Abstract:
A method of producing multiple batches of a radiopharmaceutical, such as FDG. The method includes the steps of transferring the appropriate liquids to a production apparatus, processing the liquids to produce the radiopharmaceutical, delivering the radiopharmaceutical to a container, automatically cleaning the apparatus, and repeating the previous steps, as desired. The apparatus for multi-batch production of FDG includes a reagent delivery system, a reaction vessel, a filter assembly, and a control system. The combination of these components provides a method that is capable of producing multiple batches of a radiopharmaceutical with minimal operator intervention and, consequently, minimal radiation exposure.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This Application is a Divisional of U.S. application Ser. No. 09/795,744, filed Feb. 28, 2001, now abandoned, which is a Continuation-In-Part of U.S. application Ser. No. 09/569,780, filed on May 12, 2000, now U.S. Pat. No. 6,599,484. 
    
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
     Not Applicable 
     BACKGROUND OF THE INVENTION 
     1. Field of Invention 
     This invention relates to a reagent delivery system for use in the production of radiopharmaceuticals for positron emission tomography (PET). More specifically, it relates to a method of multi-batch production of  18 F-labeled glucose, known as fluorodeoxyglucose or “FDG.” 
     2. Description of the Related Art 
     Positron Emission Tomography is a powerful tool for diagnosing and treatment planning of many diseases wherein radiopharmaceuticals or radionuclides are injected into a patient to diagnose and assess the disease. For example, the radiopharmaceutical  18 F-labeled glucose, known as fluorodeoxyglucose or “FDG”, can be used to determine where normal glucose would be used in the brain. FDG is a labeled compound in which a fluorine-18 ion ( 18 F) is substituted for part of the glucose. FDG labeled in this manner is a desirable radiopharmaceutical because the fluorine-18 is a positron emission nuclide with a half-life period of 109.7 minutes. 
     The production of PET radiopharmaceuticals requires the use of various reagents and solutions to effect the necessary chemical conversions. The reagents and solutions must be delivered to a reaction vessel, where the conversions take place. The deliveries must be accurate, reproducible and, in addition, there must be minimal cross-contamination between the various reagents. A more detailed discussion of this type of delivery system is disclosed in the above-referenced patent application Ser. No. 09/569,780, filed on May 12, 2000. 
     Generally, the production of FDG includes the steps of bombarding a target material with a particle beam, mixing the target material with other materials, processing the resulting compound in a reaction vessel, and filtering the product. An accelerator produces radioisotopes by accelerating a particle beam and bombarding a target material, housed in a target system, with the particle beam. To produce FDG, the product of bombardment, fluorine-18 ions, is further processed to produce a substance suitable for injection into the human body. These ions are further processed to produce FDG (2-deoxy-2-fluoro-D-glucose) in a process typically referred to as radiosynthesis. 
     Well known in the art are various methods for producing FDG. For example, U.S. Pat. No. 4,794,178 issued to Coenen at al. on Dec. 27, 1988 discloses a process for labeling organic compounds with fluorine-18 through a nucleophilic substitution reaction. U.S. Pat. No. 5,169,942 issued to Johnson at al. on Dec. 8, 1992 discloses a method for making FDG that uses a phase-transfer reagent U.S. Pat. No. 5,932,178 issued to Yamazaki at al. on Aug. 3, 1999 discloses an FDG synthesizer that uses a labeling reaction resin column. Although these patents disclose various methods of FDG production, none of these patents teach a method that addresses the specific objects and advantages of the present invention. 
     Fluorine-18 is a radioactive material to which human exposure should be limited. Also, the particle beam striking the target material is a radioactive process, which should also have limited human exposure. Accordingly, the radiation exposure to persons producing the FDG is an important consideration. Toward this end, efforts have been made to automate the production of radioisotopes, in particular, FDG. 
     Automation of radionuclide and radiochemical syntheses is discussed in a paper entitled “Introduction: State of the Art in Automated Syntheses of Short-lived Radiopharmaceuticals” by Jeanne M. Link, John C. Clark, and Thomas J. Ruth, Targetry &#39;91, pp 174-185. At page 174, the paper discusses the advantages and disadvantages of the various levels of automation, including manual and remote operation, remote automated operation, and robotic operation. Specifically, the paper identifies the advantages of automation as a reduction of radiation exposure and a reduction of time to perform radiosynthesis. Furthermore, at page 183, the paper describes self-cleaning automated FDG systems. 
     Many commercially available components can be used to automate the production of FDG. Valves, tubing, and fittings are well known in the art and are well suited to this application. So too are membrane filters. Other components are specially designed for the process. See, for example, the reaction vessel disclosed in the above-referenced patent application Ser. No. 09/569,780, filed on May 12, 2000, and the related patent application Ser. No. 09/795,744 filed on Feb. 28, 2001 by Zigler, et al. 
     Although the prior art systems have proven successful for the production of FDG, there exists a need for further automation, including the capability of producing multiple batches of FDG with minimum operator intervention. Furthermore, to minimize operator intervention, multi-batch capability requires that the apparatus be self-cleaning and include automated testing of components, such as the membrane filters. 
     Therefore, it is an object of the present invention to provide an apparatus for performing multiple FDG production runs with a single set up. 
     It is another object of the present invention is to minimize radiation exposure to the apparatus operators. 
     It is yet another object of the present invention to provide an apparatus that is easy to handle and economic to use. 
     Another object of the present invention is to provide an apparatus that is self-cleaning. 
     Still another object of the present invention is to provide an apparatus which includes means for automating the pressure integrity test of the membrane filtration device used in final product sterilization. 
     BRIEF SUMMARY OF THE INVENTION 
     According to a preferred embodiment of the present invention, a method for multi-batch production of FDG is disclosed. The method includes the steps of selecting the reagents necessary for producing FDG, transferring said reagents to a reaction chamber, producing FDG, filtering the produced FDG, delivering the FDG to a container, cleaning the production apparatus, and repeating the previous steps to produce multiple batches of FDG. 
    
    
     
       BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 
       The above-mentioned features of the invention will become more clearly understood from the following detailed description of the invention read together with the drawings in which: 
         FIG. 1  is a block diagram of an apparatus for multi-batch production of FDG. 
         FIG. 2  is a pictorial view of the reagent carousel and linear actuator with two concentric needles. 
         FIG. 3  is a block diagram of the automated pressure integrity test for the membrane filtration device. 
         FIG. 4  illustrates a dual, parallel needle assembly used for liquid transfer. 
         FIG. 5  illustrates a concentric needle assembly used for liquid transfer. 
         FIG. 6  illustrates a close-up view of the concentric needle assembly used for liquid transfer. 
         FIG. 7  is a flow chart of the process for multi-batch production of FDG. 
         FIG. 8  is a flow chart of the process for the delivery of reagents and solvents to the FDG production system. 
         FIG. 9  is a flow chart of the process for the automatic pressure integrity test of the filter assembly. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       FIG. 1  illustrates a preferred embodiment of the present invention which comprises a reagent delivery system  10  for an automated apparatus for multi-batch production of FDG. The reagent delivery system  10  includes a rotary carousel  102 , a linear actuator  114  with needles  112 ,  132  used for liquid transfer, a plurality of liquid sensors  116 , an FDG production system  120 , a filter assembly  142 , and a control system  160 . The reagent delivery system  10  uses electronic mass flow controllers  134  and various valves, tubing, and fittings. 
       FIGS. 1 and 2  show the rotary carousel  102 , which holds a plurality of septum-sealed glass vials  104  containing the reagents and solvents used in the production process. A variety of reagents and solutions are necessary for the production of FDG. In addition, solvents are necessary for cleaning the apparatus between production runs. Vials  104  containing the necessary quantities of these reagents and solvents are placed in the rotary carousel  102 . The use of the rotating carousel  102  permits a single group of needles  112 ,  132  to be used to transfer these reagents and solvents. The rotary carousel  102  rotates on a pneumatically driven mechanism  106  that has positional feedback for the control system  160 . A spring loaded detent mechanism assures accurate positioning of the rotary carousel  102 . The control system  160  causes the pneumatical drive mechanism  106  to rotate the rotary carousel  102  so that the desired vials  104  are positioned under the needles  112 ,  132  used to transfer the liquid. Finally, the rotary carousel  102  is readily removable to allow access to the vials  104 . Those skilled in the art will recognize that an in-line vial holder having a linear transfer mechanism can be used without interfering with the objects and advantages of the present invention. 
     In the preferred embodiment, the rotary carousel  102  has two concentric rings of holes  202  in which the vials  104  are placed. Five vials  104   i  fit in the inside ring of holes  202   i , and ten vials  104   o  fit in the outside ring of holes  202   o . Vials with tight internal diameter tolerances are commercially available, such as those by Kimble Glass Inc. The vials  104  may be large volume (20 ml) or small volume (10 ml), and are securely mounted in the individual vial holes  202 . Also in the inside ring are smaller holes or slots placed between the openings for the vials  104   i . The purpose of these smaller holes or slots is to provide a place for the inside needles  112   i ,  132   i  to pass when the rotary carousel  102  is positioned so that only one outside vial  104  is being used. The reagent which is the target material is placed in the inside vials  104   i.    
     As illustrated in  FIG. 2 , the linear actuator  114  positions the needles  112 ,  132  vertically above either one or two vials  104  in the rotary carousel  102 . Separate sets of needles  112 ,  132  are used to access the vials  104  in the inner and outer rings of the rotary carousel  102 . Referring to  FIG. 2 , the linear actuator  114  includes a set of needles  112 ,  132  mounted on a head  216 , which mounts to a screw shaft  214 . When an electric motor  212  turns the shaft  214 , the needle head  216 , and consequently, the needles  112 ,  132 , move up or down to the desired vertical position. A belt driven rotating potentiometer is coupled to the screw shaft  214  to provide vertical position feedback for the needle head  216 . Power to the drive motor  212  and the feedback from the potentiometer are interfaced to the control system  160  to allow accurate positioning of the needles  112 ,  132 . Those skilled in the art will recognize that other mechanisms may be used for the linear actuator mechanism without interfering with the objects and advantages of the present invention. 
     The needles  112 ,  132  provide a gas inlet to the septum-sealed reagent vials  104  and a liquid outlet from the vials  104 . In the preferred embodiment, the needles  112 ,  132  are comprised of separate, concentric needles. In this embodiment, which is shown in  FIGS. 5 and 6 , gas enters the vial  104  through the annulus between the inner needle  112  and the outer needle  132 , and the increasing gas pressure in the vial  104  forces liquid through the inner needle  112 . The gas needle  132  is positioned higher than the liquid needle  112 , thereby avoiding the formation of bubbles near the inlet of the liquid needle  112 . In an alternative embodiment, shown in  FIG. 4 , separate, parallel needles are used for the gas inlet  132  and liquid outlet  112 . 
     Both needle embodiments deliver liquids with the required accuracy and reproducibility, but the concentric needle embodiment offers several advantages over the parallel needle embodiment. First, the concentric design allows for the use of a smaller gauge needle  112  for liquid delivery. This reduces the effect of sudden pressure changes and thus provides more control during the liquid delivery. Second, the increased structural integrity provided by the larger gas needle  132  dramatically reduces the possibility of bending the liquid needle  112 , even when the liquid needle  112  has a blunt tip (a blunt tip affords more accurate liquid deliveries than a slanted needle tip). The added strength eliminates the need for a needle guide or other means to prevent the bending of small gauge needles. Finally, a common problem encountered in repeated punctures of a septum  402  with a needle is “coring,” or the shredding of small pieces of the septum material with the needle annulus. The resulted pieces lodge in the needle and block the flow of gas or liquid. This problem especially holds for larger gauge needles. Since the smaller gauge needle forms a “pilot” hole for the larger gauge needle, the concentric needle design greatly reduces the incidence of septum coring. Thus, the concentric design simultaneously allows the use of a non-bending, small gauge liquid needle  112  (to better control liquid delivery) and a non-coring, large gauge gas needle  132  (to provide structural integrity). A more detailed discussion of the needle configuration is disclosed in a related patent application Ser. No. 09/795,214 filed on Feb. 28, 2001 by Zigler, et al. 
     The gas (for example, nitrogen, helium, argon, or other non-reactive gas) used to pressurize the reagent vials  104  is delivered to the needles  132  through electronic mass flow controllers  134 . The mass flow controllers  134  are commercially available devices that are interfaced to the control system  160  to allow remote gas flow set points and feedback. The mass flow controllers  134  control the gas flow to within less than 1 standard cm3/minute. 
     The liquid outlet needle  112  is connected to small-bore flexible tubing (for example, 1/16″ outside diameter Teflon or polyethylene tubing) to route the liquid during the transfer process. To ensure the successful transfer of liquid, the reagent delivery system  10  employs liquid sensors  116  that detect the presence of liquid in the tubing and supply this data to the control system  160 . The preferred embodiment uses a miniature ultrasonic transmitter and receiver affixed to the outside of the tubing, such as the commercially-available detectors manufactured by Introtek. When liquid is present in the tubing, the receiver generates a signal that is sent to the control system  160 . 
     The liquid sensor  116  allows an operator to fill the reagent vials  104  in the rotary carousel  102  with any volume of liquid, and then perform an “auto-detect” sequence to determine the quantity of liquid in the vials. Thus, a key feature of the reagent delivery system  10  is that the operator does not have to measure the volume of liquid, thereby facilitating the set up process. An important feature of the liquid sensors  116  is that they do not directly contact the liquid, which eliminates the possibility of reagent contamination and detector corrosion. 
       FIG. 1  also shows the FDG production system  120 , which includes the equipment and processes necessary to produce FDG. This equipment includes an accelerator, a target chamber, and a reaction vessel. The preferred embodiment uses the reaction vessel disclosed in the above-referenced patent application Ser. No. 09/569,780, filed on May 12, 2000, which contains a more detailed discussion of the equipment and the process. 
     Electronically controlled valves are used in the reagent delivery system  10  to route the flow of reagents and solvents throughout the automated apparatus for multi-batch production of FDG. Critical valves provide positional feedback to the control system  160  to ensure proper operation. The materials of construction for all the valves, tubing, and fittings are selected to minimize cross-contamination and dead space. These components are commercially available, for example, the valves are readily available through the Hamilton Company. 
       FIGS. 1 and 3  show the filter assembly  142 , which includes an automated pressure integrity test. The membrane filters  302  are commercially available devices designed for the removal of bacterial organisms from the product before it enters the final product vial  320 . In order to ensure complete removal of bacteria, it is necessary to maintain the integrity of the membrane filters  302  during the filtration process. Operators assure this by testing the integrity of the wetted membrane filters  302  after completing the filtration process. The two most commonly used integrity tests are the bubble point test and the pressure retention test. In the bubble point test, the wetted membrane filtration device is attached to a source of compressed gas and the pressure slowly increased until gas passes through the membrane (i.e., the outlet of the membrane filtration device “bubbles” when placed in water). In the pressure retention test, the pressure of the gas on the wetted membrane is set to a point just below the bubble point. After initial pressurization, the supply of gas is removed, and the pressure is monitored to determine if the membrane “holds” pressure. Both integrity test methods typically involve manual manipulation of the membrane filtration device and, since the membranes contain residual FDG, result in radiation exposure to the operator. 
     In the illustrated embodiment, an automatic pressure integrity test, based on the pressure retention method, reduces manual manipulation of the filter assembly  142 , thereby reducing radiation exposure to the operator. Referring to  FIG. 3 , the automated pressure integrity test components include a supply valve  306 , which isolates the nitrogen gas supply from the filter assembly  142 , a pressure sensor  308 , a 3-way stopcock or isolation valve  304  which isolates the membrane filters  302  from the pressure sensor  308 , and a vent valve  310  for exhausting the pressure after the test is completed. Referring to the flow chart in  FIG. 9 , the control system  160  opens the supply valve  306  and positions the isolation valve  304  such that one of the membrane filters  302  is pressurized with nitrogen or another gas. After the membrane filter  302  is pressurized, the control system  160  closes supply valve  306 , and the control system  160  monitors the pressure sensor  308 . After the testing period is completed, the pressure is vented by the control system  160  opening vent valve  310 , which exhausts into a waste collector. This test is repeated for the other membrane filter  302 . If both of the membrane filters  302  have no pressure loss over the time period tested, then the previous batch of FDG is deemed to have been properly filtered. Those skilled in the art will recognize that other plumbing arrangements for pressurizing and monitoring the filter assembly  142  may be used without interfering with the objects and advantages of the present invention. Another embodiment of the filter assembly  142  uses manual control of the filter assembly  142 . In the manual control embodiment, the operator monitors the pressure at the pressure sensor  308  and manually operates the valves as described above. 
     In the preferred embodiment, the control system  160  includes a personal computer communicating with a microcontroller which interfaces with the various components of the reagent delivery system  10 . The personal computer is running automation software by Intellution, Inc. Those skilled in the art will recognize that other means for controlling the reagent delivery system may be used without interfering with the objects and advantages of the present invention. For example, a dedicated controller with appropriate software may be used instead of the personal computer and microcontroller. 
     Referring to  FIGS. 7 and 8  for the operation of the invention, the operator places  700  vials  104  containing the proper quantities of reagents and solvents in the rotating carousel  102 . The operator then remotely operates the reagent delivery system  10  in order to produce multiple batches of FDG. The control system  160  determines which vials  104  the reagent delivery system  10  needs for its current operation  702 , for example, target exposure, FDG production, or cleaning, and the control system  160  causes the rotating carousel  102  to rotate so that the appropriate vials  104  are positioned under the needles  112 ,  132 . The control system  160  also aligns the various valves and mass flow controllers. The control system  160  then lowers  806  the needles  112 ,  132 , penetrating the septum seal of the vials  104 . After penetration, a controlled flow of gas exits needle  132  and the liquid sensors  116  monitor whether the needle  112  has reached the liquid surface in the vial  104 , as indicated by detecting liquid in the tubing  808 . The control system  160  determines the position of the linear actuator  114  corresponding to the liquid level in the vial  104 . The control system  160  causes the linear actuator  114  to descend into the liquid in the vial  104  to a depth corresponding to the liquid volume required for the current operation  812 ,  814 . Once that volume of liquid has been pushed through the needle  112 , the liquid level falls below the opening of the needle  112 , ensuring that only the predetermined volume of liquid has entered the reagent delivery system  10 . The reagent delivery system  10  control system  160  then determines whether another reagent is necessary for the current operation  706 ,  818 . If so, the control system  160  selects another vial  104  and repeats the above steps. 
     The reagent delivery system  10  uses a simple method to accurately and reproducibly dispense small quantities of reagents from the septum-sealed vials  104 . The volume of reagent in the vial  104  may be calculated  812  from the diameter of the vial and the height of the liquid within the vial. For example, if the diameter of a vial  104  is 2 cm and the height of the liquid is 1 cm, then the volume of the liquid is (πr2×h), or 3.14 cm3. Different volumes may be dispensed from the vial  104  by changing the depth of the needle  112  used to remove the liquid. 
     With this method of liquid dispensing, only two sources of error contribute to variation in the volume of delivered reagent: error in the diameter of the vial  104  and error in the vertical position of the needle  112 . The design of the reagent delivery system  10  minimizes the first source of error by specifying commercially-available vials with tight internal diameter tolerances, such as those sold by Kimble Glass Inc. The second source of error is minimized by accurately controlling the needle position with a linear actuator  114 . 
     After the processing equipment  120  has produced a batch of FDG  708 , the reagent delivery system  10  uses gas pressure to push the product  710  through the filter assembly  142  and into the final product vial  320 . The next step  712  is to verify the integrity of the filter assembly  142 . Referring to  FIG. 9 , after the product leaves the filter assembly  142 , the gas supply valve  306  is opened  900  and the isolation valve  304  is opened  902 . After one or both membrane filters are pressurized, the gas supply valve  306  is closed  908 . The pressure is then monitored  914  with pressure sensor  308 , and if the pressure falls, the final product  152  is rejected  916  and must be refiltered. If the pressure remains substantially the same  914 , the final product  152  is considered properly filtered. After the final pressure measurement, the vent valve  310  is opened  918 , the pressure is vented to a waste system, the vent valve  310  is closed, and the isolation valve  304  is closed  920 . The reagent delivery system  10  is then cleaned  716  by extracting the necessary solvents from the vials  104  and routing the solvents through the reagent delivery system  10 . 
     Referring to  FIG. 7 , the control system  160  then determines whether a sufficient volume of reagents and solvents remain on the rotary carousel  102  for another batch of FDG to be produced  722 . If so, the process repeats until the desired number of batches have been produced. If not, the control system  160  alerts the operator. 
     While a preferred embodiment has been shown and described, it will be understood that it is not intended to limit the disclosure, but rather it is intended to cover all modifications and alternate methods falling within the spirit and the scope of the invention as defined in the appended claims.