Patent Number: 061570362
Section: summary

FIELD OF THE INVENTION This invention relates to the field of nuclear medicine and more particularly to systems and processes for producing medically useful radioisotopes. Although the present invention broadly pertains to the production of radioisotopes, it is especially, but by no means exclusively, suited for the production of radioisotopes that require concentration, such as rhenium-188. BACKGROUND OF THE INVENTION The application of numerous, generator-produced, radioactive isotopes in patients has significantly advanced the fields of medical imaging, diagnosis and even therapy. Such patient-grade, generator-produced, radioisotopes are often called "daughter" radioisotopes because they are formed by the radioactive decay of different nuclides, called "parent" radioisotopes having considerably longer half-lives. Daughter radioisotopes are harnessed in a process called "elution," whereby a sterile "eluent," such as a sodium chloride solution, passes through a radioisotope generator column, upon which a decaying parent radioisotope is adsorbed, and exits as an "eluate" containing the daughter radioisotope. Certain daughter radioisotopes, such as technetium-99 m, are primarily gamma photon emitters, making them ideal for imaging applications. Conventionally, these types of radioisotopes are prepared for medical use in a single elution step; that is, by forcing the eluent through the generator and capturing the resultant eluate. Other radioisotopes decay with beta-charged emissions that are more readily absorbed by the patient, thus making them more suitable for therapy applications, such as radiolabeling, or radioimmunotherapy, and even pain therapy. Rhenium-188, which is eluted from a Tungsten-188 parent, is one such type of radioisotope whose beta emissions are entirely absorbed by the patient's body and has a relatively short-half life of 17.0 hours. These characteristics make Re-188 particularly useful for the treatment of tumors, i.e. radiolabeling, and other diseases and disorders. However, to be effective for such applications, Re-188 eluate, and other similar radioisotopes solutions, must be highly concentrated. Thus, they require additional purification and concentration steps. In order to increase the activity concentration of the eluate produced by a typical generator, such as an alumina-based, tungsten-188/rhenium-188 (W-188/Re-188) generator, and to obtain treatment-quality Re-188, the eluate must be chemically "filtered" to remove traces of the parent radioisotope, alumina and chloride anions from the solution. The purified Re-188 isotope is then trapped, or concentrated, in an appropriate "radioisotope trap," such as an ion exchange column, and is then finally re-eluted into a container with a desired volume of fresh eluent. One such system and process, developed by the Oak Ridge National Laboratory (ORNL), is shown in FIG. 1. In particular, the system 1 calls for the use of a constant flow-rate pump 2, namely, a peristaltic pump, to drive a desired volume of saline solution eluent stored in a container or sack 4, at a desired rate, through a series of single-use columns connected by tubing. The eluent is pumped through a radioisotope generator 6 and a filter 8 and the resultant eluate is forced through a series of single-use ion exchange columns 10 and 12. The first column 10 shown is a silver halide precipitation column ("Maxi Clean IC-Ag" column, Alitech, Inc., Deerfield, Ill.) that traps therein all of the chloride anions and permits the passage of any non-halide ions in the solution. An anion exchange column 12 (Accell Plus QMA.RTM. anion column, Waters, Inc., Milford, Mass.) referred to hereinafter as a radioisotope trap, then traps the perrhenate anions (the daughter radioisotope) therewithin, thus permitting the resultant eluate, which should contain only minimal radioactivity, to pass as a waste solution into a waste collection container 14 for disposal. Once the required volume of solution has been eluted, the operator disables the pump and manually adjusts each of the three-way valves 16, 18 and 20 to bypass the generator 6 and impurity traps 10 and 12 and to redirect the output from the waste container 14, to create a direct fluid path from the pump 2 to a collection vial 22. Then, in the second step, the operator reactivates the pump 2 to drive a small, predetermined, volume of fresh eluent from the supply 4 through tubing 17 and through the radioisotope trap 12, in order to elute, or more precisely, re-elute, the daughter radioisotope adsorbed on the column in the trap 12, into the sterile collection vial 22 as a sodium perrhenate solution. While the ORNL system sets forth the basic chemistry, components and a method for the concentration and elution of discreet quantities sodium perrhenate, the system and method have several drawbacks. One problem is that the method relies on relatively significant operator intervention prior to, during, and after each elution. In particular, after setting up the system, the operator needs to set the flow rate of the pump, precisely track the on-time of the pump for the first elution, disable the pump, adjust the valves 16 and 18 to redirect the eluent for the second elution through the tube 17 to the radioactive trap 12, restart the pump for precisely long enough for the eluent to pass through tube 17, valve 18, radioisotope trap 12 (where, upon exiting, it becomes an eluate), and finally to valve 20. Just before this eluate reaches valve 20, valve 20 must be adjusted to redirect flow away from the waste container 14 and to the collection vial 22. This complex procedure is one method for maximizing the radioactive concentration in the collection vial. Alternatively, the operator can flush the system with air between elutions to purge the tubing of residual liquid that would otherwise dilute the radioactive eluate from the second elution. The air flush technique has the second advantage of reducing residual activity within the columns and tubing. All of these steps tends to 1) be time-consuming and inefficient, especially for labs that engage in multiple, continuous elutions; 2) increase the potential for human error, which can be dangerous, wasteful or both; and 3) unduly expose the operator or operators to radiation. It is understood that above-described system could be fully electronically controlled so that the electric pump would be automatically activated for the appropriate period of time, the three-way valves would then automatically be adjusted to their second stage positions, and the pump then reactivated for the final elution step. Nonetheless, such a system would add considerable complexity and cost to the conventional system, with the addition of a processor and electronic timer scheme. Further, such an automated system would not adequately address all of the aforementioned problems. Thus, it would desirable to have an inexpensive, simple, mechanical elution/concentration system that automatically produces concentrated radioisotopes and air purges the system, thus significantly reducing reliance on human intervention. Further, using a constant, flow rate, electric pump to drive the solution through the system has drawbacks. Such pumps are relatively expensive, are ill-suited for pumping the air needed to purge the system after an elution, and run the risk of creating a dangerous over-pressure condition in the, albeit relatively rare, event of a blockage in the fluid line. Additionally, the requirement of an electric pump adds to system complexity and cost when the need to design for the different voltage supplies of various foreign countries is considered. Thus, it would be desirable to eliminate the need for a constant, flow rate, pump and, even more broadly, the need for electrical power, to both reduce system cost and to enable the production of a single design for the worldwide market. A third drawback of the ORNL system is that it provides for separate, single use, concentration columns that must be properly connected and shielded by the operator for each fresh elution procedure. Further, the eluate waste created by the first stage elution must be properly disposed of. The set up and handling of these discrete components requires training, is inefficient, increases the risk of operator exposure, and creates the additional problem of the safe disposal of the spent, radioactive exchange columns and fluid waste. Thus, it would be desirable to have a system that minimizes component handling during both the set up and disposal procedures. Another issue not fully addressed by preexisting systems relates to the inefficiency of the elution of generators. As a generator ages, its radioactive yield decreases due to its decay. While the elution of a fresh generator may yield a substantial quantity of the daughter isotope, a subsequent elution of that same generator may not yield enough end product for the procedure to be worthwhile. However, since each generator is relatively costly, it would be desirable to have a system that could easily and efficiently elute more than one aged generator in series, thereby producing, with a single elution, a useful quantity of the daughter radioisotope. This would effectively extend the useful life of generators that are located together and could decrease the medicine's cost per treatment. In sum, a need therefore exists for a system and method that automatically concentrates and elutes radioisotope solutions, that automatically prepares the system for subsequent elution procedures, that does not rely on a costly and complex, processor-controlled pump arrangement, and that, at the same time, tends to minimize operator intervention and handling of the components and waste by-products. SUMMARY OF THE INVENTION The present invention, which tends to address this need, resides in an improved radioisotope concentration system and method that implements an improved mechanism and method for the elution of radioisotopes. This system and method provides significant advantages over known systems and methods, in that it, among other things, (a) automates the concentration and elution steps without the need for an electric pump system and electronic control of the pump; (b) automatically and immediately purges the fluid lines with a gas to flush the eluent through the system and to prepare the system for a subsequent procedure; (c) tends to minimize the handling of the radioactive components and waste product; (d) significantly decreases operator set up time; and (e) permits reclamation of unused isotope. According to the present invention, a novel gas-over-eluent, fluid delivery mechanism for eluting one or more processing elements having inlets and outlets, is disclosed. The mechanism includes a vertically-disposed reservoir having an output feed at the bottom thereof for connecting to the inlet of one of the one or more processing elements, a predetermined volume of eluent contained in the reservoir, a predetermined volume of gas contained in the reservoir, separated from and positioned over the predetermined volume of eluent, and a force-limited, pressure-supplying mechanism that forces the volume of eluent and then the volume of gas through the reservoir output feed and into and through the one or more processing elements. The pressure-supplying mechanism thus elutes the one or more processing elements with the predetermined volume of eluent. Immediately following the elution, the pressure-supplying mechanism purges the one or more processing elements with the predetermined volume of gas. The gas-over-eluent arrangement provides numerous advantages over preexisting, conventional systems. First, it tends to provide an automatic and relatively safe means for purging the system of eluate that may contain radioactive components, immediately following an elution. Further, this design permits a fixed volume of eluent to pass through the process, regardless of the number of processing elements and distance through which the eluent (or eluate) solution must travel. Simply, the greater the distance the solution must travel, due to an increased number of processing elements, tubing length or other factors, the more gas that is preloaded into the delivery mechanism to drive the fixed volume of solution. The improved delivery system may be advantageously designed into either of the two types of conventional radioisotope elution systems, broadly described above as 1) single step elution systems (i.e. for processes that do not require concentration, such as in the production of Tc-99m); and 2) elution and concentration systems (i.e. for the production of Re-188). Accordingly, the "one or more processing elements," as used herein, refers to any element through which the eluent (or eluate) may pass. This includes, at a minimum, single radioisotope generator. However, it also includes multiple radioisotope generators connected in series. In this case, the predetermined volume of gas is determined by the number of generators being eluted in series and the distance that the predetermined volume of eluent must travel. The one or more processing elements may alternatively comprise concentration and purification components, including, for instance the ion exchange columns described in more detail below, or a combination of one or more generators in series with concentration and purification components. In a more detailed embodiment, the force-limited, pressure-supplying mechanism comprises a plunger having a head positioned within said reservoir and over the volume of gas and a plunger pressure source that applies a downward force upon the plunger, the volume of gas, and thus the volume of eluent, in order to propel the eluent and then the gas through the reservoir, and through the one or more processing elements. An improved system for producing a concentrated radioisotope is also disclosed herein. In the preferred embodiment, the system includes a generator for producing an eluate containing a desired radioisotope to be concentrated, a radioisotope concentration subsystem in fluid communication with the generator that removes impurities from the eluate and that concentrates the radioisotope therein, a radioisotope collection vessel in fluid communication with the concentration subsystem for collecting therein a desired volume of prepared radioisotope solution, and two, gas-over-eluent, fluid delivery mechanisms. "Impurities," as used herein, refers to undesired chemical species, such as chloride anions that could interfere with further processing steps, cations, and/or radionuclide impurities, such as Tungsten W-188 breakthrough from the generator, which are undesirable for medical use in the patient. The "gas" in the fluid delivery mechanism may be any appropriate gas, but will typically be filtered air. The collection vessel may be any appropriate sterile receptacle for the isotope, such as a vented collection vial, a waterproof bag, or a syringe. A first gas-over-eluent delivery mechanism stores a first measured volume of fluid comprising a first measured volume of eluent solution and a first measured volume of a gas positioned over the first volume of solution, and includes a first pressure-supplying source that applies a first pressure upon the first volume of gas to force the first volume of eluent and then gas through the generator and the radioisotope concentration subsystem. A second gas-over-eluent delivery mechanism includes a second measured volume of fluid comprising a second measured volume of eluent solution and a second measured volume of a gas positioned over the second volume of solution and includes a second pressure-supplying source that applies a second pressure upon the second volume of gas to force the second volume of eluent and then gas through the concentration subsystem and into the radioisotope collection vessel. It should be understood, however, that the presently described gas-over-eluent invention in not limited to two gas-over-eluent delivery mechanisms. The number of mechanisms can equal the number of distinct elution steps needed or desired for a given procedure. The multiple, separate gas-over-eluent mechanisms provide numerous advantages over prior systems. First, they eliminate the need for an electric pump to supply the eluent to the generator and rest of the system. Second, since each mechanism is preloaded with a predetermined volume of eluent and gas, the need to track the volume of eluent that is supplied from a large eluent source during the procedure is eliminated. Thus, the need for timing the system, whether by the operator, or automatically via timers, and the possibility for such error during an elution is also substantially eliminated. After the first mechanism evacuates its prestored eluent and flushes the system with its gas, the second mechanism is activated to re-elute the radioisotope and to produce the final product at the desired concentration. This can be accomplished manually by the operator by applying the second pressure-supplying source to the second volume of fluid after observing that the first container is spent. Alternatively, the second elution may be initiated automatically, as described in detail below. Further, any subsequent stage mechanism, if present, can be activated after its preceding stage mechanism completes its task. In one preferred embodiment, the first and second pressure supplying sources are constant pressure supplying sources. As one example, gravity may supply the constant pressure upon the first and second gas-over-eluent combinations by means of simple weights of predetermined mass. In an alternative embodiment, the first and second pressure supplying sources are variable rate pressure supplying sources. For example, the first pressure supply source may be a first compressed spring having a spring coefficient k1 and the second pressure supply source is a second spring having a spring coefficient k2. In a more particular embodiment, the first delivery comprises a first downwardly-positioned syringe having a barrel for containing the first volume of fluid, an output feed, and a plunger that fits into the barrel and is positioned over the output feed. A first pressure supplying source, such as a mass or spring, is connected to the plunger. "Downwardly-positioned" refers to the orientation of the syringe being substantially vertically oriented so that the plunger is at the top of the syringe and pushes downwardly towards the output feed, or outlet. Similarly, the second gas over eluent delivery mechanism, typically smaller than the first, comprises a second syringe having a barrel for containing a second volume of fluid, an output feed and plunger, and a second pressure supplying source connected to the plunger that supplies a downward force to the plunger. In the broadest embodiment, the radioisotope concentration subsystem includes at least one processing element in fluid communication with the generator that processes that radioisotope therein. In a more particular embodiment, the at least one processing element comprises at least one impurity trap in fluid communication with the generator for removing impurities from the eluate and a radioisotope trap in fluid communication with the at least one impurity trap for concentrating therein the desired radioisotope in the eluate and for permitting the passage of the eluate therethrough for disposal. As used herein, "impurity trap" refers to any conventional element that processes, purifies or further prepares an eluate solution, such as an ion exchange column, chromatography column or filter. In this more detailed embodiment, the second gas-over eluent delivery mechanism forces the second measured volume of eluent and then the second measured volume of a gas into and through the radioisotope trap and into the radioisotope collection vessel to complete the process. The system further includes a waste receptacle for receiving the eluate produced by the generator and passed by the radioisotope trap and supplied by the first gas-over eluent delivery mechanism. In a preferred embodiment, the waste receptacle is contained within the radioisotope concentration subsystem, so that the waste may be safely disposed with the subsystem, without a separate handling step. A preferred method of operating the system may be completely or partially automated. Such method entails first applying a first pressure on a first volume of gas to force a first volume of eluent and then the first volume of gas through a generator and a concentration subsystem and into a fluid waste receptacle, thereby eluting the daughter radioisotope from the generator, concentrating the eluate in a radioisotope trap in the subsystem, and purging the system of fluid. Only then may the system apply a second pressure on a second volume of gas to force a second volume of eluent, and then the second volume of gas through the radioisotope trap once again and into a sterile, vented collection vessel, thereby re-eluting the concentrated daughter radioisotope into the collection vessel and purging the concentration subsystem of fluid. The second elution, or "re-elution", step may be activated by an operator or may commence automatically upon sensing the completion of the first elution. This operation may be automated either mechanically or electronically. As an example of a mechanically automated embodiment, the second pressure supply may be a spherical mass (i.e. a ball) that rests at the top of a downwardly titled track that terminates at the top of the plunger of the second syringe. The sphere is prevented from rolling down to and atop the plunger via a stopper mechanism. However, as soon as the plunger of the first syringe mechanism collapses into the barrel, the stopper mechanism automatically releases the sphere, allowing it to roll down the ramp and onto the plunger, to serve as the second pressure supply, and to thus commence the second elution step. A three-way valve is provided to redirect the fluid path which flowed in the first elution from the radioisotope trap to the waste receptacle to one that flows, in the second elution from the radioisotope trap to the collection vessel. The valve may be manually adjusted to redirect the flow after the gas from the first volume completes its purging function. Alternatively, the valve may be mechanically actuated, for example, by the rolling spherical mass described above, or may be electronically controlled and programmed to move to its "second" position after a sensor detects that the first elution is complete. The gas-over-eluent delivery mechanism and method also provide a relatively simple and low cost means for eluting two or more generators connected in series and particularly, aged and used generators that are still capable of producing some eluate but not enough to warrant subsequent, individual elutions. The application of gas to force the eluent completely through the multiple generator system permits the use of the same volume eluent as would be required to elute a single generator. This feature enables the use of only one set of costly ion exchange columns, which have a limited volume capacity, to concentrate the eluate from the multiple generators. This also provides an efficient solution to the problem of radioisotope waste. A still more detailed aspect of the invention includes a single-use, self-sealed, radioisotope concentration cartridge for concentrating therein a radioisotope contained in an eluate solution generated by a radioisotope generator. The eluate solution is carried by a first fluid delivery system which prepares the radioisotope to be re-eluted by a second fluid delivery system and to be carried into a sterile, collection vial via a third fluid delivery system. The cartridge includes at least one processing element, which, in the preferred embodiment, includes at least one impurity trap and a radioisotope trap serially connected to the at least one impurity trap, and a sealed, radioactively shielded, container that houses the at least one impurity trap and radioisotope trap. In particular, the container includes at least one opening and at least one septum that seals the at least one opening. The at least one septum (1) permits the flow of eluate from the generator into the at least one impurity trap when penetrated by the first fluid delivery system; (2) permits the flow of fresh eluent through the radioisotope trap when penetrated by the second fluid delivery system; (3) and permits the flow of the prepared radioisotope solution from the radioisotope trap to the sterile, collection vessel when penetrated by the third fluid delivery system. In still another aspect of the invention, the container includes at least three openings, each sealed by a penetrable septum: (1) a first input septum that seals the first container opening and permits the flow of eluate from the generator into the at least one column when penetrated by the first fluid delivery system; (2) a second input septum that seals the second container opening and permits the flow of fresh eluent through the anion exchange column when penetrated by the second fluid delivery system; and (3) an output septum that seals the third opening and permits the flow of the prepared radioisotope solution from the anion exchange column to the sterile, collection vial when penetrated by the third fluid delivery system. The one step, sealed and drop in feature of this cartridge greatly simplifies set up clean up and minimizes operator exposure to radiation.