figure 2] 10 is a plot of data collection file data showing yield steps according to an example embodiment. [Figure 3] 1 is a schematic diagram of a system for monitoring radiopharmaceutical production, according to an exemplary embodiment. [Figure 4] 1 is a schematic diagram of a sensor array according to an exemplary embodiment; [Figure 5] (FIGS. 5A and 5B) Yield proxy as a function of labeling Δ% and radioactivity loss in tC18, respectively. [Figure 6-1] (FIGS. 6A and 6B) Precursor events during the labeling reaction. [Figure 6-2] (FIG. 6C) Precursor events during the labeling reaction. [Figure 7] (FIGS. 7A and 7B) Precursor events during trapping of FTAG on a tC18 cartridge after labeling. [Figure 8] FIG. 1 shows yield plots during the process runs. [Figure 9] FIG. 9 shows a portion of the yield plot of FIG. 8 highlighting a first type of anomaly. [Figure 10] 1 is a flowchart of a batch browser process. [Figure 11] 1 is a flow chart for monitoring an automatic radio synthesizer during a run. DETAILED DESCRIPTION OF THE INVENTION

[0013] Those skilled in the art will appreciate that the embodiments of the invention described herein have broad utility and application. As will be readily understood by those skilled in the art, the present invention will be described herein with reference to exemplary embodiments. While the invention will be described in detail, this disclosure illustrates and exemplifies embodiments, and It should be understood that this disclosure is provided solely to provide an enabling disclosure of exemplary embodiments. It should not be construed that the present disclosure limits the embodiments of the present invention or that the present disclosure and any other embodiments, adaptations, variations, modifications, and equivalent arrangements. It is not intended to be

[0014] Below, a description of different configurations and features according to exemplary embodiments of the present invention is provided. Their composition and characteristics are similar to those of radiopharmaceuticals and other compounds containing radioisotopes or It may involve providing a system and method for the quality control of pharmaceutical preparations. The name and type of application or hardware is stated, but other names and The names provided are for illustrative purposes only and are not intended to be limiting. Further, although specific embodiments are described, those specific The embodiments are intended to be illustrative and non-limiting, and each implementation The features and functions of the form may be combined in any combination within the ability of one skilled in the art. It should be understood that this can be done.

[0015] The figures illustrate various functions and features associated with the exemplary embodiments. Although blocks, subsystems, devices or components are shown, various applications or For different application environments, exemplary blocks, subsystems, devices or components thereof may be In addition, the number of blocks, subsystems, devices or components that The elements can be further combined into integrated units. or type of block, subsystem, device or component is shown, but its configuration The structure is intended to be exemplary and non-limiting. It does not necessarily perform the described functions. This is because other structures can be used in place of that structure to achieve the same.

[0016] An exemplary embodiment of the present invention relates to an automated radiopharmaceutical synthesis system. In radio communication, such a system is also called a "synthesizer" or "radio synthesizer." The term "automatic ( "Automated" refers to the act of radiosynthesis to produce tracers. indicates that the synthesizer is programmed to cause the execution of certain steps. This synthesis system is a radiation detector for use with PET or SPECT scanners. For example, this synthesis system can be used in the Liege region of Belgium. The system may be a FASTlab™ system from GE Healthcare. The use of the FASTlab system in the examples described herein is illustrative and non-limiting. The embodiments described herein are intended to be Can be used with a variety of synthesis systems manufactured by companies other than e It should be understood that the terms "radiopharmaceutical" and "radiotracer" used herein The use of "PET tracer" or "SPECT tracer" is exemplary and non-limiting. and reference to one term in the described embodiments does not exclude substitution of the other term. It should be further understood that the term "radioactivity detector" does not exclude A detector incorporated in the sizer, which detects gamma radiation sources in the vicinity of the detector, e.g. This refers to a detector that detects radioactivity from positron-emitting isotopes. It is well known in the art.

[0017] The present disclosure provides a method for monitoring a running radio synthesizer and a method for monitoring a radio synthesizer associated with the radio synthesizer. By detecting precursors of yield decline in radioactivity data recorded by the radioactivity detector This is related to the automated synthesis of radiopharmaceuticals. It is used to predict the yield when synthesizing the tracer in the sizer, and the predicted yield Depending on the level, actions are recommended to improve yield or maintain efficiency. On automated synthesis equipment such as FASTlab synthesizers at different local manufacturing / synthesis sites Since variations in performance have been observed in the synthesis of each synthesis device, the present invention This provides a method for ensuring that the production run is optimized. The radioactive synthesis using an automated radiosynthesizer was monitored to detect any signs of yield decline. The radio synthesizer provides a method for recommending behavior when The device includes one or more radiation detectors associated with the device.

[0018] Any chemical process that emits radiation, including but not limited to nuclear and fluorescent processes are contemplated by the embodiments disclosed herein. For nuclear applications, embodiments include: Although not limited to, 18 F, 11 C. 14 C. 99m Tc, 123 l,125 l, 131 l, 68 Ga, 67 Ga, 15 O. 13 N, 82 Rb, 62 Cu, 32 P, 89 Sr, 1 53 Sm, 186 Re, 210 T.I., 111 medical isotopes such as ln or combinations thereof The preferred isotopes used for PET include: 18 F, 11 C. 68 Contains isotopes such as Ga.

[0019] FIG. 1 illustrates a method for synthesizing and administering a PET or SPECT imaging agent in accordance with an exemplary embodiment of the present invention. Figure 1 shows a flowchart of a method for extracting data from a data collection file. The illustrated method 100 includes a computer implemented system It is implemented by one or a combination of various systems, components and subsystems, including Each block shown in FIG. 1 corresponds to an exemplary method 1. One or more processes, methods and / or subroutines performed in Represents.

[0020] At block 102, a radioisotope is generated. The radioisotope (e.g., 18 F or 11 C) is typically obtained by a cyclotron (e.g., GE PETtra) for PET radioisotopes. CE 700 cyclotron) or for SPECT radioisotopes ( for example 99mTo generate Tc, a generator is used. The cyclotron or generator must be located in the manufacturing area or near the scanner. The cyclotron or generator can be integrated with the PET or SPECT scanner. When placed on-site together, transport time for the radioisotope is minimized. While references to "SPECT" and "SPECT" are made, such examples are for illustrative purposes only and are not intended to be a direct translation of the It should be understood that one does not exclude the other.

[0021] In block 104, the radioisotope is used to synthesize a radiopharmaceutical. The radioisotope is then bound to a radioligand. The synthesizer may be manually operated or semi-automatically operated. It may be automated or fully automatic. For example, GE Heal The thcare FASTlab system is a fully automated synthesizer. To protect the operator from radiation, synthesizers are typically operated in "hot cells." During the synthesis of a radiopharmaceutical, in-process data can be collected. This data can be Corresponding to the readings of a radioactivity detector or sensor at various points in the synthesis process. Data can be collected at various time intervals and stored electronically. The synthesizer can output or save the data in the form of a data collection file. The cassette is then fitted to a synthesizer and used for radiopharmaceutical synthesis. Various reagents and other equipment, such as syringe pumps and vials. The cassette may be removable and disposable. It may be configured to support the synthesis of radiopharmaceuticals.

[0022] At block 106, the synthesized radiopharmaceutical is dispensed. The radiopharmaceutical dose is administered to the patient. Dispense samples of the synthesized bulk radiopharmaceutical into collection vials for dosing and QC. , can be dispensed directly into QC systems and / or cassettes for QC testing. The C testing system and method is described in PCT application Ser. No. US11 / 029,494, filed Aug. 22, 2011. No. 1 / 2011 / 048564, the contents of which are incorporated herein by reference in their entirety. It is incorporated herein by reference.

[0023] At block 108, a quality control check is performed on the radiopharmaceutical sample. can perform several QC checks. These QC checks are automated. The QC system may include a cassette with multiple components for performing the test. The cassette may be inserted into the QC system to perform the QC check. The QC system may be a stand-alone system, or may be integrated with the synthesizer described above. Select a sample from one or more dispensed vials for QC checks These samples may be sent to a QC system. Alternatively, appropriate samples may be can be output directly from the synthesizer to the QC system. It may be connected or coupled to a synthesizer.

[0024] At block 110, the patient is administered a dose from the same production batch as the sample that was QC tested. do.

[0025] At block 112, a PET or SPECT scan is performed on the patient who received the dose. Carry out.

[0026] Block 114 creates a data collection file from the synthesizer. This file is This data collection file contains data collected during the synthesis of a radiopharmaceutical. The present invention may be formatted as described in the document and may be Alternatively, other For example, you can save this file in the GE H format as described above. Log files, such as those created by the healthcare FASTlab system, The terms "data collection file" or "log file" used herein may be used interchangeably. The use of "radioactive" is intended to be exemplary and non-limiting. It may be used for such data collection files containing data collected during the process. The data collection file can be used for any part of the synthesis process. It should be understood that the information may be created at any time.

[0027] Data collection files should be prepared in hard copy format and / or electronically. For example, the data collection file can be communicated to the synthesizer. The output may be printed by an output device such as a printer connected to the or data collection files may be output or stored in electronic format. For example, the synthesizer may have an electronic display, or coupled to a computer system for displaying the data collection files in electronic format; The data collection file may be stored in an electronic storage location either internal or external to the synthesizer. For example, a synthesizer can store random temporary solid-state storage devices such as flash memory or Having more permanent solid-state storage such as hard disk storage can be done.

[0028] In the synthesis of the radiopharmaceutical 104, information from step 116 (shown by the dashed line) is This information may be used, for example, but not limited to, single batch diagnostics. batch diagnostics), "yield advisor," or batch browser batch browser processing are shown for illustrative purposes and are not included in this specification. This is explained in more detail in the book.

[0029] 10 and 11 are specific / alternative embodiments of step 116 of FIG.

[0030] Additionally, the synthesizer has an input device to allow user interaction with the system. It should be understood that these input devices can be communicatively coupled to the system. For example, the synthesizer may be a QWERTY or equivalent type keyboard. keyboard, alphanumeric pad, and / or pointing input device A combination of input devices is also possible. The synthesizer can be connected to a computer network. For example, the synthesizer may be communicatively coupled to a local area network. The synthesizer may be communicatively coupled to a network or similar network. Through a network connection such as one or more external computers, computers The system and / or server may be communicatively coupled to the system. In the embodiment, the synthesizer may be communicatively coupled to the Internet. The user may be connected wirelessly to a computer network or may have a wired interface. The synthesizer may be connected to a device on a computer network. For example, data may be transmitted over a computer network. The collected files may be sent to another computer system or server. The computer system or server is located in a geographically distinct location from the synthesizer. It may be possible.

[0031] Further, the synthesizer may be connected to one or more computer processors. , a power supply, computer memory, and software. As mentioned above, a synthesizer can be a The synthesizer may be communicatively coupled to a computing system. is a wired or wireless computer network, or a wired and wireless network. may be communicatively coupled to an external computer system through a combination of To run the synthesizer and to collect and run data from the data collection file. and commands to the synthesizer to carry out analysis of the data. This combination of computer hardware and software may be called a synthesizer. The sizer operates automatically, and certain aspects of data collection, data analysis and data Enables the synthesizer to perform corrections or factors derived from the data It may also be something.

[0032] At block 116, the data collection is analyzed. According to an exemplary embodiment, the data collection flow The file is analyzed as described herein. As part of the analysis, the data collection file is Certain factors and information can be gathered from the file. These factors and information can be used to In this way, radiopharmaceutical processes can be altered, modified and / or adjusted. This data analysis indicates that the process is not running efficiently because it shows low yields. As a non-limiting example, this may indicate a problem in the reactor. Adjustments or modifications may be made. Such adjustments or modifications may be made may be applied manually by the operator or issued through a computer system. This may be performed automatically by the synthesizer based on the command. The system may be fully automated and may be used to perform the analysis and implement corrections or modifications to the process. No external intervention is required.

[0033] FIG. 2 illustrates the process of storing certain information, particularly yield information, in a data collection file in accordance with an exemplary embodiment. Figure 2 shows a graph that illustrates how the data can be gleaned from the FBA and representative traces of the radioactive synthesis of flucliclatide, FIG. 200 shows a plot containing an overlay of components of a radiopharmaceutical synthesis process. The total yield 202 is the sum of the first yield step 204 and the second yield step 206 These yield values ​​are used to evaluate the overall process performance as well as to identify process problems. According to an exemplary embodiment, the system may be configured to identify the rear. An exemplary or "standard" process with a yield can be determined. The resulting data collected during the test, e.g., radioactivity detector readings, are plotted. The yield can be determined as shown in Figure 2. According to the report, the radioactivity detector No. 1 is a quaternary methylammonium (QMA) cartridge. Radioactivity detector No. 2 is positioned near the reactor. Radioactivity detector No. 5 is located at the process outlet leading to the syringe or production collection vial. It is located near the

[0034] The resulting plot provides an exemplary "fingerprint" for the system. Subsequent runs performed using the system may then be analyzed using the same method as in this example. Deviations from this fingerprint can be compared with a typical process, as described above. This can be seen through the plot of the data collection file data. From the analysis of the plots, problems in the system and its processes can be easily identified and subsequently corrected. According to an exemplary embodiment, the optimal fingerprint of the process If a trace is taken (e.g., from a subsequent synthesis run or from a different site), Subsequent traces from any given area (e.g., detector) can be compared to it. 1, 2 or 5) the fingerprint of the subsequent trace If they differ significantly (e.g., by more than 2%, 5%, 10%, or 15%), the operator (or the synthesizer automatically) that step in the synthesis is not proceeding properly. According to an exemplary embodiment, the first yield step 204 and the second yield step Use the variations in step 206 to identify where in the process problems may be occurring. mosquito,[ 18 What happens during the labeling step to form [F]benzaldehyde (FBA)? mosquito,[ 18 Conjugation to form [F]fluciclatide Whether this occurs during the synthesis (or annealing) step or any purification step involved in the synthesis process It is possible to identify whether a change is occurring along with a change in the

[0035] Referring to FIG. 3, a block diagram is shown providing an overview of a radiopharmaceutical synthesis system. The system 10 includes a synthesizer 12 and a controller 14. 14 includes a user interface 16, a processor 18, a program storage unit 20, a memory The synthesizer 12 has a memory unit 22 and a communication interface 24. Suitable lab equipment, such as FASTlab™ sold by E Healthcare, The synthesizer 12 may be any radiopharmaceutical synthesizer. to perform a synthesis run on the cartridge / chip and sent to the controller 14 Actuators, sensors and The synthesizer 12 may be used in a variety of applications, including, but not limited to, local area networks and communication systems. The synth communicates with the controller 14 via a network including a LAN 26. To provide communication between the sizer 12 and the controller 14, a wide variety of devices may be used, including but not limited to: Any suitable network, including a wide area network (WAN), such as the Internet. The program storage unit 20 can store various radioactive Each corresponding radiopharmaceutical synthesizer process program for synthesizing the drug The storage unit 22 stores the synthesis program, as well as other programs as needed. In addition to the synthetic run data output by the sensor during the run, The information such as the reference value / value range of each of the various sensors in the sensor 12 is stored. Each radiopharmaceutical synthesized by the synthesizer 12 has a corresponding These reference values / value ranges will be used to Think of it as a "fiducial fingerprint" for your radiopharmaceutical synthesis process and / or cassette The reference values / value ranges can be programmed into the controller 14 and periodically adjusted as needed. The controller 14 and synthesizer 12 can further be updated as shown in FIG. As described above, radiopharmaceuticals can be transmitted via a network 31, such as the Internet. The reference values / value ranges can be received periodically from the product composition database system 32 . On a local or global database system, on a CD, DVD, USB or any other storage device The system 32 may be maintained in any suitable storage and processing configuration. It can be implemented.

[0036] As mentioned above, the respective acquired or measured data is referred to as the acquired "finger The fingerprints obtained during the synthesis run can be thought of as for example, to local and / or regional hospitals with potentially a large number of contributing hospitals, users and research institutions. The failure modes and effects analysis (FMA) are maintained on a global database. FMEA), storage, or any other comparable quality assurance In some embodiments, the FMEA can be transmitted to the radiopharmaceutical synthesis system. The controller 14 may be configured to synthesize the In this embodiment, the synthesizer 12 may be located within the synthesizer 12 or at a remote location. However, the commands and data provided by the controller 14 and the radiopharmaceutical synthesis data A controller (not shown) for processing the information provided by the database system 32. In some embodiments, the method includes: The controller 14 can be configured, and a controller (not shown) within the synthesizer A monitoring program can be run.

[0037] Figure 5A shows the yield proxy of tC18 radioactivity relative to QMA radioactivity, as a percentage of the standard The results are shown as a function of the cleavage rate Δ (delta) (100% yield is the desired result). The parameters are defined in Figure 6B and relate to the loss of yield during labeling. From Figure 5A, which shows the results from many runs at positions (position 1 and position 2), the convergence It is clear that there is a correlation between the rate and Δ% during labeling. Outliers indicate different failure modes and are precursors to yield loss. Based on this, yields can be predicted and appropriate actions can be recommended to maintain or improve yields. However, the recommended actions exemplified below relate to the predicted yield level. .

[0038] Figure 5B shows the yield proxy of tC18 radioactivity relative to QMA radioactivity, expressed as t The yield is shown as a function of radioactivity loss in C18 (100% yield is the desired result). ) This parameter is defined in Figure 7B and is related to the radioactivity loss during trapping. . Represents results from many runs at two different locations (Location 1 and Location 2). Figure 5B clearly shows a strong correlation between yield and radioactivity loss in tC18. High tC18 loss usually indicates suboptimal labeling resulting in low yields. High tC18 loss is a precursor to yield loss. As mentioned above, based on this precursor to yield loss, Yields can be predicted and appropriate actions can be recommended to maintain or improve yields. However, the recommended actions exemplified below relate to predicted yield levels.

[0039] Figures 6A and 6B show precursor events during the labeling reaction. Figure 6A shows the normalized radioactivity 3 shows a plot of data collection file data similar to that of FIG. 2, showing as a function of time. As explained in relation to 2, different radiation sensors were used to create this graph. Labeling occurs in the region indicated by 60 on the graph, and this region is shown in Figure 6B. The normalized radioactivity decrease during labeling is a measure of the yield loss. This is indicated by the label Δ (delta), which is usually expressed as a percentage. As mentioned above, a decrease in yield during labeling is an example of a precursor to a decrease in yield.

[0040] According to some embodiments, the step of detecting a precursor to yield loss comprises detecting an anomaly. The step of detecting anomalies includes measuring a decrease in yield in the selected region. Additionally, anomalies can include behaviors that provide early warning signals for yield. It can be detected by processing historical data from many previous runs to identify To be able to compare historical data from different runs, The step of processing the data involves normalizing the data from multiple previous runs at a particular point. According to some embodiments, the step of detecting anomalies may further comprise: allows you to fit a mathematical function to a selected region and to analyze the mathematical function based on its behavior. In this example, region 60 is a labeled reaction and historical data is evaluated. By doing so, the mathematical function for this region 60 is y=1-Ae-λt where y is the yield, A and λ are constants, and t is time, and the evaluation is based on the magnitude of λ.

[0041] A large λ corresponds to a "strong curve," and a strong curve has a good yield. This is equivalent to a "normal" batch. Therefore, a small λ corresponds to a low yield. 1 is a graph showing the identification λ as a function of a yield proxy.

[0042] From historical data, many correlations between yield and data from the radioactivity detectors have been identified. Another example is shown with reference to Figures 7A and 7B, which show on the tC18 cartridge after labeling in the area indicated by 70 18 F-F Precursor events during trapping of fluoro-tetraacetyl-glucose (FTAG) By analyzing historical data from many previous runs in this trapping region, It is possible to identify behaviors that give early warning signals for yield. The steps to process historical data are included to allow comparison of historical data from different runs. The method further includes normalizing data from multiple previous runs at a specific point. According to some embodiments, different analytical methods can be used to identify precursor events. These analytical methods include, but are not limited to, comparing time series, Similarity-based methods include identifying Euclidean distances, clustering, etc. Requires less domain expertise than feature-based approaches Poor sensitivity.

[0043] By summing all the "losses" in each of the valleys 71 and 72, the tC18 radioactivity loss Analysis of historical data indicates that tC18 activity losses are high. If not, this is the result of poor labeling and therefore low yield. As shown in Figure 5B, yield and loss are correlated.

[0044] Figure 8 shows the long-term yield plot and anomaly detection curve during the process run. The yield plot includes raw data and a rolling average (bold line). The anomaly occurred during a process run, where the radioactivity readings were higher than those of the previous process run. The results are different from what was expected (based on historical data collected from the run). In this example, one area 75 is emphasized. According to some embodiments, the model is created based on historical data. The recorded radioactivity data is compared with the model to detect precursors to yield loss. This is accomplished by:

[0045] FIG. 9 shows a portion of the yield plot of FIG. 8 highlighting the first type of anomaly in region 75. Radioactivity readings were used to detect anomalies, and the results are shown in the anomaly detection curve, the bottom curve in Figure 9. In this example, the detected anomalies within circle 78 give a warning signal and reduce the yield at risk. It is possible to predict the yield and to observe the behavior related to the level of yield. According to some embodiments, if the predicted yield level is above a predetermined threshold, When the output voltage is below this value, action is taken to maintain the desired output from the radio synthesizer. According to some embodiments, an automatic radio synthesizer may be configured to generate a frequency band of, for example, 75% to 85%. % production yield, and the predetermined threshold is at least 10% or 15% lower than the production yield. low.

[0046] The results of the detection of yield loss and the predicted yield of the tracer synthesis were used. Examples of recommended actions are shown below. - When synthesizing tracers, materials are introduced into the automatic radio synthesizer, and the recommended action is , including adding more ingredients. - Recommended action is due to hardware issues and / or scheduled maintenance. e) relates to, for example, a level where the yield is 10% or 15% lower than the production yield. Maintenance is initiated before the temperature drops below a predetermined acceptable level.

[0047] There are several options for detecting the precursors to yield loss. The first option is to One option is to use "batch diagnostics", in which deviating behavior is detected. This deviation can be linked to a trend, as shown in Figures 6A, 6B, 7A and 7B. An exemplary observation is that the labeling reaction is optimal. It may include things that were not 18 In the case of F-FDG synthesis, this is low This will give rise to trapping and the yield will not be optimal.

[0048] This type of problem is often caused by: 1. 18 [F]Fluoride quality parameters 2. FTAG trapping problem

[0049] A further action may be to check performance against other recent batches. Consider replacing the delivery line.

[0050] The second option is to use the Yield Advisor, which calculates the yield of raw data. A long-term yield plot including the data and moving average is used. Events can also be included using automatic anomaly detection as shown in Figures 8 and 9. , can give an early warning signal that yield is at risk.

[0051] FIG. 10 shows a flow chart 80 of the third option, the batch browser process. The flow starts at 80, where a batch is selected at 81. As shown at 82, If data from a master or similar batch is used, the flow continues to 83. If not, the flow goes to 84, where the selected batch is Overlay historical data from a range of batches or from a specific batch.

[0052] In 83, characteristics specific to the selected batch are specified, as shown by 50 in FIG. 5A. The flow proceeds from 83 and 84 to 85. The results are displayed in 85. According to the first option 86, the results are displayed in 86 for the selected batch class. According to the second option87, the results are presented as a trend view of the data. A timeline and overlay of when the switch occurred, e.g., as a maintenance event, are presented.

[0053] At 88, actions are initiated to prevent yield loss based on the results presented at 85.

[0054] Different considerations regarding connectivity and deployment are addressed. ,This is reflected in different levels of connectivity.

[0055] local The local version offers different options for detecting precursors to yield loss and for detecting the effects of yield loss. The analysis required to predict yield based on precursors is performed in software on a radio synthesizer. The advantage is minimal on-site operation. However, the downside is that updates are rolled out slowly. , and lack of flexibility.

[0056] Cloud In the cloud-based version, manual data is transferred to a web-based interface. The data is uploaded using the cloud, which provides secure data storage. The advantages of a software-based implementation include rapid customization, mobile and remote access, Data backup and incorporating new features as data sets grow The drawback is that it can affect the security and privacy of users of the system. It is necessary to prove that Basi

[0057] FIG. 11 shows a flow chart for monitoring an automatic radio synthesizer during a run; The radio synthesizer may include a number of separate components operatively associated with the radio synthesizer. It has a radioactivity detector.

[0058] Yield is an important parameter when producing tracers with radiosynthesizers. If an unexpected yield loss occurs, the user of the system must be prepared for this event. The purpose of this disclosure is not only to predict the yield itself, but also to detect the signs of a decline in yield. These precursors may be related to the underlying chemical process or processes involved in that process. It is related to the hardware components used.

[0059] The yield is calculated by dividing the radioactivity remaining after radiochemical synthesis by the radioactivity of the material entering the device. The exact definition may vary from user to user. Most users report that yield variability is a major challenge, but some customers (large commercial suppliers) For the fermentation process, it is also important to have a high absolute yield. It is important to improve yield by proposing actions that achieve improved rates.

[0060] Variability in yield levels poses a problem (at least for FDG). This claim may improve yield reliability.

[0061] In FIG. 11, the flow starts at step S1, and at step S10, Radioactivity data from the radioactivity detector is recorded.

[0062] In step S20, historical data is accessed from the data storage device. According to the embodiment, the method includes data from a previous run on the same radio synthesizer. According to some embodiments, the method further includes selecting S22 the historical data so as to include: The method may be adapted to further include data from previous runs on other radio synthesizers. Further included is selecting S24 the historical data.

[0063] According to some embodiments, the method includes using a device located external to the radio synthesizer. As such, it is preferably deployed externally to the radio synthesizer in a cloud-based implementation. and selecting S26 the data storage device as the one in which the data is stored. According to some embodiments, the method further comprises creating a model based on historical data S28. The precursors to yield loss and the associated radiation loss were detected by comparing recorded radioactivity data with the model. According to some embodiments, a local decoder is provided within the radio synthesizer. and a local data storage device is arranged, and the method includes storing the model in the local data storage device. and S29.

[0064] In step S30, a sign of a decrease in yield in the recorded radioactivity data is detected based on historical data. According to some embodiments, the step of detecting the precursor to yield loss comprises detecting an abnormal According to some embodiments, the step of detecting an anomaly includes detecting S32. , from numerous previous runs to identify behaviors that give early warning signals for yield. Further includes processing S34 the historical data. According to some embodiments, the historical data The data processing step normalizes data from multiple previous runs at a particular point. It further includes:

[0065] According to some embodiments, the step of detecting anomalies comprises applying a mathematical function to the selected region. including applying numbers S36 and evaluating mathematical functions based on their behavior According to some embodiments, the mathematical function is: y=1-Ae-λt where y is the yield, A and λ are constants, t is time, and the evaluation is performed at the magnitude of λ. Based on size.

[0066] According to some embodiments, detecting anomalies comprises detecting a convergence in the selected region. measuring the decrease in rate S38.

[0067] In step S40, the yield of the tracer synthesized using a radio synthesizer is measured. In step S50, the predicted yield level is The automatic radio synthesizer's production yield, i.e., output product, The residual radioactivity in the feedstock divided by the radioactivity of the input material is typically in the range of 75% to 85%. However, this number may vary depending on the type of tracer produced.

[0068] According to some embodiments, the method further comprises: determining whether the predicted yield level exceeds a predetermined threshold; S52 to maintain the desired output from the radio synthesizer when According to some embodiments, the method further includes: The method has a predetermined threshold value that is at least 10% lower than the production yield. According to some embodiments, the method further comprises selecting S54 a value that is and selecting the predetermined threshold S56 to be at least 15% lower than the success rate. According to some embodiments, the tracer is synthesized using an automatic radio synthesizer. Ingredients are introduced into the mix, and actions include adding more ingredients. According to the form, the action initiated may be related to hardware problems and / or scheduled maintenance. do.

[0069] Additionally, the synthesizer's on-board computer provides automatic radio synthesizer monitoring. That is, the present invention further provides a non-transitory computer-implemented The present invention contemplates providing a non-transitory computer-readable storage medium, the non-transitory computer-readable storage medium being capable of being read by a radio an executable program for performing steps for monitoring a synthesizer, comprising: Execution of the computer readable program code causes the processor to Radioactivity data from the detector was recorded, and signs of yield decline in the recorded radioactivity data were analyzed. based on historical data accessible from a data storage device and using a radio synthesizer. The yield of the tracer synthesized using the radioactive material was predicted based on the detected precursors of yield decline. and performing the step of recommending an action related to the predicted yield level of the synthesizer. The present invention includes an executable program of such a type.

[0070] The present disclosure relates to a computer program for monitoring a running automatic radio synthesizer. which, when executed on at least one processor, a computer program including instructions that cause a processor to perform the method described with respect to FIG. Additionally, the present disclosure includes a computer program for monitoring an automatic radio synthesizer. The present invention also includes a computer-readable storage medium containing a program.

[0071] The present disclosure further provides a method for controlling an automatic radio synthesizer during a run, as described with respect to FIGS. The radio synthesizer includes a controller for monitoring the radio synthesizer. a number of separate radiation detectors operatively associated with the detector, and the control system M is, - Recording the radioactivity data from each radioactivity detector; - Predictors of yield decline in recorded radioactivity data are accessible from the data storage device based on historical data, - The yield when the tracer is synthesized using a radiosynthesizer is calculated as the detected yield. Based on the following signs, - Recommend actions related to predicted yield levels It is structured as follows.

[0072] According to some embodiments, the control system includes an externally located data storage device. is configured to access [Explanation of symbols]

[0073] 10 Systems 12 Synthesizer 14 Controller 16 User Interface 18 processors 20 Program Storage Unit 22 Memory Unit 24 Communication Interface 26 Local Area Network (LAN) 31 Network 32 Radiopharmaceutical Synthesis Database System

Claims

1. 1. A method of synthesizing a radiopharmaceutical using an automated radiosynthesizer in a run, said radiosynthesizer having several separate radioactivity detectors operatively associated with said radiosynthesizer, said method comprising: - recording (S10) the radioactivity data from each radioactivity detector; - accessing historical data from a data store (S20); - detecting (S30) precursors of yield degradation in the recorded radioactivity data based on the historical data, the step of detecting precursors of yield loss (S30) comprises fitting a mathematical function to a region during the labeling reaction in a graph showing normalized radioactivity as a function of time (S36), and evaluating the mathematical function based on its behavior to detect anomalies (S32); The mathematical function is: y=1-Ae －λｔ is selected to be y is the normalized radioactivity fraction yield, A and λ are constants, t is time, and the assessment is based on the magnitude of λ, where a small λ is indicative of a poor yield. Step (S30), - predicting the yield of a radiopharmaceutical synthesized using the radiosynthesizer based on the detected signs of yield decline (S40); - initiating an action related to the predicted yield level (S50), and initiating (S52) operations to maintain a desired output from the radio synthesizer when the predicted yield level is below a predetermined threshold; creating a model based on the historical data (S28), and detecting precursors to yield degradation by comparing the recorded radioactivity data with the model; The method further comprises:

2. 2. The method of claim 1, wherein the autoradiosynthesizer has a production yield, the method further comprising selecting (S54) the predetermined threshold to be at least 10% lower than the production yield.

3. 3. The method of claim 2, further comprising selecting (S56) the predetermined threshold to be at least 15% lower than the production yield.

4. introducing materials into the automated radiosynthesizer when synthesizing the radiopharmaceutical; The method of any one of claims 1 to 3, wherein the action comprises adding more material.

5. the action being initiated relates to a hardware problem and / or scheduled maintenance; The method according to any one of claims 1 to 4.

6. The method of any one of claims 1 to 5, further comprising selecting (S22) said historical data to include data from previous runs on the same radio synthesiser.

7. 7. The method of claim 6, further comprising selecting (S24) the historical data to further include data from a previous run on another radio synthesizer.

8. The method of any one of claims 1 to 7, further comprising selecting (S26) the data storage device to be located external to the radio synthesizer.

9. 2. The method of claim 1, wherein a local data store is located within the radio synthesizer, the method further comprising storing (S29) the model in the local data store.

10. the step of detecting the anomaly further comprises: - Processing historical data from many previous runs to identify behaviors that give early warning signals for yield (S34) The method of claim 1 further comprising:

11. The method of claim 10 , wherein the step of processing historical data further comprises normalizing the data from the multiple previous runs at a particular point.

12. The method of claim 1 , wherein the step of detecting anomalies further comprises measuring a reduction in yield in the selected region (S38).

13. 13. A computer program for monitoring an automatic radio synthesiser in operation, the computer program comprising instructions which, when executed on at least one processor, cause said at least one processor to perform the method of any one of claims 1 to 12.

14. 14. A computer readable storage medium containing a computer program for monitoring a running automatic radio synthesizer according to claim 13.

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