Medical imaging is used extensively to diagnose and treat patients. A number of modalities are well known, such as Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Positron Emission Tomography (PET), and Single Photon Emission Computed Tomography (SPECT). These modalities provide complimentary diagnostic information. For example, PET and SPECT scans illustrate functional aspects of an organ or region of interest.
PET and SPECT are classified as “nuclear” medicine because they measure the emission of a radioactive material which has been injected into a patient. After the radioactive material, e.g., radiopharmaceutical, is injected, it is absorbed by the blood or a particular organ of interest. The patient is then subjected to PET or SPECT detection which measures the emission of the radiopharmaceutical and creates an image from the characteristics of the detected emission. A significant step in conducting PET or SPECT scans is the acquisition and/or the manufacture of the radiopharmaceutical.
The half-lives of these radiopharmaceuticals range from two minutes to two hours, for example. Thus, the injection into the patient and the imaging must take place within a very short time period after production of the radiopharmaceutical. In order to meet the need of the growing practice of using nuclear medicine, portable or compact radiopharmaceutical production devices have been developed, such as the FASTlab® system and the Tracerlab® system, both sold be GE Healthcare, to offer a true multi-tracer or multi-radiopharmaceutical production facility to produce multiple radiotracers without requiring costly expansion of the production areas. In addition, often many radiopharmaceutical production runs or synthesis runs are performed on the device in one day.
Many of these compact synthesizers such as GE's FASTlab® are arranged to operate a single-use cassette, cartridge or chip that is removably mounted to the synthesizer. The spent cassette is removed after the synthesis run and replaced by a fresh cassette. Cassettes may be tailored to produce a specific radiotracer, and the synthesizer is programmed to operate each different type of cassette to synthesize the particular radiotracer.
Quality control (QC) remains a major issue in PET and SPECT radiotracer production since it requires sophisticated equipment, time and trained personnel. Multiple efforts target a reduction of QC efforts such as QC test simplification, elimination or reduction of reagents inappropriate for patient injection and quality by design. In current activity or process monitoring, radiopharmaceutical synthesizers operate in an open loop mode. Hence, the determination as to whether a synthesis has been successful is usually made after the synthesis is completed. The QC analysis is performed post synthesis on the radiopharmaceutical that has been synthesized. Therefore, it is only after the synthesis process is completed that a determination is made as to quality and yield based on QC analysis. Quality control requires sophisticated equipment and is labor, time and cost intensive. In addition, the post-production QC analysis takes time and slows down the process of radiopharmaceutical synthesis, which affects the number and timelines of patients that can be treated.
System and method for monitoring a synthesis process in a synthesizer. The system and method detect a synthesizer parameter value for one or more synthesizer parameters of a radiopharmaceutical synthesis process in a radiopharmaceutical synthesizer, and compare the synthesizer parameter value of each of the synthesizer parameters to a corresponding reference synthesizer value or value range. The radiopharmaceutical synthesis process is either continued, aborted, or interrupted based on a comparison result.
These and other features and aspects of embodiments of the present invention will become better understood when the following detailed description is read with reference to the accompanying drawings in which like characters represent like parts throughout the drawings, wherein:
As used herein the terms “cassette,” “cartridge,” “chip,” and “microfluidic chip” will be used interchangeably to mean a permanently installed or interchangeable element containing the full and/or partial fluid path of a device that is configured to produce tracers for use in medical imaging and therapy.
Also, as used herein, “radiopharmaceutical,” “radiotracer,” “tracer,” and “radioactive label,” will be used interchangeably to mean a radioactive compound used in medical imaging and therapy.
Embodiments disclosed herein provide a closed loop control for radioactive on-chip or on-cassette processes, early detection of synthesis failures, reduced quality control efforts through quality by design and radioactive monitoring during processing, where a measurement or sensor array adapts to chips/cassettes with changing design layout without requiring re-assembling, or the addition or removal of certain sensors, such as radioactivity detectors.
Embodiments disclosed herein are directed to increasing system reliability and decreasing quality control efforts by measuring activity levels at multiple points across a cassette or a chip during radiosynthesis over time utilizing a sensor array or multiple sensors. In addition, for increased system integration and downscaling for microfluidic chip-based synthesis devices, activity measurements can be conducted across the disposable cassette or chip utilizing an array of sensors or multiple sensors. Such an assembly can be utilized to measure the current status of a machine and provide early detection of system failures or malfunctions, as well as quantification of synthesis efficiency. In addition, embodiments provide for performance monitoring of single synthesis elements such as drying and purification as a feature for new chemistry development and process debugging, and enable flexibility to various cassette or chip designs which are utilized for different radiotracer syntheses. Quality by design can be achieved by storing the data from the sensors to create a cassette or chip “fingerprint,” or cassette profile. During synthesis, data from the sensors is compared to corresponding reference values or reference value ranges to provide real-time feedback on the quality of the synthesis. The fingerprint or cassette parameter profile could be a single measurement after the end of synthesis or a continuous activity monitoring over time and in parallel to other sequence parameters with respect to the reference value ranges for validation of the product.
According to embodiments disclosed herein, a radioactivity detector array could be realized by semiconductor-based elements such as diodes, diodes in combination with scintillator materials, cadmium zinc telluride (CZT) detectors, MEMS-based detectors, Geiger-Mueller assemblies or combinations thereof arranged in discrete positions across the cassette or chip or as a mesh with a constant or varying pitch between the sensor elements. Depending on the system structure and the sensor technology chosen, alpha, beta (including positrons) and/or gamma radiation can be detected and the information processed within an electronics and software unit of a controller. The operating mode could be binary detection of activity, e.g., true, if activity is within a reference value range, or quantified, e.g., proportional to actual activity level. Substrate materials for a measurement array could be e.g. metals, silicon, glass, polymers, ceramics and low temperature co-fired ceramics (LTCC) or combination of all these.
All chemistry processes that emit radiation are contemplated by embodiments disclosed herein including, but not limited to, nuclear and fluorescent, for example. With respect to nuclear applications, embodiments include, but are not limited to, medical isotopes and corresponding radiation properties such as 18F, 11C, 14C, Tc-99m, I-123, I-125, I-131, Ga-68, Ga-67, O-15, N-13, Rb-82, Cu-62, P-32, Sr-89, Sm-153, Re-186, Tl-201, In-111, or combinations thereof. Preferred isotopes include those used for PET such as 18F, 11C and 68Ga.
Referring to
As previously noted, each acquired or measured data can be considered an acquired “fingerprint.” This acquired fingerprint obtained during synthesis runs can be fed into a Failure Modes and Effects Analysis (FMEA), a storage device, or some other comparable quality assurance system, for example, which is maintained on a local and/or global database with potentially multiple contributing hospitals, users and research institutions, for example. In some embodiments, the FMEA can be maintained in the radiopharmaceutical synthesis data base system 32. The controller 14 may reside within the synthesizer 12 or in a remote location. In the current embodiment, the synthesizer 12 includes a controller (not shown) to process the commands and data supplied from controller 14 and the information provided by the radiopharmaceutical synthesis data base system 32. In some embodiments, the controller 14 can be arranged to initiate the real-time synthesis monitoring process and the controller (not shown) within the synthesizer can run the monitoring program.
In other embodiments, multiple radioactivity sensors can be provided in various positions within the synthesizer 12 to measure the radioactivity instead of the sensor array 36 shown in
The output from the sensors, and the associated electric signals or information supplied by the read-out electronics 40 provide a fingerprint of where the activity is on the cassette at a certain point in time. The fingerprint is a mapping of the measured location and intensity of radiation on the chip/cassette 34 for a specific point in time or time frame. This information is stored in the storage unit 22. Together with the synthesis sequence that is executed, the synthesizer system 10 can evaluate whether the actually measured results or synthesis run data (“fingerprint”) correlate to a reference value or a reference value range (“reference fingerprint”). As previously noted, the data acquired during synthesis can be fed into a FMEA, which is maintained on a local and/or global database, such as the radiopharmaceutical synthesis data base system 32, with potentially multiple contributing hospitals, users and research institutions. This could have an impact on the reduction of quality control since a large part of the reduction of quality control is based on number of runs that are within reference values/value ranges where batch is released so that you can reduce the number of times quality control processing is performed, once a week, for example. A determination about the output quality and the system performance during radiotracer production can be made prior to the standard quality control, which is performed after synthesis is complete. Embodiments of the invention can lead to quality by design and hence help to reduce subsequent quality control efforts in radiopharmaceutical production.
According to exemplary embodiments, the controller 14 detects when a cassette 34 is fitted or loaded onto the synthesizer 12 and identifies the cassette. The storage unit 22 in the controller can be configured to store cassette information corresponding to identification information provided on the cassette 34. The identification information may include the radiopharmaceutical to be synthesized in the cassette 34 and/or the cassette architecture. The cassette 34 includes identification information such as a bar code, electronic unit or Radio Frequency Identification (RFID), for example, that can be detected by the controller 14. The cassette and/or radiopharmaceutical to be synthesized can be identified by data obtained from other data carriers including, but not limited to, CD, USB FOBs, DVD, network sources, local databases or memories, etc., where the information is not read directly from the cassette, but may be provided by the operator by inserting an extra CD or picking the correct synthesis routine from a database, for example. Any other suitable identification method can be used to enable the cassette 34 to be identified by the controller 14. The controller 14 then retrieves the radiopharmaceutical processing program corresponding to the radiopharmaceutical to be synthesized from the program storage unit 20. The controller 14 also retrieves the corresponding reference value data or reference value range information for the pharmaceutical to be synthesized from the storage unit 22. The controller 14 can also selectively activate and/or identify the sensors 37 of the sensor array 36 (or the sensors from a group of sensors arranged in the synthesizer 12) that will be needed to monitor the synthesis of the radiopharmaceutical in the particular cassette 34 based on the cassette information.
In addition to the radioactivity sensors discussed in the exemplary embodiments, other sensors are provided in the synthesizer 12 to detect other parameters including, but not limited to, syringe pump positions, fluid levels, valve positions, pressures, temperatures, flow rates, volumes, fluorescence, fluid clarity and optical testing, pH testing, electrical voltages or currents, magnetic and electric fields, process times, and user modifications, for example. The output of each sensor corresponds to associated reference data such as a reference value or reference value range. The data from these sensors can also be included in the “fingerprint” or information supplied to the controller and can also be compared with corresponding reference sensor values or value ranges to provide even more information of the synthesis process.
The processes in both
Referring to
As described herein, embodiments of the invention provide for closed-loop, real-time monitoring of a radiopharmaceutical synthesis process based on information received from sensors and actuators in the synthesizer. The real-time monitoring allows the system to abort a synthesis process as soon as data from a sensor somewhere in the process detects an error based on the reference value/value ranges. Cost and time are saved by aborting as soon as an error is detected. The embodiments also provide a quantification of the synthesis efficiency. In addition, the embodiments disclosed herein enable flexibility to various cassette or chip designs which are utilized for different radiotracer syntheses, respectively. The multiple sensor and/or the sensor array structure can be applied for the measurement of cassettes of different designs and layouts for varying radiotracers to be synthesized on respective specialized cassettes. Embodiments of the invention also help to reduce quality control efforts after the synthesis is completed by providing an activity or parameter measurement during processing and allowing for early detection of system failures and synthesis assessment. The data from the sensors that is stored can be used as a “fingerprint” of a cartridge, cassette or chip. Fingerprint collection and synchronization with FMEAs ensures improved confidence intervals for radiopharmaceutical processing and may lead to further reduction of quality control efforts.
While only certain features of the invention have been illustrated and described herein, many modifications and changes will occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.