JP5687283B2 - Method for eluting daughter nuclide and computer program for managing elution - Google Patents

Description

  The present invention relates to the field of radioisotope generators. More specifically, the present invention is directed to a multi-generator elution system.

  The supply of fission produced Mo-99 is in an uncertain state. Only two reactors, the Canadian NRU reactor and the Petten HFR reactor, represent approximately 60-70% of the worldwide supply of fission-generated Mo-99. If either of these reactors goes offline for scheduled maintenance or unscheduled repairs, in effect, nuclear medicine methods will be reduced to only essential cases. All reactors used in the production of fission Mo-99 are approaching the end of their service life and currently only one alternative reactor is planned, which is an alternative to Petten called Pallas. A further concern is that the diffusion of highly enriched uranium (HEU), the target material for fission Mo-99, falls into the hands of terrorists and unscrupulous governments. HEU is used to manufacture nuclear weapons.

  Alternatively, the gel-based generator uses Mo-99 obtained from neutron activation (n, γ) of natural molybdenum, which can be performed in any nuclear reactor, including a power reactor. Unfortunately, Mo-99 produced by the n, γ method, whether HEU or low enriched uranium (LEU), has a specific emission compared to Mo-99 produced from U-235 fission. The performance tends to be low. The low specific activity means that Mo-99 can be placed on a very large alumina column to adsorb all of the inert molybdenum, or the entire eluting column (eg, zirconium molybdate or titanium molybdate). This means that the volume must be changed to an insoluble gel matrix that reduces the volume. Subsequently, particularly when an alumina column is used, a large elution amount is required to elute the column of Tc-99m daughter nuclide. The prior art has not addressed all the challenges encountered by low specific activity and / or low activity generators.

  Nucl. Med. Comm. , 25 609-614 (2004) discuss the need to obtain high radioactivity concentrations of Tc-99m from zirconium molybdate gel generators ("cold kit" formulation as well as economics in larger radiopharmaceuticals) For reasons, higher concentrations are often required).

  US Pat. No. 5,729,821 discloses a method for concentrating Tc-99m from Mo-99 sorbent on an alumina-based column. The system requires multiple columns to achieve eluate concentration. Since Tc-99m is eluted from the primary column by ion exchange with chloride ions in saline, multiple columns must be used. Next, a cation (sodium) is removed by a secondary column (in this case, a silver halide base) and the pertechnetate is subsequently eluted with saline to form sodium pertechnetate, thereby forming a tertiary anion column. To be concentrated. This method uses acidic salts or weak acids to separate and elute Tc-99m from the parent nuclide Mo-99 (eg, an alumina column) and to allow pertechnetate ions to be concentrated on an anion column. It is necessary to remove cations by elution using an ion column.

  Applied Radiation and Isotopes 66 (2008) 1814-1817 discloses a method for extracting Tc-99m from a solution containing Mo-99. This is a complex procedure that requires extracting and concentrating Tc-99m using an organic solvent (tetrabutylammonium bromide solution in methylene chloride).

  Applied Radiation and Isotope 66 (2008) 1295-1299 describes a cited method, which is a modification of the above-described method, wherein a low specific activity alumina-based generator is eluted with saline to remove Tc-99m. Disclosure. The eluate is concentrated on a strong anion exchanger Dowex column. Tc-99m is removed by elution with tetrabutylammonium bromide solution and collected in a vial using methylene chloride. The organic solvent is removed to dryness by vacuum pumping and reduced with saline for use with the cold kit. This method is impractical in terms of the time required to prepare concentrated Tc-99m.

  US Pat. No. 6,157,036 discloses a method for a low specific activity ion exchange generator (ie, alumina). The system uses multiple columns similar to the method of US Pat. No. 5,729,821. The method uses positive pressure instead of safer negative pressure to move fluid (negative pressure (vacuum) is inherently safer with respect to transfers involving radioactive material).

  Therefore, there is a need for a system that manages daughter-nuclide growth-in for efficiency purposes. There is also a need in the art for an elution system that minimizes waste and maximizes the use of daughter nuclides generated by a series of generators. Furthermore, there is a need for an elution system that can reduce the risk of HEU growth. There is also a need for a manifold kit operable by an automatically activated system to direct eluate from a series of generators into a collection vial.

  In view of the need in the art, the present invention provides a multi-generator elution system comprising a plurality of parent-daughter nuclide generators and a control system that tracks the nuclear proliferation of each of the parent-daughter nuclide generators.

The control system receives demand (also referred to as “demand”) data indicating requirements for radioactivity generation and supplies a desired amount of daughter nuclide from a selected one of the generators to a first eluate. It is comprised so that it may elute using. The receiving unit receives demand data including at least the amount of daughter nuclides to be generated and a schedule for generating the amount of daughter nuclides. The receiver can be operated by the control system such that the control system schedules elution of daughter nuclides from the plurality of generators to meet the demand represented by the demand data. The receiver will also receive supply data.

  The present invention also provides a concentration column for collecting daughter nuclides from selected ones of the plurality of generators. The concentration column contains a suitable column medium. For example, when the daughter nuclide is Tc-99m, the concentration column is preferably an anion column from which the daughter nuclide is eluted. A collection container is also provided for receiving daughter nuclides from the concentration column.

  In addition, the present invention provides a multi-generator elution system that tracks the intranuclear growth of each parent daughter nuclide generator and schedules elution from the generator to meet the input demand for the daughter nuclide. provide.

  The present invention may also provide a second eluent source for eluting the column. Depending on the application, the second eluent may be different from the first eluent, or both may be the same. In addition, in embodiments where the same eluent is used to elute both the generator and the concentration column, the eluent may be removed from a single source. Alternatively, the first eluent source may be supplied individually to each generator rather than from a common source. The present invention also provides an example where, when high purity water such as water for injection is supplied from a common reservoir that elutes the generator, this water may also be used to rinse the components of the elution system during the elution process. provide. The present invention also contemplates an example where a high purity water source may be provided only for rinsing the components of the multi-generator elution system.

  In addition, the present invention adjusts the demand data entered for daughter nuclides generated by the generator, tracks the available radioactivity of each generator over time, and schedules elution from the generator. Thus, a method of operating a multi-generator elution system that meets the input demand for daughter nuclides is provided.

  Furthermore, the present invention provides a kit for a manifold system that may be operated by a control system to direct elution from a plurality of parent-daughter generators to a separation column.

  The present invention solves the problem for those skilled in the art of generator management and operation in nuclear pharmacy. Using a Tc-99m / Mo-99 generator for purposes of illustration and not limitation, the present invention combines and concentrates and evaporates daughter nuclide [Tc-99m] pertechnetate from multiple generator sections or Extend the useful life of low-activity generators. The present invention, in conjunction with demand data from the ERP system and manual input, automatically manages isotope “intranuclear growth” to maximize efficiency and cost savings. The present invention also allows an operator to model “hypothesis” scenarios, such as when modeling supply shortages and unexpected increases in demand. In addition, the present invention may be housed behind the radiation shield, which securely stores the generator as well as all components handling radioactivity. The present invention allows a gamma gel-based Mo-99 generator to be more operatively competitive with a fission generator, and thus a viable alternative to Mo-99 produced by irradiating highly enriched uranium (HEU). Things are promoted, resulting in reduced proliferation of nuclear bomb grade materials. Furthermore, the present invention provides prescription formulation data exchange for electronic medical records.

  Mo-99 used in a Tc-99m / Mo-99 generator generally represents 75% or more of the total cost of the generator. The purchase of generators and isotopes is generally the largest single expense item. Mo-99 decays at a known exponential rate to Tc-99m, and Tc-99m also decays at a known exponential rate. A typical generator contains a known amount of radioactivity when delivered. As the generator elutes, Tc-99m is removed leaving Mo-99, which continues to decay to Tc-99m. The calculations required to accurately determine the amount of Tc-99m available for a generator at any given time are very complex and not easily performed. The present invention provides a control system incorporating software that performs these calculations simply and quickly. By utilizing this software in conjunction with a multi-generator elution system, the control system can select an efficient combination of generators for any given demand. In addition, historical or real-time demand can be obtained by manual input by an operator or by a data link from an enterprise resource planning system.

  Titanium molybdate “gel” generators use Mo-99, which has a very low specific activity, which is less concentrated than the industry standard fission Mo-99 generator and has a total radioactivity content. Overall leads to low elution. The multi-generator elution system of the present invention eliminates these challenges and enables gel-based generators to compete more operatively than industry standard fission-based generators.

It is a schematic sectional drawing of the parent daughter generator of a prior art. It is a figure which shows the radioactive decay curve of a Mo-99 / Tc-99m generator. It is a figure which shows the decay curve of Tc-99m in the Mo-99 / Tc-99m generator after continuous elution of Tc-99m isotope ion. It is a figure which shows the multi-generator elution system for gel-type Mo-99 generators. FIG. 5 illustrates an alternative to the elution system of FIG. It is a figure which shows the multi-generator elution system for alumina type | system | group Mo-99 generators. FIG. 7 shows an alternative to the elution system of FIG. It is a figure which shows the cassette type manifold as a part of the multi-generator elution system of this invention. 3 is a flowchart illustrating the method of the present invention. It is a figure which shows the example of a screen of the graphical user interface (GUI) of this invention which supplies supply information to the multi generator elution system of this invention. It is a figure which shows the example of a GUI screen of the elution management system for multi-generator elution systems.

  The present invention concentrates the eluate from the bulk elution to reduce using a “cold kit” that requires a higher radioactivity concentration. In one embodiment, the present invention provides a system for concentrating Tc-99m. The present invention can concentrate the eluate in larger radiopharmaceuticals to achieve workflow efficiency, particularly using the QC test of the eluate, and reduce the time it takes to individually elute the multi-generator. Exclude. In addition, the present invention makes it possible to make full use of generators approaching maturity, which tend to be used because of low yields and therefore low eluate radioactivity concentrations, and cost is improved. Achieve reductions. The present invention incorporates software that better matches demand with supply, thus achieving cost savings and minimizing waste and loss. The present invention alleviates the need to use organic solvents, thus eliminating waste and the use of hazardous organic solvents.

  The present invention provides a multi-generator elution system that uses multiple parent-daughter generators to enrich the output of the eluted generators that track the parental daughter isotope intranuclear growth relationship in each generator. All three of these concepts combine to solve the essential challenges of generators with low specific activity, both in application and usage efficiency.

  The multi-generator elution system is desirably enclosed within a radiation shielding enclosure, such as a hot cell surrounded by a lead wall. Although the present invention serves to manage elution from a single generator, in a preferred embodiment, multiple generators are managed. One embodiment of the present invention provides a number of Mo-99 titanium / Tc-99m titanium [Mo-99] molybdate gels that utilize Mo-99 resulting from neutron activation of natural molybdenum (n, γMo-99). Use a generator. Although specific reference is made to the management of elution from the Mo-99 / Tc-99m parent-daughter generator, the present invention uses other types of generators to elute other daughter isotopes or daughter nuclides. I think that it may be.

  Accordingly, in one embodiment of the present invention, the lead shield enclosure includes one or more Mo-99 / Tc-99m generators. The generators are connected to each other via a flow path system that can elute any combination of generators into one or more concentration columns. In the case of Tc-99m, the concentration column is an anion column. Concentrated Tc-99m is then eluted through the concentration column into a collection vial at the required radioactivity concentration ready for use in radiopharmaceuticals. The control system selects the most efficient combination of generators based on demand, available supply, and future demand.

  Both the available supply of radioactivity and the current and future demand for radioactivity are manually entered into the receiver and control system, either from the generator itself or from the Radiopharmaceutical Enterprise Resource Planning (ERP) system, respectively. Or may be transferred electronically. For example, data transferred from the generator itself can be electronically read or scanned from a label on the generator, such as a barcode. Such data for the generator, also referred to as “feed data”, can include calibration data for the generator that provides both date and radioactivity. In addition, it is envisioned that the feed data includes the date and time when the generator is available and the date of the first elution setting. Similarly, data including the required radioactivity and the time that such radioactivity is required by the system may be entered into the control system either manually or electronically. It is envisaged in the present invention that the data receiver is configured for manual and / or electronic input of demand data.

  Using the feed data, the control system can calculate the available radioactivity for each generator, preferably at set intervals, for example every 30 minutes, and display it to the operator. The demand data is desirably displayed similarly over the same time interval as the supply data. The control system chooses which of the available generators to elute at a given time and fills the demand data in the most efficient way possible, thus maximizing the useful life of each generator A computer that calculates a best-fit elution profile or schedule that minimizes waste and minimizes waste. The control system is preferably programmed to perform a generalized gradient reduction algorithm analysis of demand data and the activity levels of multiple generators to determine an optimal elution schedule to minimize waste. Alternatively, the present invention allows the control system to simulate various elution schedules from multiple generators and select elution schedules to minimize the waste of daughter nuclides when meeting demand data. Conceive. The elution schedule is also supplied to the operator.

  Desirably, the elution schedule is displayed in a GUI that gives the operator the option of overriding the calculated optimized elution schedule by instead scheduling different generators to elute at a given time. The When the operator decides to modify the elution schedule, the control system recalculates the elution schedule, the availability of updated radioactivity over time for each generator, as well as the scheduled elution from each generator. Display both time. If the updated elution schedule is satisfactory for the operator, follow the elution instructions to elute selected generators according to the schedule. In this way, the present invention provides an “operator in the loop” option to monitor and manage the elution from the generator, allowing the operator to override the calculated schedule. Alternatively, the present invention can operate without the need for operator intervention and thus can automatically perform scheduled elution without operator input, thereby allowing the operator to perform other pharmaceutical operations. You can pay attention to your work.

  The elution instruction is used to electronically control the elution of the selected generator. As the generator is eluted, the control system updates the ingrowth calculation and updates the elution schedule if necessary. The present invention contemplates that either the operator or the system performs the step of confirming that the selected generator has actually been eluted.

  The calculations used to capture the elution schedule desirably include the half-life and decay equation of the parent nuclide, the half-life and decay equation of the daughter nuclide, the yield efficiency of the elution, and the fraction of elution available for decay of the parent nuclide. Take into account known constants such as rate. In addition, the control system considers the balance equation for the parent and daughter and the expiration time of the generator. Most generators have a lifetime of 2 weeks, which is a pharmaceutical maturity requirement, but can be much longer if the parent isotope has a long half-life, such as Sr-90 / Y-90.

  The present invention provides a number of advantages, both technically and economically. The present invention can therefore function as a concentration device for the radioactivity eluted from the generator selected for each elution step. This not only allows efficient use of generators, but also concentrates generators that are approaching maturity, so they can still be used in combination with each other. Automatic operation can reduce the radiation dose to which pharmaceutical workers are exposed. Labor efficiency is also realized. For example, if four generators are eluted individually, four separate quality control tests are required. The present invention allows a single quality control test to be performed on the concentrated elution by concentrating individual elutions, retaining a greater amount of radioactivity in the collection vial for clinical use be able to.

  The present invention makes their use a commercially viable option even though gel generators are lower than the relative specific activity of fission generators. The multi-generator elution system (MGES) of the present invention is intended to eliminate the disadvantages of the gel-based generator system described above. In addition, the use of gel generators improves the management of isotope supply during the loss or shortage of conventional sources.

  The system desirably includes a shielded area that houses two or more gel generators. These generators are connected to individual valve manifolds, which can be selected by the control system to elute one or more selected generators at the appropriate time to meet the planned demand. Tc-99m is eluted by passing the eluent through one or more selected generators. Tc-99m is collected in an alumina concentration column. When collection from one or more generators is complete, the control system elutes the concentration column with eluent and places it in an industry standard shielded collection vial. The eluent can be removed from the reservoir or from individual saline vials currently used to elute the generator.

  The flow path, concentration column, and collection vial facility are all preferably shielded by a hot cell to provide radiation protection for the operator. Individual component shielding may also be provided within the radiation shielding hot cell.

  Various methods of concentrating Tc-99m elution have been demonstrated. Calculations that determine the ingrowth relationship of parent-daughter isotopes are well known, but are less commonly used due to their complexity. It is also known to use n, γMo-99 in gel generator systems and other generator systems. The present invention brings all three concepts into a single elution system that manages supply data, available radioactivity, and demand data for multiple generators, providing specific activity in both application and usage efficiency. Solve essential problems with low generators.

  The present invention works with a zirconium or titanium molybdate gel generator system. With modifications, the invention (as detailed) also works with alumina-based systems. Therefore, additional columns and flow paths are required to work with the alumina system.

  The concept of titanium molybdate gel generator design has been proven. Gels are produced after irradiation from irradiated natural molybdenum metal. Established methods include irradiating a pre-formed gel or molybdenum trioxide. Irradiating the metal provides the advantages of yield, safety, and processing efficiency.

  Referring now to FIG. 1, a prior art parent-daughter generator 110 incorporated into the multi-generator elution system of the present invention includes a long-lived parent nuclide that decays to a shorter-lived daughter nuclide. Because the parent and daughter nuclides are not isotopes, the daughter nuclides can be chemically isolated. The eluent is directed through the column containing the parent and daughter nuclides, but carries only the daughter nuclides as eluent from the column. After elution, the parent nuclide (remaining in the generator) collapses, resulting in a new supply of daughter nuclides. Therefore, the generator can supply new daughter nuclides as needed until the parent's radioactivity is consumed.

  Generator 110 includes a generator body 112 formed from a radiation shielding material such as lead. Generator body 112 defines a column cavity 114 containing a column 116 that holds the parent nuclide. Generator body 112 extends in fluid communication between eluent cavity 122 and collection cavity 124 and elongate eluent channel 118 extending in fluid communication between column cavity 114 and eluent cavity 122. An elongated eluate channel 120 is defined. Column 116 includes a medium 126 to which parent nuclides bind and from which daughter nuclides may be eluted. The eluent cavity 122 supports the eluent vial 130 and the collection cavity 124 supports the collection vial 132 therein. An eluent conduit 134 extends in fluid communication between the eluent vial 130 and the column 116 to deliver the eluent from within the vial 130 to the column 116. At each end, eluent conduit 134 terminates with elongated needles 125a and 125b that pierce the septum of vial 130 and column 116, respectively. The eluent conduit 136 extends from the column 116 to the collection vial 132 to deliver eluate from the column 116 to the vial 132. At each end, eluent conduit 136 terminates with elongated needles 129a and 129b that pierce the septum of vial 132 and column 116, respectively. Generally, since the collection vial 132 is an exhaust vial, the low pressure within the vial causes the eluent fluid to be removed from the eluent vial 130 through the column 116 and into it. A separate air supply conduit 140 extends in fluid communication between the eluent vial 116 and the air supply filter 142 to assist in draining the eluent from the eluent vial 130. Generally, since the collection vial 132 is housed within its own radiation shield 144, as the shield 144 is removed from the collection cavity 124, the filled collection vial 132 may be further processed. The collected eluate is transported to a location where the pharmacist may remove it.

  In one embodiment, column 116 contains Mo-99, which collapses to Tc-99m with acidic alumina as the sorbent. Thus, the column 116 is an acidic alumina column, but other types of columns may be used as described above. The present invention contemplates incorporating multiple generators 110. As will be shown below, the present invention further contemplates replacing the collection vial with each generator with a conduit leading to a common collection vial. In addition, instead of each generator having its own eluent vial 130, the present invention may be provided with a common eluent source that may be directed to all generators as needed. Conceive. For example, when the column 116 is an acidic alumina column containing Mo-99, the eluent vial 130 may provide a saline source that elutes Tc-99m nuclides from the column. Alternatively, for example, in the case of a gel generator, a water source for injection may be provided as an eluent.

  The present invention contemplates that the generator used by the present invention may be either a fission or an n, γ generator. For example, a TechneLite (R) (Technetium Tc-99m generator) commercially available from Lantheus Medical Imaging (331 Treble Cove Rd., N. Billerica, MA 01862, USA) may be used. The TechneLite generator is known as a dry generator, that is, it has an external saline source that elutes the system. Most generators tend to be this way. Like other fission generators, the TechneLite generator is based on an acidic alumina column to facilitate the storage of Mo-99 and subsequent separation of the daughter isotope Tc-99m. Similarly, generator 110 may comprise an Ultra-Technek ™ DTE (Technetium Tc-99m generator commercially available from Coviden (Mallinckrodt, 2703 Wagner Place, Maryland Heights, MO 63043, USA)). Ultra-Technekow is very similar to the TechneLite unit. Further alternatively, DryTec® (Technetium Tc-99m generator) may be used with the present invention. The DryTec generator is commercially available from GE Healthcare (The Grove Centre, White Lion Road, Little Chalet, Buckinghamshire HP7 9LL, UK) and is similar to the other fission generators listed above.

  Furthermore, the generator 110 may be an n, γ or gel generator. One gel generator is a Tc-99m Geltech generator commercially available from the Indian Ministry of Nuclear Energy (BRIT / BARC Vash Complex, Sector-20 Vashi, Navi Mumbai-400 705, India). The geltech generator for 99mTc is a dual column system consisting of a primary zirconium molybdate 99Mo gel column and a secondary purified acidic alumina column. These types of generators are structurally different from fission type generators, but still function in the same way to produce sodium pertechnetate using a salt eluent. Gel generators are not truly chromatographic, but the term “eluent” is used herein to describe the fluid that is directed into the generator, and the term “eluent” In the description, it will be used to describe fluid exiting a gel generator containing daughter nuclides.

FIG. 2 shows the radioactive decay curve of the Mo-99 / Tc-99m generator. FIG. 3 shows how the available radioactivity decays over time until a point is reached where the generator is no longer useful. FIG. 3 also shows the decay curve of Tc-99m in the Mo-99 / Tc-99m generator after continuous elution of Tc-90m isotope ions. Line A shows the overall decay of the parent nuclide Mo-99, and lines B to D are daughter nuclides up to the approximate maximum at which the daughter nuclide is eluted so that nothing remains in the generator column. Intranuclear proliferation of Tc-99m is shown. As the parent nuclide continues to decay to become the daughter nuclide, an increase over time in the available radioactivity of the daughter nuclide is shown. Equation 1 shows the theoretical Tc-99m present in the generator at any time (t) after the previous elution when the Mo-99 radioactivity A ⁰ 1 present at the time of the previous elution is known. It is an equilibrium equation describing radioactivity (A2).

In the formula, λ1 is the decay constant of Mo-99, and λ2 is the decay constant of Tc-99m. The present invention links the demand for radioactivity with the calculated availability of radioactivity for each generator.

  FIG. 4 shows a multi-generator elution system 200 of the present invention. Multi-generator elution system 200 incorporates multiple generators 110. Generator 110 is preferably connected to a manifold (not shown) that includes valves and conduits such that each individual valve is in selectable fluid communication with its corresponding individual generator. Desirably, the manifold is connected to a low pressure or vacuum source that draws eluent into the system 300. The manifold directs the eluate output of the generator to the concentration column 212. The eluent is directed from the first eluent source 214 to a selected one of the generator 110 and all resulting eluate from the selected generator is directed to the column 212. Concentration column 212 captures daughter nuclides from the generator therein. Second eluent from second eluent source 216 is directed through concentration column 212 to elute daughter nuclides into collection vial 218. Generator 110, column 212, eluent sources 214 and 216, and collection vials are desirably placed within cavity 224 of radiation shielding hot cell 222 to limit operator exposure.

  The system 200 includes a control system 226 and a receiving unit 228. The receiver 228 and the control system 226 may be provided as part of a single computer system. The receiver 228 can receive both supply data and demand data, which can be used by the control system 226 to create an elution schedule for the generator 110 as described with respect to FIGS. Based on the calibration data, including the known starting activity and date, the date and time when the generator was available, and the date and time of the first elution offset, depending on the supply data, The amount can be calculated. Demand data relates to the amount of radioactivity required and the point in time. The demand data may be automatically input from the ERP module 231 such as SAP or Slimline to the receiving unit 228 or may be manually input to the receiving unit 228. Control system 226 preferably matches which demand data for available radioactivity and when to elute which generators to maximize the daughter nuclides that are eluted with minimal waste. Calculate the elution schedule by determining The control system 226 then preferably downloads instructions for the actuation system 235 located within the hot cell 222 that performs the elution. The present invention further contemplates that the control system 226 may alternatively be provided in the hot cell 222 as a separate computerized system that performs the functions of both or separately from the actuation system 235.

  By way of example and not limitation, in this configuration, generator 110 is a Mo-99 / Tc-99m generator (titanium molybdate [99Mo]) gel generator. The first eluent source 214 desirably supplies a weak acid as the first eluent that elutes the daughter nuclide Tc-99m from the generator, but high purity water such as sterile water for injection is also used to elute the gel generator. May be. Concentration column 212 includes an alumina sorbent that captures pertechnetic acid in the eluate from generator 110. Second eluent source 216 elutes pertechnetic acid from column 212 and provides saline for collection into collection vial 218. Next, sodium pertechnetate may be used with a cold kit to label the radioactive tracer.

  The present invention may be used to elute any combination of generators and collect the radioactivity from the eluted generators in column 212. The final radioactivity concentration is determined by elution of the concentration column 212, which can be eluted in very small amounts. In addition, since the radioactivity can be collected and concentrated from multiple generators, the generator may be used continuously until maturity.

  Referring now to FIG. 5, an alternative representation of the multi-generator elution system 200 is shown. In FIG. 5, five gel generators 110a-e connected to the valve manifold 250 are shown. Manifold 250 is preferably based on a linearly arranged stopcock manifold used in a FASTlab ™ cassette commercially available from GE Healthcare (Liege, BE). Manifold 250 includes 16 three-way / 3-position stopcock valves 1-17. Each of the valves 1-17 includes three open ports for adjacent manifold valves and individual lures located therebetween. Each valve includes a rotatable stopcock that fluidly isolates a third port while fluidly communicating any two of the three associated ports. The present invention further contemplates that the stopcock can include a T-shaped internal passage therein so that all three ports can be in fluid communication across the valve, although such embodiments are continuous. In order to prevent contamination from occurring during the fluid flow, this results in dead space that may require additional rinsing. The manifold 250 further includes first and second socket connectors 18 and 19 that define vacuum ports 18a and 19a, respectively, at opposite ends thereof. The manifold 250 and the stopcocks of valves 1-17, as well as the conduits described below, are desirably formed from a polymeric material, such as PP, PE, polysulfone, Ultem, or PEEK. As shown in FIG. 8, the manifold desirably includes 25 three-way / 3-position stopcock valves, but the actual number of valves can be expanded to meet user requirements. Unused valves may simply have their luer connections covered by luer fittings and their stopcocks to provide fluid communication for flow between adjacent valves.

  Each of the valve connections described herein is made with a port defined by its luer connector. As shown in FIG. 5, the valve 1 supports a filtered vent 251 at its luer connection. Valve 2 is connected to a first eluent source 214 by an elongated conduit 252. The first eluent source 214 supplies an eluent that elutes daughter nuclides from generators 110-e. The first eluent source 214 is desirably also connected in fluid communication with a filtered vent 233 to assist in draining the eluent through the conduit 252 toward the valve 2. The valve 3 is connected to the second manifold 256 by an elongated conduit 254 to provide an open connection to the eluent channel 118 of the generators 110a-e. That is, the present invention desirably provides a single eluent source that elutes each generator, but the present invention includes each generator having its own eluent source, as shown in FIG. I also think of good things. The eluate channels 120 of generators 110a-e are each connected backwards to manifold 250 by elongated conduits 260a-e. Conduits 260a-e extend between valves 4-8 between individual eluent channels 120 of generators 110a-e, respectively.

  The valve 9 is connected to the input port of the concentration column 212 by an elongated conduit 262 so that the eluate from the generator may be directed to the column 212. Valve 10 is connected to a second eluent source 216 by an elongated conduit 264. The second eluent source 216 provides an eluent that elutes daughter nuclides from the column 212. The second eluent source 216 is desirably also connected in fluid communication with the filtered vent 263 to assist in flowing the second eluent through the conduit 262 toward the valve 9. Valves 11 and 12 are covered by luer fittings and their stopcocks that are oriented to provide fluid flow between valves 10 and 13. The valve 13 is connected to the input port 268 of the collection vial 218 by an elongated conduit 266 so that the product fluid therein can be directed. The valve 14 is connected to the input port 272 of the waste vial 219 by an elongated conduit 270. The valve 15 is connected to the output port of the column 212 so that the column 212 desirably connects directly to the valve 15. The valve 16 is connected to the output port 275 of the waste vial 215 by an elongated conduit 274. Valve 17 is connected to output port 278 of collection vial 218 by an elongated conduit 276.

  Next, sample elution will be described. An elution schedule that requires elution of radioactivity from generators 110a and 110c has been calculated. The first eluent is withdrawn from the first source 214 by applying a vacuum (ie, a sufficiently low pressure) at port 19a. Valves 1-17 are set so that the first eluent flows into valves 256 through valves 2 and 3 and conduit 254. Initially, valves 5-8 are set so that the eluate flow from generator 110a can flow through conduit 260a to valve 9. Valve 9 directs the eluate to flow through conduit 262 to the inlet port of column 212. The eluate is withdrawn from column 212 through valve 15 and into valve 14 and into waste vial 219. The volume of waste vial 219 is sufficient to collect all of the liquid and thus deliver from column 212. Next, the stopcock of the valve 4 is rotated to isolate the generator 110a and the stopcock of the valve 6 is rotated so that the first eluent flows from the second manifold 256 into the generator 110c. Next, the eluate from generator 110c is directed to valve 9 through valves 6-8. Valve 9 directs the eluate to flow through conduit 262 to the inlet port of column 212. The eluate is withdrawn from column 212 through valve 15 and into valve 14 and into waste vial 219. In this way, daughter nuclides from generators 110a and 110c are collected in concentration column 212.

  In order to elute the daughter nuclide from the column 212, the valve 10 is set to direct the second eluent from the source 264 through the conduit 264 toward the valve 9 with suction at the port 19a. The second eluent is withdrawn through conduit 262, through the inlet port of column 212, and through column 212. Upon exiting column 212 and entering valve 15, column 212 eluate contains daughter nuclides that are distributed into collection vial 218. This eluate is directed into valve 13 and through conduit 266 into vial 218, and suction from port 19 a is applied through valve 17 and conduit 276. The vial 218 may then be removed or withdrawn to supply the daughter nuclide for further processing by the pharmacist. Thus, subsequent distributions from the generator may be directed to the same collection vial, or the control system 226 may direct any remaining radioactivity distributed from the generators 110a-e to meet demand data requirements. Since it is included in the calculation, it may be combined in a different way with the unused eluate from the previous distribution.

  The manifold 250 is preferably formed attached to an actuation system 235 that engages and sets the orientation of the valve stopcock and provides low pressure suction or vacuum to draw fluid through the manifold and into the vial. Actuation system 235 includes rotatable arms that can engage each stopcock of valves 1-17 and position each in a desired orientation throughout the elution operation. Actuation system 235 also includes a pair of cocks that engage one of ports 18a and 19a, respectively, in a fluid tight connection to provide a low pressure or vacuum source for the manifold in accordance with the present invention. Desirably, the manifold 250 is attachable to a FASTlab ™ (commercially available from GE Healthcare, Liege, BE) synthesis device that is programmed to operate a valve and apply a vacuum. Since the FASTlab synthesizer is already designed to operate in a hot cell environment, it is ideally suited as an operating device for the system 200. The actuation system 235 is instructed to act by the control system 226 according to the calculated elution schedule.

  FIGS. 6 and 7 show a multi-generator elution system 300 for an alumina-based Mo-99 generator 110. Multi-generator elution system 300 incorporates multiple generators 110. In this embodiment, generator 110 is a Mo-99 / Tc-99m alumina generator (ie, alumina is incorporated into the generator column). Generator 110 is preferably connected to a manifold (not shown) that includes valves and conduits such that each individual valve is in selectable fluid communication with its corresponding individual generator. The manifold directs the eluate output of the generator to the cation column 315. Generator eluate flows through cation column 315 and then into concentration column 312. Desirably, the manifold is connected to a vacuum source that draws eluent into the system 300. The cation column is not used to capture daughter nuclides, but contains a suitable medium that removes competing ions that adversely affect the concentration column. Thus, in the system 300, the eluent is directed from the first eluent source 314 to the selected one of the generator 110 and all resulting eluate from the selected generator is directed through the column 315 to the column 312. Attached. Concentration column 312 captures daughter nuclides from the generator therein. Second eluent from second eluent source 316 is directed through concentration column 312 to elute daughter nuclides into collection vial 318. Generator 110, column 312, eluent sources 314 and 316, and collection vials are desirably placed within cavity 324 of radiation shielded hot cell 322 to limit operator exposure.

  The system 300 includes a control system 326 and a receiving unit 328. The receiver 328 and the control system 326 may be provided as part of a single computer system. The receiver 328 can receive both supply data and demand data, which can be used by the control system 226 to create an elution schedule for the generator 110 as described with respect to FIGS. Based on the calibration data, including the known starting activity and date, the date and time when the generator was available, and the date and time of the first elution offset, depending on the supply data, The amount can be calculated. Demand data relates to the amount of radioactivity required and the point in time. The demand data may be automatically input to the receiving unit 328 from the ERP module 331 such as SAP or Slimline, or may be manually input to the receiving unit 328 by an operator. The control system 326 preferably determines when to elute which generator to match the demand data for available radioactivity and maximize the daughter nuclides that are eluted with minimal waste. To calculate the elution schedule. The control system 326 then preferably downloads instructions for the actuation system 335 located in the hot cell 322 that performs the elution. The present invention further contemplates that the control system 326 may be provided in the hot cell 322, alternatively or separately from the actuation system 335, or as a single computerized system that performs both functions.

  In this configuration, the first eluent source 314 desirably provides an acid salt or weak acid, typically saline, as the first eluent that elutes the daughter nuclide Tc-99m from the generator. Since the first eluent is saline, sodium ions are first removed using cation column 315 so that concentration on concentration column 312 is possible. Concentration column 312 includes an alumina sorbent that captures pertechnetic acid in the eluate from generator 110. Second eluent source 316 elutes sodium pertechnetate from column 312 and provides saline for collection into collection vial 318. Next, sodium pertechnetate may be used with a cold kit to label the radioactive tracer.

  The present invention may be used to elute any combination of generators and collect the radioactivity from the eluted generators through column 315 and into column 312. The two-column method allows generators based on fission Mo-99 and alumina technology to take advantage of the efficiency of the concentrator system of the present invention. The final radioactivity concentration is determined by the elution of the concentration column 312 which can be eluted in very small amounts. In addition, since the radioactivity can be collected and concentrated from multiple generators, the generator may be used continuously until maturity.

  Turning now to FIG. 7, an alternative representation of a multi-generator elution system 300 is shown. In FIG. 7, five gel generators 110a-3 connected to the valve manifold 350 are shown. Manifold 350 is preferably based on a linearly arranged stopcock manifold used in FASTlab ™ cassettes commercially available from GE Healthcare (Liege, BE). Manifold 350 includes 16 three-way / 3-position stopcock valves 1-17. Each of the valves 1-17 includes three open ports for adjacent manifold valves and individual lures located above them, with the luer ports located between the other opposing ports. Each valve includes a rotatable stopcock that fluidly isolates a third port while fluidly communicating any two of the three associated ports. The present invention further contemplates that the stopcock can include a T-shaped internal passage therein so that all three ports can be in fluid communication across the valve, although such embodiments are continuous. In order to prevent contamination from occurring during the fluid flow, this results in dead space that may require additional rinsing. Manifold 350 further includes first and second socket connectors 18 and 19 that define vacuum ports 18a and 19a, respectively, at opposite ends thereof. The manifold 350 and the stopcocks of valves 1-17, as well as the conduits described below, are desirably formed from a polymeric material, such as PP, PE, polysulfone, Ultem, or PEEK. As shown in FIG. 8, the manifold desirably includes 25 three-way / 3-position stopcock valves, but the actual number of valves can be expanded to meet user requirements. Unused valves may simply have their luer connections covered by luer fittings and their stopcocks to provide fluid communication for flow between adjacent valves.

  Each of the valve connections described herein is made with a port defined by its luer connector. As shown in FIG. 8, the valve 1 supports a filtered vent 351 at its luer connection. Valve 2 is connected to a first eluent source 314 by an elongated conduit 352. The first eluent source 314 supplies an eluent that elutes daughter nuclides from generators 110-e. The first eluent source 314 is desirably also connected in fluid communication with a filtered vent 333 to assist in draining the eluent through the conduit 352 toward the valve 2. The valve 3 is connected to the second manifold 356 by an elongated conduit 354 to provide an open connection to the eluent channel 118 of the generators 110a-e. That is, the present invention desirably provides a single eluent source that elutes each generator, but the present invention includes each generator having its own eluent source, as shown in FIG. I also think of good things. The eluate channels 120 of generators 110a-e are each connected backwards to manifold 350 by elongated conduits 360a-e. Conduits 360a-e each extend between the individual eluent channels 120 of generators 110a-e to valves 4-8.

  Valve 9 is connected to the inlet port of cation column 315 by an elongated conduit 362. The cation column 315 serves to remove competing ions from the eluate from the generator prior to concentration. Valve 10 is connected to a second eluent source 316 by an elongated conduit 364. The second eluent source 316 supplies an eluent that elutes daughter nuclides from the column 312. The second eluent source 316 is desirably also connected in fluid communication with the filtered vent 363 to assist in flowing the second eluent through the conduit 362 toward the valve 9. The valve 11 is connected to the output port of the cation column 315. The valve 12 is connected to the inlet port of the concentration column 312 by an elongated conduit 365.

  Valve 13 is connected to an inlet port 372 of waste vial 319 by an elongated conduit 370. The valve 14 is connected to the input port 368 of the collection vial 318 by an elongated conduit 366 so that the product fluid therein can be directed. The valve 15 is connected to the output port of the column 312 such that the column 312 preferably connects directly to the valve 15. The valve 16 is connected to the output port 375 of the waste vial 315 by an elongated conduit 374. Valve 17 is connected to an output port 378 of collection vial 318 by an elongated conduit 376.

  Next, sample elution will be described. An elution schedule that requires elution of radioactivity from generators 110a and 110c has been calculated. The first eluent is withdrawn from the first source 314 by applying a vacuum (ie, a sufficiently low pressure) at port 19a. Valves 1-17 are set such that the first eluent flows into valves 356 through conduits 354 and valves 354. Initially, valves 5-8 are set so that the eluate flow from generator 110a can flow through conduit 360a to valve 9. Valve 9 directs the eluate to flow through conduit 362 to the inlet port of cation column 315. The eluate is withdrawn from the column 315 through the valve 12 and flows into an elongated conduit 265 that enters the inlet port of the concentration column 312. Waste continues to flow through column 312, through valve 15 to valve 13, and into waste vial 319. The volume of waste vial 319 is sufficient to collect all of the liquid and thus deliver from column 315. Next, the stopcock of valve 4 is rotated to isolate generator 110a, and the stopcock of valve 6 is rotated so that the first eluent flows from second manifold 356 into generator 110c. Next, the eluate from generator 110c is directed to valve 9 through valves 6-8. Valve 9 directs the eluate to flow through conduit 362 to the inlet port of column 315. The eluate is withdrawn from the column 315 through the valve 12 and flows into an elongated conduit 265 that enters the inlet port of the concentration column 312. Waste continues to flow through column 312, through valve 15 to valve 13, and into waste vial 319. In this way, daughter nuclides from generators 110 a and 110 c are collected in concentration column 312.

  To elute daughter nuclides from column 312, valve 10 is set to direct the second eluent from source 316 through conduit 364 toward valve 12 with suction at port 19 a. The second eluent is withdrawn through conduit 365, through the inlet port of column 312 and through column 312. Upon leaving column 312 and entering valve 115, column 312 eluate contains daughter nuclides that are distributed into collection vial 318. This eluate is directed into valve 14 and through conduit 366 into vial 318 and suction from port 19a is applied through valve 17 and conduit 376. The vial 318 may then be removed or withdrawn to supply the daughter nuclide for further processing by the pharmacist. Thus, subsequent distributions from the generator may be directed to the same collection vial, or the control system 326 will direct any remaining radioactivity distributed from the generators 110a-e to meet the demand data requirements. Since it is included in the calculation, it may be combined in a different way with the unused eluate from the previous distribution.

  Manifold 350 is formed attached to actuation system 235 that engages and sets the orientation of the valve stopcock and provides low pressure suction or vacuum to draw fluid through the manifold and into the vial. Actuation system 335 includes rotatable arms that engage each stopcock of valves 1-17 and can be positioned in a desired orientation throughout the elution operation. Actuation system 335 also includes a pair of cocks that engage one of ports 18a and 19a, respectively, in a fluid tight connection to provide a low pressure or vacuum source for manifold 350 in accordance with the present invention. Desirably, the manifold 350 can be attached to a FASTlab ™ (commercially available from GE Healthcare, Liege, BE) synthesis device that is programmed to operate a valve and apply a vacuum. The FASTlab synthesizer is ideally suited as an operating device for the system 300 because it is already designed to operate in a hot cell environment. The actuation system 335 is instructed to act by the control system 326 according to the calculated elution schedule.

  Referring now to FIG. 8, an elution cassette 400 for use with a multi-generator elution system is shown. In FIG. 8, four alumina generators 110a-d that produce Tc-99m by the decay of Mo-99 are shown connected to a valve manifold 450. Cassette 400 includes a case 402 with a planar front wall 404 that is bounded by a peripheral wall 406 that defines a case cavity 408. Cassette 400 supports elongated manifold 450 within cavity 408 adjacent to bottom wall 406a. Manifold 450 is preferably based on a linearly arranged stopcock manifold used in FASTlab ™ cassettes commercially available from GE Healthcare (Liege, BE). Manifold 450 includes 25 three-way / 3-position stopcock valves 1'-25 '. Each of the valves 1'-25 'includes three open ports for adjacent manifold valves and individual lures located thereon, with the luer ports positioned between the opposing ports. Each valve includes a rotatable stopcock that fluidly isolates a third port while fluidly communicating any two of the three associated ports. The present invention further contemplates that the stopcock can include a T-shaped internal passage therein so that all three ports can be in fluid communication across the valve, although such embodiments are continuous. Contamination occurs during the fluid flow, resulting in dead space that may require additional rinsing to prevent loss of fluid trapped in the dead space therein. Manifold 450 further includes first and second socket connectors 26 and 27 that define vacuum ports 26a and 27a, respectively, at opposite ends thereof. Manifold 450 and stopcocks of valves 1'-25 'and the conduit connector described below are desirably formed from a polymeric material, such as PP, PE, polysulfone, Ultem, or PEEK. As shown in FIG. 8, the manifold includes 25 three-way / 3-position stopcock valves, but the actual number of valves can be expanded to meet user requirements. Unused valves may simply have their luer connections covered by luer fittings and their stopcocks to provide fluid communication for flow between adjacent valves.

  Cassette 400 is a variation of a pre-assembled synthesis cassette designed to be adaptable to synthesize clinical batches of different radiopharmaceuticals with minimal customer installation and connection. . The cassette 400 is preferably provided in the form of a kit, where the conduit material and supported connectors and filters are all connected to a generator, vial, and one or more eluent sources for eluting nuclides according to the present invention. Is done. Desirably, the cassette 400 is provided to the user with each conduit already connected to its valve luer, so that only the free end needs to be engaged with the appropriate components. The cassette so provided may be assembled and packaged in a sterile state that maintains an appropriate level of sterilization for the pharmaceutical process when opened in an appropriate clean environment.

  Each connection in the valve described herein is made with a luer port defined by its luer connector. As shown in FIG. 8, the valve 3 'supports a filtered vent 451 at its luer connection. The valve 4 ′ is connected to the rinse fluid source 415 by an elongated conduit 452. A rinse fluid source 415 provides a rinse fluid to rinse the manifold 250 as desired during the elution process. The rinse fluid source 415 is preferably also connected in fluid communication with a filtered vent 433 to assist in draining the eluent through the conduit 452 toward the valve 4 ′. That is, while the present invention contemplates that cassette 400 can provide a single eluent source that elutes a generator as shown in FIGS. 5 and 8, respectively, in the embodiment of FIG. As shown in FIG. 1, each generator has its own eluent source provided in the form of an eluent vial 130. Providing each generator with its own eluent source 130 may be desirable to prevent the risk of overdiluting the eluate volume from a common reservoir. In addition, by providing each generator with its own associated elution source, a greater number of manifold valves 5'-14 'are available for connection to the generator. The air port on the manifold is used to extract excess or unused vacuum. The eluent channels 120 of generators 110a-d are each connected rearward to manifold 450 by elongated conduits 460a-d. Conduits 460a-d extend between the individual eluent channels 120 of generators 110a-d to valves 15'-18 '.

  Each of the valves 5'-14 'is covered by a luer joint that seals the luer port of each valve. Valves 5'-14 'are available to expand the cassette 400 to accommodate additional generators if the user desires.

  The valve 19 ′ is connected to the input port of the cation column 415 by an elongated conduit 462. The cation column 415 serves to remove competing ions from the eluate from the generator prior to concentration. The valve 20 ′ is connected to the output port of the cation column 415. The valve 21 ′ is connected to the inlet port of the concentration column 412 by an elongated conduit 465. Valve 22 ′ is connected to a second eluent source 416 by an elongated conduit 464. The second eluent source 416 supplies an eluent that elutes daughter nuclides from the concentration column 412. The second eluent source 416 is desirably also connected in fluid communication with a filtered vent 463 to assist in flowing the second eluent through the conduit 462 toward the valve 22 ′. Valve 24 'is connected to the output port of column 412 such that column 412 preferably connects directly to valve 24'.

  The connection to waste vials and collection vials will now be described. The valve 23 ′ is connected to the inlet port 472 of the waste vial 419 by an elongated conduit 470. The valve 25 ′ is connected to the inlet port 468 of the collection vial 418 by an elongated conduit 466. The valve 1 ′ is connected to the outlet port 478 of the collection vial 418 by an elongated conduit 476. The valve 2 ′ is connected to the outlet port 475 of the waste vial 415 by an elongated conduit 474.

  Next, sample elution will be described. An elution schedule that requires elution of radioactivity from generators 110b and 110d has been calculated. By applying a vacuum (ie, sufficiently low pressure) at port 26a, the first eluent is withdrawn from the first source vial 130 for generator 110b. Valves 1'-25 'are set such that the first eluent flows through generator 110b, through conduit 460b, to valves 16' and 19 '. Valve 19 ′ directs the eluate to flow through conduit 462 to the inlet port of cation column 415. The eluate is withdrawn from column 415 through valve 21 'and flows into elongated conduit 465 that enters the inlet port of concentration column 413. Waste continues to flow through column 412, through valve 24 ′ to valve 23 ′, and into waste vial 419. The volume of the waste vial 419 is sufficient to collect all of the liquid and thus deliver it from the column 412.

  Next, the stopcock of valve 16 'is rotated to isolate generator 110b and the stopcock of valve 18' is rotated so that the first eluent flows from vial 130 connected to generator 110d. The eluate from generator 110d is then directed through conduit 460d to valve 18 'and then to valve 19'. Valve 19 ′ directs the eluate to flow through conduit 462 to the inlet port of column 415. The eluate is withdrawn from column 415 through valve 21 ′ and flows into elongated conduit 465 that enters the inlet port of concentration column 412. Waste continues to flow through column 412, through valve 24 ′ to valve 23 ′, and into waste vial 419. In this way, daughter nuclides from generators 110b and 110d are collected in concentration column 412.

  To elute the daughter nuclide from the column 412, the valve 22 'directs the second eluent from the source 416 through the conduit 464 and the valve 22' to the valve 21 'with suction at the port 26a. Is set. The second eluent is withdrawn through conduit 465, through the inlet port of column 412, and through column 412. Upon exiting column 412 and entering valve 24 ′, column 412 eluate contains daughter nuclides that are distributed into collection vial 418. This eluate is directed into valve 25 'and through conduit 466 into vial 418, and suction from port 26a is applied through valve 1' and conduit 476. The vial 418 may then be removed or withdrawn to supply the daughter nuclide for further processing by the pharmacist. Thus, subsequent dispenses from the generator may be directed to the same collection vial, or the control system of the present invention will allow any remaining radioactivity to be dispensed from generators 110a-d to meet demand data requirements. May be combined with the unused eluate from the previous distribution in another way.

  Cassette 400 is formed attached to an actuation system that engages and sets the inorganicity of the valve stopcock and provides a low pressure suction or vacuum that draws fluid through the manifold and into the vial. The actuation system includes a rotatable arm that can engage each stopcock of valves 1'-25 'and position each in the desired orientation throughout the elution operation. The actuation system also includes a pair of cocks that engage one of the ports 26a and 27a, respectively, in a fluid tight connection to provide a low pressure or vacuum source for the manifold 450 in accordance with the present invention. Desirably, the manifold 450 can be attached to a FASTlab ™ (commercially available from GE Healthcare, Liege, BE) synthesis device that is programmed to operate a valve and apply a vacuum. Since the FASTlab synthesizer is already designed to operate in a hot cell environment, it is ideally adapted as an operating device for the cassette 400 and receives operating instructions from the control system 3 that operate according to the calculated elution schedule.

  In all embodiments of the cassette and manifold system of the present invention, including those detailed in FIGS. 5, 7, and 8, the cassette or manifold is desirably attachable to a FASTlab device. All liquid transfers are performed by the applied vacuum (or low pressure). It is envisioned that all connections to the manifold cassette are by standard luer locks. The conduit used to connect to the generator is preferably a silicone tubing that terminates in a septum that can be punctured with needles 125a and 129a at individual ports of generator 110. If the eluent vial 130 is attached to a generator, a standard connection may be used. Thus, the generator need not be modified to work with the present invention.

  In addition, in all embodiments, an external source of rinse fluid, such as water for injection (WFI), may also be connected to the manifold for cleaning and rinsing purposes. When eluting the gel generator, a WFI source may be connected to each generator and also act as the first eluent. As described more specifically with respect to FIG. 8, the present invention can be that the first eluent is from a reservoir or pre-measured container, or an “elution vial” individually connected to each generator. . A pre-measured source is desirable to prevent over-dilution of the eluate volume and to fully open an additional manifold valve for connection to the generator. The air port on the manifold is used to extract excess or unused vacuum.

  The present invention further provides that, in some embodiments, depending on the required elution chemistry, the first eluent source connected directly to the manifold (as shown in FIGS. 5 and 7) includes a generator and a concentration column. It may be used to elute both and consequently avoid the need to connect a second eluent source to the manifold. For example, if the system 300 of FIG. 7 uses an alumina generator and an alumina concentration column, the present invention may provide a first eluent source to supply saline used for both generator elution and concentration column elution. Think good.

A cation column is used to remove competing ions such as chloride from the eluate. In some embodiments, pertechnetate ions flow through the cation column and to the acidified alumina column where it is captured (concentrated). The liquid can flow through the column and into a waste collection container for later disposal. An acidified alumina column (as described above) is used to capture and concentrate pertechnetate ( ^99m Tc). While pertechnetate is captured on the alumina column, the liquid (essentially water) is removed from the bottom of the column by vacuum and collected in a waste container. Once the enrichment step is complete, the alumina column is preferably used in essentially the same way as current fission generators in order to remove saline pertechnetate as sodium pertechnetate [Na ^99m TcO ₄ −]. To be collected and collected in product collection vials.

  Referring to FIG. 9, the present invention uses demand and supply data to determine and implement the most efficient use of a set of parent-daughter generators in radiopharmaceutical operations. The feed data makes it possible to automatically calculate the amount of activity (daughter nuclide) available at any given time. Generators are sold with a known amount of radioactivity. Feed data can be obtained from generator barcodes or manual data entry. Demand data is the amount of radioactivity required at a particular time to satisfy a customer order. The data can be obtained from either an ERP software system, eg, SAP or Slimline (or equivalent) via electronic transfer, or manual input. In general, in a radiopharmaceutical environment, customer orders are separated into delivery steps scheduled at specific times of the day.

  The present invention compares the demand radioactivity requirement with the radioactivity available at any given time. In addition, the system attempts to configure the generator elution plan to deliver the best-fit solution that represents the best efficiency for elution from a given generator. Once the best-fit solution has been calculated, the operator a) executes the elution plan determined by the system, b) manually reconfigures the elution plan, the system calculates the effect and the operator Or c) by entering specific demand requirements and / or supply data and reviewing the calculated dissolution schedule determined by the system under the entered constraints. There are several options, such as modeling.

  When the operator confirms that the calculated elution plan is acceptable, the present invention sends data to the operating system to elute selected generators according to the elution schedule. All elution from the selected generator is passed through a cassette to concentrate, for example, Tc-99m onto an alumina column. When all generator elution is complete, the alumina column is eluted with the required amount of eluent, eg, saline (generally 5-6 mL). When this operation is complete, the control system updates the radioactivity data, recalculates nuclear growth, and updates the elution schedule with any necessary changes.

  In general, ERP systems are integrated computer-based applications that are used to manage internal and external resources, including tangible assets, financial resources, materials, and human resources. Its purpose is to facilitate the flow of information between all business functions within organizational boundaries and to manage connections to external stakeholders. Built on a centralized database, typically using a common computing platform, the ERP system integrates all business operations into a uniform enterprise-wide system environment. The ERP system can reside on a centralized server or can be distributed among modular hardware and software units that provide "services" and communicate over a local area network. The distribution design allows businesses to assemble modules from different vendors without having to place multiple copies of a complex and expensive computer system in an area that does not use their full capacity.

  Accordingly, the method of the present invention includes an input stage 610 that inputs supply data for each generator to the receiver of the elution system. The method then includes a second stage 620 of inputting demand data from a plurality of generators as to which radioactivity is needed and when to the receiver. A calculation and selection step 630 is then followed that determines an optimal elution schedule for each of the plurality of generators according to the input supply data and the input demand data. The calculation and selection stage 630 preferably compares the current demand for radioactivity, the future demand for radioactivity, and the radioactivity available from the generator at both the current and subsequent demand points or elution times, and the demand data In order to minimize the waste of daughter nuclides generated by the generator when satisfying, select which generator to elute and when. Next, there is an elution stage 670 for eluting daughter nuclides from the selected generator.

  Step 610 further includes step 612 for entering calibration data for each generator, typically the activity and date for each generator, step 614 for entering the date and time the generator is available, and the first elution is offset from the reference time. A step 616 of inputting the date and time of the date. Stages 612, 614, 616 may be performed by manually inputting information from each of these stages into the receiver, such information is typically provided by each generator. Alternatively, steps 612, 614, and 616 may be performed electronically or automatically by scanning such information from a bar code associated with each generator. Similarly, step 620 may be performed manually or electronically using demand data commonly supplied by ERP systems. When performing step 620 manually, the operator takes demand data information and inputs it to the receiver. Desirably, when demand data is entered manually, the receiver or control system compiles the information into a demand data set, but the operator may also compile before entering aggregate demand data. Alternatively, the ERP system may communicate electronically with the receiver so that individual orders are automatically entered into the system and an elution schedule is calculated.

  The present invention further contemplates that step 610 can include a step 618 of inputting a known data constant. Stage 618 may consider such data constants at stage 630. The data constants are preferably: As well as the expiration time of the generator.

  Stage 630 includes calculating 632 and displaying 634 the available radioactivity of each generator, preferably at fixed intervals such as 30 minutes. Preferably, the calculating step 632 uses equation (1), and the displaying step 634 displays the activity of each generator at the calculated interval. Further, step 630 may include performing a generalized gradient reduction algorithm analysis of the demand data and the activity levels of the plurality of generators to determine an optimal elution schedule to minimize waste. Alternatively, step 630 is conceived to simulate various elution schedules from multiple generators and select an elution schedule to minimize the waste of daughter nuclides when meeting demand data. In addition, the method desirably includes a step 638 of displaying demand data over the same interval as the supply data. Stage 630 further desirably selects which of the available generators to elute at a given time to meet demand data in the most efficient manner possible, resulting in a useful life for each generator. Step 638 to calculate the best-fit elution profile, i.e., schedule, to maximize waste and minimize waste. Next, the method may include a step 640 of providing an elution schedule to the operator.

  Desirably, the elution schedule is displayed in a graphical user interface (GUI) and the method has the option of overriding the calculated optimized elution schedule by instead scheduling different generators to elute at a given time. Is provided to the operator 642. If the operator declines to override the system, the method then proceeds to step 660 where an elution command is sent to the actuation system. If the operator chooses to override the elution instruction from step 638, the method further includes a step 644 in which the operator manually inputs a modification of the elution schedule. Step 644 allows the operator to select when to elute a particular generator. Next, the method displays 646 both the recalculation of the elution schedule and the availability of updated radioactivity over time for each generator, as well as the scheduled time of elution from each generator. Including. Step 646 desirably uses the same algorithm as step 630 to determine an optimal elution schedule given any additional operator constraints. Next, the method includes a step 650 of allowing the operator to accept the updated elution schedule. If the operator accepts the updated elution schedule, the elution schedule is set and the control system proceeds to step 660 where the operating system provides appropriate instructions for elution from the generator. If the operator does not accept the updated elution schedule, the method repeats steps 644, 646, and 648 until the operator accepts the elution schedule. Once the latest elution schedule is satisfactory for the operator, the method will move to step 660.

  After step 660, the actuation system performs step 670 and elutes the generator according to the elution schedule. Stages 642, 644, 646, 648, and 650 provide an “operator in the loop” option to monitor and manage elution from the generator, allowing the operator to override the calculated schedule To do. In either case, the present invention can operate without the need for operator intervention, thus allowing the author to perform a scheduled elution without having to enter the schedule once, thereby allowing the operator to You can pay attention to other pharmaceutical tasks. However, it may be desirable to have the operator accept the elution schedule at some point during the cycle.

  After eluting step 670, the method can include a step 672 of confirming that the selected generator has been eluted. In addition, the method is preferably best adapted to recalculate the ingrowth of activity 674, modify the activity data of step 632, and, if necessary, meet demand data. Recalculating the elution schedule, repeating step 638 below.

  The present invention further provides a computer program product for managing elution from a multi-generator elution system according to the present invention. The present invention further provides a multi-generator elution system including computer hardware for executing the computer program product of the present invention. The computer program product includes a computer usable medium having computer usable program code for performing the method of the present invention. The computer program code includes a computer usable medium having computer usable program code for managing a multi-generator elution system. The computer program product includes computer usable program code that receives input of supply data for multiple parent daughter generators and radioactivity demand data from the generator. The computer program is further selected among the generators to the operating system of the elution system according to the computer usable program code and the elution schedule to calculate the elution schedule of the generator based on the available radioactivity and demand data of the generator. Includes computer program code that commands to elute from the pool.

  The computer program product preferably further includes computer program code for displaying at least one of supply data, demand data, generator available radioactivity, and elution schedule. In addition, the computer program code that calculates the elution schedule also performs a generalized gradient reduction algorithm analysis of demand data and multiple generators' radioactivity levels to determine the optimal elution schedule that minimizes waste Contains program code. Alternatively, the computer program code that calculates the elution schedule can also simulate various elution schedules from multiple generators, select elution schedules, and minimize the waste of daughter nuclides when meeting demand data. Computer program code. The computer program product also preferably calculates a new elution schedule based on the new program constraints and computer program code that allows the operator to override the calculated elution schedule by entering new constraints on the computer program product. Computer program code. Furthermore, the computer program product is preferably a computer program that can serve for storing supply data, demand data, and elution schedules for later retrieval, and for the purpose of record keeping or assisting with record keeping. Contains code.

  FIG. 10 shows an example of a graphical user interface (GUI) screen of the present invention for supplying feed data information to the multi-generator elution system of the present invention. FIG. 10 shows a supply data input screen 700. Screen 700 shows a Microsoft Excel® screen showing the supply data for the six generators listed in row A, columns 6-11. Row B, columns 6-11 list the reference times for each generator. Row C, columns 6-11 list the first elution offset (in hours) for each listed generator. If there is no input, it is treated as a zero offset. Row D, columns 6-11 list the starting activity at the reference time for each generator. Row E, columns 6-11 list when each generator became available for use. As an error check for data entry, the reference time for row A must be at least 12 hours prior to the time available for use of row E. Row F, columns 6-11 show any error messages for each generator. Row E, columns 2-3 show the net efficiency of the generator, i.e. the elution yield efficiency, which is generally about 0.83.

  FIG. 11 shows an example screen of the GUI of the present invention that provides elution schedules calculated for the six generators of FIG. FIG. 11 shows an elution management window 800 that provides supply data, demand data, and elution schedules for a multi-generator elution system. This is a worksheet or best fit result of balancing efficiency with future radioactivity requirements based on demand. FIG. 11 shows an expansion of the relevant information in columns 46-69, representing July 11, 2010, 10:00 pm to July 12, 2010, 9:30 am, but the information in window 800 is the generator lifetime. Until it generally lasts 2 weeks and may be scrolled. Row A, columns 46-49 show the calculation and distribution interval times that occur over the time period shown. Time intervals are given at 30 minute intervals. Row D, columns 46-69 list the time at which distribution should occur according to demand data. The listed times allow for additional processing time required for post-elution where the user obtains the nuclide in the desired state. Thus, for example, row D shows elution performed on Monday, July 12, 2010 at 12:00 am, 2:00 am, 4:00 am, and 7:00 am. By scrolling further down the table to a hidden column, you can see demand and other information at a later time. Row E shows the residual left over from any previous elution that was not used, indicating decay over time. Rows F, P, Z, AJ, AT, and BD indicate when the elution of generators listed in column 1, rows G, Q, AA, AK, AU, and BE, respectively, is scheduled. The number “1” is entered in rows F, P, Z, AJ, AT, and BD at the time when radioactivity was eluted from the individual generators. As can be seen, for each eluted generator, the next column after elution shows much lower radioactivity, indicating that post-elution radionuclide growth is occurring.

  As shown in row D, column 50, there is a demand for radioactivity of 14,350 mCi at midnight (column 50). The control system best meets all known demands in row D, so generators 1 and 5 are eluted to meet this demand and provide 27 mCi of unused surplus that may be incorporated into later elutions. Calculating to do. Similarly, at 2:00 AM elution (row 54), 2405.5 mCi of radioactivity is eluted from generator 2 and 2405.5 mCi of radioactivity is generated from generator 3 to meet the demand for radioactivity of 15,931 mCi. Eluted, 120.5 mCi of radioactivity is eluted from generator 4 to provide 22 mCi of unused residue. The remaining radioactivity from the previous elution is also included in this elution, so in some cases the total current elution may not meet the listed demand as it is.

  The operator may override the provided elution schedule by removing “1” from the elution row and selecting another generator to elute. The control system recaptures the input in window 800 to indicate the new elution schedule and the available activity of each generator at each given time, the demand at each elution time, and any remaining activity remaining. . With the modeling function of the present invention, for example when a supply shock occurs, the present invention is particularly useful for assessing the impact of “hypothesis” scenarios and ultimately delivering the most dose for a given supply situation Can be. In either case, when the operator is satisfied with the elution schedule, it may be left to operate automatically as shown. If elution is performed automatically, the operator can pay attention to other tasks. In addition, the software provides a record of the elution performed, simplifying the purpose of record keeping. Further, while the feed data screen 700 and elution management window 800 track six generators, the present invention can be expanded in that it can monitor as many generators as are included in a multi-generator elution system.

  The present invention can bring cost savings to radiopharmaceuticals. The largest single cost of radiopharmaceuticals is the Tc-99m / Mo-99 generator used to construct a “cold kit” (diagnostic drug). Action workouts by experienced radiopharmacists have shown that the average pharmacy generator efficiency is 65-68%. After the implementation of new tools, the average efficiency has steadily increased to 98-100%. In general, the average pharmacy may consume four 18 Ci generators per week. Each generator has a useful shelf life of 2 weeks. Therefore, on a weekly basis, pharmacy needs to manage the collapse and use cycle of the eight generators. Currently, it costs $ 1.456 million each year, using four 18 Ci units at $ 7,000 per week. If the efficiency of the same pharmacy is improved from 65% to 100% by using the present invention, the annual cost is reduced by about $ 0.5 million.

  While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that changes and modifications may be made without departing from the teachings of the invention. The matter set forth in the foregoing description and accompanying drawings is offered by way of illustration only and not as a limitation. The actual scope of the invention is to be defined in the following claims when viewed in their proper perspective based on the prior art.

Claims (22)

Entering feed data into the elution system that includes information that allows calculation of the available radioactivity of the generator;
Inputting demand data into the elution system comprising at least the amount of radioactivity of the daughter nuclide produced and a schedule for producing the amount of the daughter nuclide;
Calculating and selecting an optimal elution schedule for each of the plurality of generators based on the demand data, minimizing waste of daughter isotopes generated by the plurality of generators when satisfying the demand data; Comprising comparing the available radioactivity at both the current demand , the future demand , and the current and subsequent demand time points to
Eluting the daughter nuclide from a selected one of the plurality of generators according to the optimal elution schedule;
A step of collecting the daughter from each of those said selected of said plurality of generators of enrichment column,
Eluting the daughter nuclide from the concentration column into a collection vessel. The eluting daughter nuclides from a plurality of parent-daughter generators according to claim 1, wherein the step of calculating and selecting further comprises performing a generalized gradient reduction algorithm analysis of the demand data and the radioactivity levels of the plurality of generators. Method. The step of calculating and selecting includes simulating various elution schedules from the plurality of generators, and selecting the elution schedule to minimize waste of the daughter nuclide when satisfying the demand data. The method of eluting daughter nuclides from a plurality of parent-daughter generators according to claim 1, further comprising: The method of eluting daughter nuclides from a plurality of parent-daughter generators according to claim 1, wherein the step of inputting demand data further comprises inputting the demand data to a receiving unit that supplies the demand data to the control system. . Said step of inputting the demand data, further comprising the step of manually entering the demand data to the receiving unit supplies the demand data to said control system, eluting daughters from a plurality of parent-daughter generators of claim 4, wherein how to. Wherein said step further comprises eluting the daughter nuclide from a plurality of parent-daughter generators of claim 4, wherein the step of electronically entered automatically to the receiver with the demand data for inputting demand data. 7. The step of eluting daughter nuclides from a plurality of parent-daughter generators according to claim 6, wherein said step of automatically and electronically inputting said demand data into a receiver further comprises receiving said demand data from a web-based order processing site. how to. 5. A method for eluting daughter nuclides from a plurality of parent daughter generators as claimed in claim 4, wherein the step of calculating and selecting is performed by a control system that receives the demand data from the receiver.   The step of inputting the supply data includes inputting the calibration data of each generator, inputting the date and time when each generator is available for use, and inputting the date and time when the first elution of each generator is offset And eluting daughter nuclides from the plurality of parent-daughter generators according to claim 1.   The steps of calculating and selecting include the half-life of the parent nuclide, the decay equation of the parent nuclide, the half-life of the daughter nuclide, the decay equation of the daughter nuclide, the elution yield efficiency, and the elution available for the decay of the parent nuclide. The method of eluting daughter nuclides from a plurality of parent-daughter generators according to claim 1, taking into account fractions, balance equations, and expiration times of each generator. Displaying the available radioactivity of each of the plurality of generators calculated against a time schedule;
Displaying the demand data in a table in the time schedule;
2. The method of eluting daughter nuclides from a plurality of parent daughter generators according to claim 1, further comprising the step of displaying a selected elution schedule profile from said step of calculating and selecting. Manually overriding the selected elution schedule profile;
And calculating the overriding elution schedule profile,
And displaying the previous Symbol override elution schedule profile,
12. The plurality of parent-daughters of claim 11, further comprising: allowing an operator to perform one of confirmation of the override elution schedule profile and manual override of the override elution schedule profile. A method for eluting daughter nuclides from a generator.   The daughter nuclide is eluted from a plurality of parent-daughter generators according to claim 12, wherein the step of manually overriding further comprises selecting which of the plurality of generators to elute at a time of the time schedule. Method.   The plurality of parent-daughters of claim 1, wherein the step of inputting feed data further comprises calculating a nuclear proliferation activity level of the selected one of the plurality of generators after the step of eluting. A method for eluting daughter nuclides from a generator.   The method of eluting daughter nuclides from a plurality of parent-daughter generators according to claim 1, wherein the steps of calculating and selecting and the step of eluting are performed by a control system.   16. The method of eluting daughter nuclides from a plurality of parent daughter generators according to claim 15, wherein the control system performs each of the steps of eluting according to the selected elution profile without further operator input. A computer program for managing elution from a multi-generator elution system, comprising a computer-usable medium having computer-usable program code for managing the multi-generator elution system, the input supply data of a number of parent-daughter generators A computer usable program code for receiving the radioactivity demand data from the generator, and the generator elution schedule based on the available radioactivity of the generator and the demand data. Computer operative program code to calculate and instruct the operating system of the elution system to elute from a selected one of the generators according to the elution schedule Computer program and a code, a computer program that. The computer program of claim 17, further comprising computer program code for displaying at least one of the supply data, the demand data, the available radioactivity of the generator, and the elution schedule. The computer program code for calculating an elution schedule performs a generalized gradient reduction algorithm analysis of the demand data and the radioactivity levels of the plurality of generators to determine an optimal elution schedule that minimizes waste The computer program according to claim 17, further comprising: The computer program code for calculating an elution schedule simulates various elution schedules from the plurality of generators, selects the elution schedule, and minimizes the waste of daughter nuclides when filling the demand data. The computer program of claim 17, further comprising computer program code.   Computer program code that allows an operator to override the calculated elution schedule by entering a new constraint for the computer program; and computer program code that calculates a new elution schedule based on the new constraint. The computer program according to claim 17, comprising: 18. The computer program product of claim 17, further comprising computer program code for storing the supply data, the demand data, and the elution schedule for later retrieval.