Patent Application
20150004060
The embodiments generally relate to a system for controlling reaction boxes, and in particular to such a system for controlling the environment in the reaction boxes.
Today radioactive tracers, so called radiotracers, for single-photon emission computed tomography (SPECT) and positron emission tomography (PET), and radiopharmaceuticals for therapeutic uses are produced in hot laboratories or special production facilities, which are run under regulatory rules in order to meet good manufacturing practice (GMP) production criteria. The hot laboratories are large facilities, generally divided into separate sections and working compartments, mostly denoted hot cells, with room for operators, laboratories with radiation-shielding and storehouse for radioactive waste.
The hot cells in the hot laboratories are chambers with strong radiation shielding of high-density materials. The interior surfaces of the hot cells are typically lined with stainless steel coated by oil paints or polyethylene films to facilitate decontamination.
A hot laboratory is typically part of a radiochemical laboratory complex, requiring extensive planning to house the extensive facility. High demands are also put on the staff working in the hot laboratory with significant documentation in order to meet, among others, the regulatory demands on ventilation classification, radiation safety and measurements of biologics, all with the emphasis on the safety for personal and the production of the radiotracers and the radiopharmaceuticals for the patients within the facilities
Today qualification of hot laboratories according to GMP is typically made by independent companies or regulatory bodies to test and qualify the protocols and documentation of the hot laboratories. All important information is then documented in standard operation procedure (SOP) for the hot laboratories as well as for the production of the various labeled products. Such qualifications are generally performed two to three times per year.
It is obvious that building and running hot laboratories is very expensive and requires significant amount of regulatory documentation and control, which thereby put limitations to which medical facilities that have access to radiotracers and other radioactively labeled substances for diagnosis or therapy. Furthermore, the need for separate hot laboratories limits the type of radioactive isotopes (radionuclides) that can be used in the radiotracers and labeled substances to have a half-life that is long enough to allow transport of the radiotracers or labeled substances from the hot laboratories to the PET/SPECT or treatment center and still have sufficient radioactivity for efficient diagnosis or treatment of a patient. This means that in practical applications fluorine-18 (18F) with a half-life of about 110 minutes is commonly used as radionuclide. However, there is a general need to be able to use other radioisotopes with a much shorter half-life, such as 11C, 13N or 15O with half-life of about 20, 13 and 2 minutes, respectively. These radionuclides, however, need on-site production facilities.
Thus, there is a need for a system that can be used to manufacture radiotracers and other radioactive substances in a safe and cost-effective manner. It is a further need that such a system is miniaturized so that it can be arranged in or close to the PET/SPECT or treatment center to enable usage of radioisotopes with relatively short half-lives. These needs are also present for the manufacture of other, non-radioactive, substances, in particular for various diagnostic and therapeutic substances.
U.S. Pat. No. 7,829,032 discloses a microfluidic device that can be used in a fully automated synthesis system of radioactive compounds for PET-imaging in a fast, efficient and compact manner. The system is in the form of an automated, stand-alone, microfluidic instrument for a multi-step chemical synthesis of radiopharmaceuticals.
US 2011/0008215 discloses a system for a fully automated synthesis of radioactive compounds for PET-imaging in an efficient, compact and safe-to-the-operator manner. The system comprises a hot component unit and a cold component unit provided as separate units that are operatively connected to each other.
The systems disclosed in the above two patent documents enable miniaturization of the synthesis of radiotracers and other radioactively labeled substances. However, the prior art systems are not designed to meet the high demands of GMP in the synthesis process.
It is a general objective to provide a system for controlling environment in a reaction box.
It is a particular objective to provide a system capable of producing and verifying GMP clean room environment in a reaction box.
These and other objectives are met by embodiments disclosed herein.
An aspect of the embodiments defines a system for controlling the environment in a reaction box. The system comprises a gas inlet connector connectable to at least one gas source comprising a respective gas and a gas outlet connector connectable to at least one reaction box. A gas multiplexer is connected to the gas inlet connector and the gas outlet connector and is configured to interconnect a gas flow from the gas inlet connector to the gas outlet connector. A vacuum pump is connected to the gas multiplexer and is configured to generate an under pressure inside a reaction box when the gas multiplexer interconnects the vacuum pump with the gas outlet connector. A controller controls the gas multiplexer to switch between applying an under pressure in a reaction box and applying a gas flow from a gas source to the reaction box multiple times in a cyclic manner to reduce the amount of particles present in the reaction box. The controller is also configured to control a particle monitor to generate particle information representing a concentration of particles present in the reaction box following an end of the cyclic switching between applying the under pressure and applying the gas flow. The particle information is stored in a memory of the system as a good manufacturing practice clean room classification notification for the reaction box.
The invention, together with further objects and advantages thereof, may best be understood by making reference to the following description taken together with the accompanying drawings, in which:
Throughout the drawings, the same reference numbers are used for similar or corresponding elements.
The embodiments generally relate to a system for controlling reaction boxes, and in particular such a system that is used for controlling the environment in the reaction boxes and logging information of the controlled environment.
The system of the embodiments can be used to control miniaturized reaction boxes in which various synthesis steps and other reactions can take place. The system is advantageously used in combination with synthesis of various radiotracers useful in diagnosis, such as in SPECT or PET systems, or in therapeutic applications. Also other substances and molecules lacking radionucleotides could be produced in the reaction boxes controlled by the system of the embodiments.
The reaction boxes controlled by the system could, in a simplified approach, be regarded as downscaled versions of traditional hot laboratories and production facilities. However, the reaction boxes are designed to be sufficiently small to be arranged at various desired sites in healthcare facilities, such as in SPECT/PET centers or in therapeutic centers. In fact, the small size of the reaction boxes and the system enables arrangement even in or in direct connection with the particular diagnostic or treatment room where the actual diagnosis or treatment is to take place of a patient. Thus, the size of each reaction box is typically in the range of centimeters or decimeters. For instance, each side of the reaction box could be in the range of about 5 cm up to about 50 cm as non-limiting but illustrative examples. Hence, it is in fact possible to organize several reaction boxes together controlled by a single system and still the arrangement will only occupy a very limited space.
The gas sources 200, 210, 220 could comprise any gas or gas mixture, preferably in pressurized form. Non-limiting examples of such gases or gas mixtures include air, nitrogen (N2), helium (He) and argon (Ar).
The system 100 also comprises a gas outlet connector 120 having connector terminal(s) connectable to the reaction box(es) 300, 310, 320. The gas outlet connector 120 comprises at least one such connector terminal per connected reaction box 300, 310, 320. In an embodiment, a single such connector terminal is used to affect both gas flow into the reaction box 300, 310, 320 but also enable a gas flow out from the reaction box 300, 310, 320 and into the gas outlet connector 120. Alternatively, multiple connector terminals can be arranged in the gas outlet connector 120 per reaction box 300, 310, 320, where at least one connector terminal is used for providing gas connection and gas flow into the reaction box 300, 310, 320 and at least one connector terminal is used for providing gas connection and gas flow out from the reaction box 300, 310, 320.
A gas multiplexer 130 is arranged in the system 100 connected to the gas inlet connector 110 and the gas outlet connector 120. The gas multiplexer 130 is configured to interconnect a gas flow from the gas inlet connector 110 to the gas outlet connector 120. Thus, the gas multiplexer 130 interconnects a connector terminal of the gas inlet connector 110 to a connector terminal of the gas outlet connector 120 to form a gas connection from a gas source 200, 210, 220 to a reaction box 300, 310, 320. This means that gas from the gas source 200, 210, 220 connected to the selected connector terminal in the gas inlet connector 110 will flow through the connector terminal, the gas multiplexer 130 and into the selected connector terminal in the gas outlet connector 120 and thereby reach the reaction box 300, 310, 320 connected to this connector terminal.
The operation of the gas multiplexer 130 is controlled by a controller 150 as is further described herein. Thus, the controller 150 sends control signals to the gas multiplexer 130 to identify which connector terminal in the gas inlet connector 110 that should be interconnected to which connector terminal(s) in the gas outlet connector 120.
The system 100 further comprises a vacuum pump 140 or other device configured to generate an under pressure. The vacuum pump 140 is connected to the gas multiplexer 130 to thereby generate a sucking or under pressure inside a reaction box 300, 310, 320 when the gas multiplexer 130 interconnects the vacuum pump 140 with the gas outlet connector 130 and the connector terminal assigned to the reaction box 300, 310, 320.
The previously mentioned controller 150 is thereby configured to control the operation of the gas multiplexer 130 and in particular control the gas multiplexer 130 to switch between applying an under pressure in a selected reaction box 300 and applying a gas flow from a gas source 200 to the reaction box 300 multiple times in a cyclic manner. Thus, the controller 150 thereby controls the gas multiplexer 130 to first interconnect the reaction box 300 to the vacuum pump 140 to apply an under pressure in the reaction box 300 and thereby vent any gas and particles present in the reaction box 300. Then the gas multiplexer 130 interconnects the reaction box 300 to one of the gas sources 200, 210, 220 to thereby open up a gas flow from the gas source 200 to the reaction box 300. This completes one cycle. The procedure is then repeated at least once more with gas venting followed by filling up with clean, fresh gas.
Optionally, the controller 150 could control the gas multiplexer 130 to interconnect the gas inlet connector 110 to the gas outlet connector 120 to thereby provide gas inside a reaction box 300 before initiating the cycles of switching between applying the under pressure and applying the gas flow.
In a particular embodiment, the controller 150 is configured to control the gas multiplexer 130 to switch between applying the under pressure in the selected reaction box 300 by connecting the reaction box 300 to the vacuum pump 140 and applying a gas overpressure from the selected gas source 200 to the reaction box 300.
The cyclic venting of gas inside the reaction box 300 and filling up with fresh, clean gas is performed by the system 100 in order to reduce the amount of particles present in the reaction box 300. Hence, the system 100 thereby forms a controlled clean room environment in the reaction box 300 by the cyclic venting and filling of gas.
The gas multiplexer 130 can connect the reaction box 300 to the same gas source 200 in each cycle. However, it is also possible to switch gas sources 200, 210, 220 to thereby use a first gas source 200 in one cycle and then use a second, different gas source 210 in another cycle.
The system 100 also comprises a particle monitor 160 that is connectable to the reaction boxes 300, 310, 320. The particle monitor 160 is configured to generate particle information representing a (current) concentration of particles present in a reaction box 300, 310, 320. The controller 150 controls the particle monitor 160 to generate the particle information representing the concentration of particles in the selected reaction box 300 following the end of the cyclic switching between applying the under pressure in the reaction box 300 and applying the gas flow. Thus, at least when the cyclic switching discussed above is completed for a selected reaction box 300 the particle monitor 160 is controlled by the controller 150 to monitor the concentration of particles inside the reaction box 300 and generate or log particle information representing this current concentration of particles.
The particle monitor 160 could be directly connected to the reaction boxes 300, 310, 320 through the gas outlet connector 120. If each reaction box 300, 310, 320 comprises an assigned connector terminal for gas flow into the reaction box 300, 310, 320 and another connector terminal for gas flow out from the reaction box 300, 310, 320, the particle monitor 160 is preferably connected to at least the connector terminal for the gas flow out from the reaction box 300, 310, 320.
In another embodiment, the particle monitor 160 is connected to the gas multiplexer 130. When the particle monitor 160 is to monitor the particle concentration and generate the particle information, the controller 150 controls the gas multiplexer 130 to interconnect the particle monitor 160 to the gas outlet connector 120 and the connector terminal therein that is connectable to the reaction box 300.
The embodiments can be used in connection with any suitable particle monitor 160 available in the art. Non-limiting examples of such a particle monitor that can be used are the airborne particle counters marketed by Lighthouse Worldwide solutions, such as Remote 3104, 5104 or indeed any other such airborne particle counter available from Lighthouse Worldwide Solutions or any other company.
The generated particle information from the particle monitor 160 is stored in a memory 170 of the system 100. There the particle information forms part of a good manufacturing practice (GMP) clean room classification notification or information for the particular reaction box 300. The memory 170 preferably stores the GMP clean room classification notification comprising the particle information together with an identifier of the particle reaction box 300 for which the particle information has been generated. This is particularly preferred if the system 100 is connected to and configured to control the environment in multiple reaction boxes 300, 310, 320.
The GMP clean room classification notification constitutes a verification that a desired environment in terms of a sufficient low concentration of particles is present in the reaction box 300 when a synthesis is to be started. Thus, the system 100 thereby verifies that clean room level has been reached in the reaction box 300 prior to synthesis of the desired radiotracer or other substance in the reaction box 300.
This is a significant advantage as compared to the prior art hot laboratories and synthesis facilities where no such clean room verification is feasible in connection with each separate synthesis procedure. In clear contrast, such a clean room verification is only practically possible two to three times per year. It is then assumed that the clean room level is maintained between these two or three verification occasions, although no guarantee exist that the clean room level is indeed maintained and there is no possibility to verify or document this.
The system 100 of the embodiments in clear contrast controls the environment in the reaction boxes 300, 310, 320 through the cyclic switching between applying gas under pressure and gas overpressure to remove most of the particles present in the reaction boxes 300, 310, 320 prior to the start of a synthesis process. The system 100 also generates and logs information describing the clean room standard achieved after the cyclic switching between applying gas under pressure and gas overpressure. This means that GMP clean room classification defining the correct and current concentration of particles in a reaction box 300 immediately prior to the start of the synthesis process is generated and stored in the memory 170. The GMP clean room classification notification can therefore then be used as verification that a correct environment was indeed achieved for the synthesis process.
In an embodiment, the system 100 is configured to control the environment in multiple reaction boxes 300, 310, 320 at least partly in parallel. Thus, the controller 150 could control the gas multiplexer 130 to interconnect one of the reaction boxes 300 to a gas source 200 to provide clean gas in the reaction box 300 simultaneously as the gas multiplexer 130 interconnects another reaction box 310 to the vacuum pump 140 to empty the reaction box 310. Thus, the cyclic switching between applying gas under pressure and gas overpressure can be synchronized to be run in parallel for multiple reaction boxes 300, 310, 320 thereby reducing the total time until the reaction boxes 300, 310, 320 have achieved GMP clean room environment and synthesis can be started.
Alternatively, the system 100 processes the different reaction boxes 300, 310, 320 in series to thereby first achieve clean room environment in a first reaction box 300 prior to processing the next reaction box 310.
Experiments have been conducted with the system 100 as illustrated in
Thus, the system 100 is typically able to reach a desired clean room environment in a reaction box 300 already after 2-5 cycles, preferably 3-5 cycles. Hence, a clean room environment is quickly reached by the system 100 only requiring about one or a few minutes.
In an embodiment, the controller 150 is configured to control the gas multiplexer 130 to perform the cyclic switching a predefined number of times for each reaction box 300, 310, 320. This approach is possible by testing on average how many cycles are required in order to reach the desired clean room environment for a certain type of reaction box 300, 310, 320. The controller 150 could then be configured to run a number of cycles that is at least equal to but preferably slightly larger (to have safety margin) than this average number of cycles. It is generally expected that the predefined number of cycles required is within the interval of 3 to 5.
In an alternative approach, the controller 150 is configured to control the particle monitor 160 to generate a concentration measure after each cycle of applying an under pressure in a reaction box 300 and applying a gas flow to the reaction box 300. The concentration measure then represents a current concentration of particles in the reaction box 300 following the current cycle. The controller 150 compares the concentration measure with a concentration threshold, preferably stored in the memory 170 or otherwise available to the controller 150. If the current particle concentration in the reaction box 300, as represented by the concentration measure, is equal to or lower than the concentration threshold, sufficient clean room environment has been reached and no further cycle is needed for the reaction box 300. The latest concentration measure generated by the particle monitor 160 can then be used as particle information for the reaction box 300. Alternatively, a new concentration measurement is performed by the particle monitor 160 to get the particle information that is stored in the memory 170 as GMP clean room classification notification for the reaction box 300.
If the concentration measure, however, exceeds the concentration threshold the controller 150 controls the gas multiplexer 130 to perform a new cycle of applying under pressure and applying gas flow to the reaction box 300. The particle monitor 160 then performs a new measurement to generate a new concentration measure that is compared by the controller 150 to the concentration threshold. This procedure is preferably repeated until the concentration measure no longer exceeds the concentration threshold.
In the above described embodiment, the cyclic switching is therefore performed until the current particle concentration in the reaction box 300 has been reduced down to the desired clean room level.
In an embodiment, the system 100 comprises or is connected to a notification unit 196 comprising a display or screen and/or a loudspeaker, see
In an embodiment, the controller 150 also, or in addition, generates a synthesis trigger signal when the concentration measure is equal to below the concentration threshold and clean room level has been reached for a reaction box 300. The synthesis trigger signal is then preferably transmitted from the controller 150 to the particular reaction box 300. An automatic synthesis of the desired substance can then be started based on the synthesis trigger signal.
The particular concentration threshold used by the system 100 and the controller 150 has preferably previously been entered by an operator. It could then be possible to use the same concentration threshold for all reaction boxes 300, 310, 320 or different concentration thresholds for different reaction boxes 300, 310, 320 depending on how critical cleanness and particle concentration is for the particular synthesis to be run in a reaction box 300, 310, 320. In a particular embodiment, the system 100 comprises or is connected to a user input 194 as shown in
Different clean room standards exist one of which is presented in Table 1 below.
Other such clean room standards mentioned in the art include ISO 14644-1 clean room standard, BS 5295 clean room standard and US FED STD 209E clean room standard.
An example of a suitable concentration threshold that can be used by the system 100 corresponds to a maximum of 3,500 particles with a size of at least 0.5 μm per cubic meter. This should be compared to ambient air which generally contains about 35,000,000 particles per cubic meter in the size range of 0.5 μm and larger in diameter.
Each reaction box 300, 310, 320 preferably comprises at least one respective door that is movable from a closed state to an open state. In such a case, the particle monitor 160 could also be configured to perform particle concentration measurements of ambient air present around the reaction boxes 300, 310, 320. The controller 150 is preferably configured to control the particle monitor 160 to generate an ambient concentration measure representing the particle concentration present in the ambient air outside of the reaction boxes 300, 310, 320. The controller 150 is further configured to compare the ambient concentration measure with an ambient concentration threshold, which is preferably stored in the memory 170 or otherwise accessible to the controller 150. The controller 150 preferably activates the previously mentioned notification unit 196 (see
Thus, if there is currently a very high concentration of particles in the air around the reaction boxes 300, 310, 320 the system 100 could warn the user not to open the reaction boxes 300, 310, 320 to thereby prevent the polluted air from entering into the reaction boxes 300, 310, 320. A reason for this is that otherwise the process of anew reaching clean room level inside a reaction box 300, 310, 320, which has been opened, can take some time due to the high concentration of particles entering the reaction box 300, 310, 320. The notification unit 196 thereby provides visual and/or audible information to the user urging him/her to try to reduce the amount of particles in ambient air before opening the reaction boxes 300, 310, 320. The user could for instance activate ventilation in the room where the reaction boxes 300, 310, 320 and the system 100 are present.
The controller 150 preferably controls the particle monitor 160 to, periodically or upon certain activation events, measure the particle concentration in ambient air. Once the particle concentration in ambient air has reduced to lower levels, i.e. equal to or below the ambient concentration threshold, the controller 150 preferably controls the notification unit 196 to stop displaying the visible closing signal and/or generate the audio closing signal. The notification unit 196 could in addition be controlled to display or audibly present a signal indicating to the user that the doors of the reaction boxes 300, 310, 320 can now be opened.
The above mentioned activation events when the particle monitor 160 performs a new concentration measure could be the reception of a user-triggered activation of the user input 194 or the elapse of a certain time period.
In an alternative, or additional, embodiment the doors of the reaction boxes 300, 310, 320 are moved automatically by the system 100. In such a case, the controller 150 generates an opening signal if the ambient concentration measure from the particle monitor 160 is equal to or below the ambient concentration threshold. This opening signal is forwarded from the controller 150 to a selected reaction box 300 in order to open its door. The reaction box 300 preferably comprises a controllable motor or other device that opens the door based on the opening signal. Alternatively, or in addition, the doors of the reaction boxes 300, 310, 320 could be locked when they are in the closed state. In such a case, a locked door is automatically unlocked based on the opening signal. The user can then move the unlocked door from the closed state to the open state.
In a particular embodiment, the system 100 is configured to be operated to reduce the amount of particles that can enter a reaction box 300 when its door is open. This embodiment can be used as a combination to the automatic locking/closing or visual/audio signal discussed in the foregoing. Alternatively, there is no need to monitor the particle concentration in ambient air since this embodiment will effectively prevent a high amount of particles to enter a reaction box 300 even if opened in a polluted environment.
With reference to
The door sensor 192 preferably also generates a closing signal when the door of the reaction box 300 once more is closed. This closing signal could be the same signal as the activation signal that is further discussed here below. The controller 150 is then responsive to this closing signal (or activation signal) to stop the gas flow into the reaction box 300 since the door is once more closed and no more particles can enter the reaction box 300.
In an embodiment as shown in
In an embodiment, the reaction boxes 300, 310, 320 connectable to the system 100, or at least a portion thereof, have a dual-wall system, which is schematically indicated in
Surrounding the inner wall enclosure of a reaction box 300 with an under pressure provides a safety measure in the case the reaction box 300 contains at least one substance that could be harmful for a user if the substance escapes out of the reaction box 300. Thus, if there is a leakage in the inner wall enclosure any harmful gaseous substances or indeed radioactive substances present in the reaction box 300 will be effectively trapped in the intermediate space and cannot leave the outer wall enclosure. In such a case, the reaction box 300 preferably comprises a waste outlet connected to the intermediate space. This waste outlet is preferably in connection with a waste storage that is either locally arranged together with the reaction boxes 300, 310, 320 but can advantageously be remotely arranged in another part of the building. Any leaking substances will then be drawn by the under pressure into the intermediate space and further out from the waste outlet to enter the waste storage, where they are safely kept out of reach from any user.
The radioactivity monitor 190 of the system 100 is preferably configured to generate a radioactivity measure representing a current radioactivity level in the intermediate space 313 between the inner wall enclosure 302 and the outer wall enclosure 301. The controller 150 is connected to the radioactivity monitor 190 and is configured to compare the radioactivity measure generated by the radioactivity monitor 190 with a radioactivity threshold, typically stored in the memory 170 or otherwise accessible to the controller 150. If a current radioactivity level as represented by the radioactivity measure exceeds a safety level as represented by the radioactivity threshold, the controller 150 preferably opens a waste outlet 307 of the radiation-shielded reaction box 300 (see
Any radioactivity monitor 190 available in the art can be used according to the embodiments. Non-limiting examples are market by Carroll/Ramsey Associates.
In an embodiment, the radioactivity monitor 190 is, alternatively or in addition, configured to generate radioactivity information representing a radioactivity level in a radiation-shielded or radiation-shielding reaction box 300. The controller 150 is then configured to control the radioactivity monitor 190 to generate this radioactivity information at least following the end of the cyclic switching between applying the under pressure and applying the overpressure in the radiation-shielded reaction box 300. The generated radioactivity information is stored in the memory 170 as part of the GMP clean room classification notification for the reaction box 300. Thus, the GMP clean room classification notification then not only comprises clean room information with regard to the particle concentration inside the reaction box 300 but also radioactivity information representing the radioactivity level inside the reaction box 300 and optionally also in the intermediate space 313 between the outer and inner wall enclosures 301, 302 of the reaction box 300.
The controller 150 may additionally control the radioactivity monitor 190 to generate a radioactivity measure representing a current radioactivity level in the radiation-shielded reaction box 300. The controller 150 compares this radioactivity measure with a radioactivity threshold and activates the previously mentioned notification unit 196 to display a visible closing signal and/or generate an audio closing signal if the radioactivity measure exceeds the radioactivity threshold. Thus, if the current radioactivity level inside the radiation-shielded reaction box 300 is too high for safely opening a door of the reaction box 300 from a closed state to an open state, the notification unit 196 preferably presents a visible and/or audio alarm (visible closing signal and/or audio closing signal) informing the user of the remaining radioactivity inside the radiation-shielded reaction box 300.
The controller 150 could be configured to control the radioactivity monitor 190 to periodically perform the radioactivity measurements inside the reaction box 300 to generate the radioactivity measure. Alternatively, the controller 150 is responsive to an activation signal generated by the user input 194 when the user presses one of its keys or a selected activation area of the user input 194. The activation signal thereby triggers the controller 150 to activate the radioactivity monitor 190 to perform a new radioactivity measurement as disclosed above.
In an alternative or additional embodiment, the door of the radiation-shielded reaction box 300 is automatically opened, i.e. moved from the closed state to the open state, in response to an opening signal from the controller 150. The controller 150 preferably generates the opening signal if the radioactivity measure generated by the radioactivity monitor 190 is equal to or below the radioactivity threshold. Thus, in such a case the controller 150 can safely open the door to the radiation-shielded reaction box 300 since there is no radioactivity left therein or any remaining radioactivity is at safely low levels.
The controller 150 can additionally be configured to control the radioactivity monitor 190 to generate an ambient radioactivity measure representing an ambient radioactivity level in ambient air outside of the radiation-shielded reaction boxes 300, 310, 320. The controller 150 compares this ambient radioactivity measure with an ambient radioactivity threshold and activates the notification unit 196 if the ambient radioactivity measure exceeds the ambient radioactivity threshold. The notification unit 196 is thereby caused to display a visible alarm signal and/or generate an audio alarm signal that informs the user of radioactivity present in the facility with the reaction boxes 300, 310, 320.
In similar to the previously described particle monitor 160 and the radioactivity monitor 190, the system 100 can also comprise a bioactivity monitor 185 connectable to a reaction box 300, 310, 320 and configured to generate bioactivity information representing presence of any microorganisms inside the reaction box 300, 310, 320. The controller 150 is then configured to control the bioactivity monitor 185 to generate bioactivity information indicative of presence of microorganisms in the reaction box 300 at least following the end of the cyclic switching between applying the under pressure and the overpressure in the reaction box 300. The generated bioactivity information is stored in the memory 170 as part of the GMP clean room classification notification for the reaction box 300. Thus, in this embodiment the GMP clean room classification notification not only comprises the particle information but also the bioactivity information and preferably also the radioactivity information. Hence, a more complete set of the conditions inside a reaction box 300 is thereby obtained and can be used to verify that the environment inside the reaction box 300 was correct at the time of starting a synthesis therein.
In a particular embodiment and as previously discussed herein, the interior of a reaction box 300 is preferably kept at an overpressure, whereas any intermediate space between the inner and outer wall enclosures of the reaction box 300 is preferably kept at an under pressure. In such a case, the system 100 can comprise a pressure monitor 180 that is controlled by the controller 150 to generate a pressure measure representing a current pressure level in the reaction box 300. There are several pressure monitors and sensors available on the market and that can be used according to the embodiments. For instance, Gems™ Sensors & Controls have pressure sensors that can be used by the embodiments.
The controller 150 is configured to compare the pressure measure with at least one pressure threshold, preferably two such pressure thresholds. In such a case, a first or lower pressure threshold could represent the lower end of a suitable pressure interval for the reaction box 300 with a second or higher pressure threshold representing the upper end of the pressure interval. If the current pressure inside the reaction box 300 is within the pressure interval, a correct overpressure is present in the reaction box 300. However, if the pressure measure is below the first pressure threshold, the controller 150 preferably controls the gas multiplexer 130 to interconnect the gas inlet connector 110 and thereby a gas source 200 to the gas outlet connector 120 and the reaction box 300 to provide a gas flow into the reaction box 300 to thereby increase the pressure inside the reaction box 300. Correspondingly, if the pressure measure exceeds the second pressure threshold, the controller 150 preferably controls the gas multiplexer 130 to interconnect the vacuum pump 140 to the gas outlet connector 120 and the reaction box 300 to vent gas from the reaction box 300 to thereby reduce the pressure inside the reaction box 300. Thus, in this embodiment the controller 150 is configured to control the gas multiplexer 130 to interconnect one of the gas inlet connector 110 and the vacuum pump 140 to the gas outlet connector 120 to apply one of a gas overpressure and an under pressure to the reaction box 300 based on a comparison of the pressure measure and at least one pressure threshold.
The reaction box 300 can be a radiation-shielded reaction box 300 as previously discussed herein. In such a case, at least one of the inner wall enclosure 302 and the outer wall enclosure 301, preferably the outer wall enclosure 301, constitutes a radiation shield to thereby prevent any radiation present inside the reaction box 300 from passing through the outer wall enclosure 301.
The figure also illustrates the previously discussed waste outlet 307 that preferably interconnects the intermediate space 313 with a remote waste storage (not illustrate).
Single or multi-way gas connections 308, 309 interconnect the interior of the reaction box 300 and preferably the intermediate space 313 with the gas outlet connector 120 of the system 100 and optionally the radioactivity monitor 190. Reference numbers 311, 312 represent pressure sensors 311, 312 present in the reaction box 300 and in the intermediate space 313, which could be connected to the pressure monitor 180.
The reaction boxes 300, 310, 320 connected to the system 100 can be arranged as separate devices. Alternatively, a reaction box 300 could have its separate inner wall enclosure 302 but then share a common outer wall enclosure, such as a radiation-shielded outer wall enclosure with at least one other reaction box.
The reaction boxes 300 are designed to enclose a controlled environment in which a synthesis of a desired substance, such as radiotracer or radiopharmaceutical, is to take place. The synthesis inside the reaction box 300 is preferably taking place in one or more synthesis chips or microfluidic cassettes. Such microfluidic cassettes are well known in the art and disclosed, for instance, in U.S. Pat. No. 7,829,032 and US 2011/0008215.
Such microfluidic cassettes can be manufactured at very small sizes, such as having largest dimensions of one or few centimeters. Hence, the interior volume of the reaction box 300 can be kept very small, for instance, from part of a liter up to one or few tens of liters. For instance, an internal size of 10 cm×20 cm×30 cm (width×height×length) gives a total internal volume of 6 L and can efficiently house one or more microfluidic cassette. The outer dimensions of a reaction box 300 can also be kept very small even when using radiation-shielding material in the outer wall enclosure 301. Thus, the outer dimensions of a reaction box 300 can generally be in the order of one or more tens of centimeters. For instance, an external size of a reaction box could be 20 cm×30 cm×40 cm (width×height×length).
Any radioactivity that is to be used in the synthesis can be produced by an in-site or remotely arranged generator or cyclotron connected to the reaction boxes 300, 310, 320.
The small size of the reaction boxes 300, 310, 320 implies that the complete reaction box 300, 310, 320 could be sterilized prior to starting a synthesis reaction and prior to connecting the reaction box 300, 310, 320 to the system 100. For instance, the reaction box 300, 310, 320 could be autoclaved.
The very small size of the reaction boxes 300, 310, 320 and the system 100 implies that the system 100 with connected reaction box(es) 300, 310, 320 can be efficiently arranged in a healthcare facility and even in the relevant diagnostic (SPECT/PET) or treatment room.
The small size of the system 100 and the reaction boxes 300, 310, 320 and the possibility of conducting the synthesis close to or even in the same room as the diagnosis or therapy, implies that radionucleotides with short half-lives can be used since the produced radiotracer or radiopharmaceutical can be administered to the patient directly following synthesis without any long and time-consuming transports of the radiotracer/radiopharmaceutical from a remote hot laboratory.
The small overall size also means that the total cost of the system 100 and the reaction boxes 300, 310, 320 is vastly lower as compared to the total cost for a complete hot laboratory. The system 100 will therefore lead to a more flexible usage of radiotracers and radiopharmaceutical, among others, that do not need to be limited to healthcare facilities situated in connection with hot laboratories.
The system 100 of the embodiments is easily operated and does not require qualified synthesis personal to be run. Hence, the system 100 can be used also by medical personnel in healthcare facilities lacking any expertise in radiotracer/radiopharmaceutical synthesis.
A further advantage is that a single system 100 can be connected to and configured to control the environment in multiple reaction boxes 300, 310, 320 to enable production, even parallel production, of different radiotracers and/or radiopharmaceuticals or other substances in the different reaction boxes 300, 310, 320. Thus, it is possible to form and maintain different individual environments in the reaction boxes 300, 310, 320 that are adapted to the particular synthesis conditions taking place in the given reaction box 300, 310, 320.
A further significant advantage of the embodiments is that a current GMP qualification is obtained at each synthesis in a reaction box 300, 310, 320. The GMP clean room classification notification thereby provides relevant verification data defining the actual conditions in the reaction box 300, 310, 320 at the time of synthesis. This is not possible within hot laboratories where GMP verifications are done at scheduled points in time and not in connection with actual synthesis.
The embodiments described above are to be understood as a few illustrative examples of the present invention. It will be understood by those skilled in the art that various modifications, combinations and changes may be made to the embodiments without departing from the scope of the present invention. In particular, different part solutions in the different embodiments can be combined in other configurations, where technically possible. The scope of the present invention is, however, defined by the appended claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1250005-4 | Jan 2012 | SE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/SE2012/051425 | 12/19/2012 | WO | 00 |
