IBA Molecular N A FDG000001 Multi-Purpose Synthesis System User Manual
IBA Molecular N. A. Multi-Purpose Synthesis System
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![SYNTHERA ™ USER MANUAL FDG000130 11/17/2006 Rev.: 1 Pg. 55 of 60 An automated self-check process is initiated before synthesis. The self-check process verifies IFP™ configuration, plumbing integrity, and basic functionality of the processing unit (ex: pumping efficiency, heater operability and other elements that may adversely affect the process). The reaction scheme for the production of FDG is represented below: 95 50 oC+ NaOH Figure 20 The automated synthesis of FDG is a six-step process consisting of two chemical reactions: a nucleophilic [18F] fluorination followed by a base-catalyzed hydrolysis (modified Hamacher, et al., 1990). The first reaction incorporates the 18F-label into the organic precursor 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-b-D-mannopyranose, or mannose triflate. The mechanism for this reaction is an SN2 nucleophilic substitution of trifluoromethanesulfonyl group with [18F] IBA Molecular | Apr 06 Direction: MANXXXX © IBA/All Rights Reserved](https://usermanual.wiki/IBA-Molecular-N-A/FDG000001/User-Guide-730108-Page-55.png)
![SYNTHERA ™ USER MANUAL FDG000130 11/17/2006 Rev.: 1 Pg. 56 of 60 fluoride ion. The second reaction, the base-catalyzed hydrolysis of the acetyl protecting groups, generates the free hydroxyl groups of the final drug product. In addition to these reactions, the process includes a drying step, purification steps, and a product collection step. Step #1. The first step is extraction of [18F] fluoride ion from the aqueous mixture (target water) delivered from the cyclotron. To eliminate possible cationic, organic and insoluble in water impurities, this mixture is passed through a cartridge containing 30 mg of a anion exchange sorbent Accel Plus QMA Sep-Pak™ supplied by Waters Corp. [18F] fluoride ion is retained on the cartridge while all soluble cationic impurities as well as soluble in water non charged (organic) substances pass through the column into a waste water (H218O) collection vial. Target water is passed through the cartridge by means of vacuum applied to the collection vial. Retained on the resin [18F] fluoride ion is eluted with aqueous acetonitrile solution containing potassium carbonate and equimolar amount of Kryptofix™ 222. Solution is delivered from reagent vial #1 by means of vacuum applied to the reactor vial. This eluate containing typically 97-99% of initial activity in a form of potassium [18F] fluoride complex with Kryptofix™ 222 is collected in the reaction vessel. Step #2 takes place in the reactor vial. Solution from 18F collection vial is delivered into the reaction vessel by means of aspiration as described above. Under nitrogen or helium flow, the water/acetonitrile mixture is evaporated leaving potassium [18F] fluoride complex with Kryptofix 222. Temperature of reaction vessel increases from ambient to 95° C to facilitate evaporation. 2 min. before the end of evaporation step gas flow is stopped and vacuum is applied to the vessel to complete drying. Total duration of the evaporation step including vacuum drying of the residue is 12 min. Hydrogen-bonding solvents significantly lower the reactivity of [18F] fluoride ion. Therefore, it is essential that virtually all water be removed in this step. Water removal is not considered a chemical reaction, but is accomplished by applying a combination of heat and vacuum. Step #3 in the manufacturing process is the production of the [18F] fluorinated intermediate. This involves reaction of the K+/[18F] F-(anhydrous) prepared in Step #2 with mannose triflate in anhydrous acetonitrile which is added to the reaction vessel from reagent vial #2 by evacuating reactor vessel. The [18F] fluoride ion displaces the trifluoromethanesulfonyl, or triflate, leaving group on carbon-2 of mannose triflate, breaking a carbon-oxygen bond and creating a carbon-[18F] fluorine bond. This displacement occurs via the SN2 mechanism, which leads to complete inversion of stereochemistry at carbon-2 to give the glucose configuration. As a result of this inversion, no 2-deoxy-2-[18F] fluoro-D-mannose is produced by this synthesis. Labeling reaction takes place at 85° C. Duration of this step is 3 min. During this time, some mannose triflate either reacts with [18F] fluoride ion to produce the [18F] fluorinated intermediate (2-deoxy-2-[18F] fluoro-1,3,4,6-tetra-O-acetyl-b-D-glucopyranose), self-condenses to octa-O-acetyl-beta-sophorose (Engelskirchen, et al., 1989), or polymerizes (caramelizes). The octa-O-acetyl-beta-sophorose is converted back to glucose during Step #4 (vide infra) and the dark-colored sugar polymers are removed by adsorption onto the C-18 and Alumina purification cartridge at the final filtration (Step 6). Step #4. The next step is evaporation of the acetonitrile yielding a residue containing fluorinated intermediate. This is achieved by applying a combination of nitrogen flow and then vacuum to the reaction mixture. Temperature during this step is at 75° C. Duration of this step is 5 min. Step #5. This step is the base-catalyzed hydrolysis of the residue remaining in the vessel. Sodium Hydroxide solution in water containing ethanol as stabilizer is added to the reaction vessel from reagent vial #3 and the mixture is heated under flow of gas at 50°C (temperature of reaction mixture). This step removes the acetyl protecting groups from the [18F] fluorinated intermediate producing [18F] FDG and unreacted precursor producing L-Glucose. The acetyl groups are converted to acetic acid and the free hydroxyl groups of [18F] FDG generated by the addition of water across the ester linkage. Duration of this step is 4 min. IBA Molecular | Apr 06 Direction: MANXXXX © IBA/All Rights Reserved](https://usermanual.wiki/IBA-Molecular-N-A/FDG000001/User-Guide-730108-Page-56.png)
![SYNTHERA ™ USER MANUAL FDG000130 11/17/2006 Rev.: 1 Pg. 57 of 60 Step #6. The final step in the process, the purification and delivery of the final product, is accomplished by passing the hydrolyzed reaction mixture through several successive purification columns. First column contains Strong Cation Exchange resin (used to remove positively charged complex K+/Kryptofix 222 and neutralize sodium hydroxide and to remove any remaining ionic species. Attached to this column are basic Aluminum oxide cartridge Sep-Pak™ Plus B (to adsorb unreacted [18F] fluoride) and finally, C-18 bonded silica cartridge Sep-Pak™ C18 (to retain relatively non-polar species such as traces of unhydrolyzed [18F] fluorinated intermediate). Two portions of sterile water for injection (a total of 10.0 ml) from reagent vial #4 are then added to the reaction vessel and passed through the purification columns to recover as much product as possible. Eluates of the purification column are filtered through sterile 0.22-micron filter and combined in the final product container. If required, this container prior to synthesis may be charged with a 0.68 ml of 14.6% sodium chloride (inactive ingredient) to make the final solution isotonic. Transfer of the final product from the product collection container to final product container completes computer-controlled preparation. 8.1.5 Operator’s instructions Synthera ® system is designed to make operation as simple as possible. Although specific training and attention to details is essential, all manual operations are extremely simple and in many cases designed to prevent mistakes. To further simplify FDG processing the FDG IFP™ is supplied complete with reagent vials and cartridges. In some cases reagent vials and cartridges may be supplied in a separate packing to reduce refrigerated storage space needed. The following steps are required to produce FDG using Synthera ®: 8.1.5.1 Power on and start up Turn on inert gas supply to the unit; verify the pressure level is between 2 and 2.2 bar absolute. Turn on compressed air supply and check air pressure min 7 bar gauge. Turn on electrical power to the unit; switch is located on the bottom of control box. If PC is off or is not connected you will hear audible signal approximately every second indicating that the unit is functional but not communicating with PC. Turn on PC, log on to Windows and start control program Load FDG method and Check indicators on the screen (see Software section). Verify that IFP™ holder is in its neutral position and no IFP™ is installed. If not, press red button once to eject the IFP™. STAY CLEAR OF THE IFP™ HOLDER. Inspect fluid connectors and actuators, verify that they are undamaged. 8.1.5.2 Preparation Supplies and materials are described above. Prior to each synthesis these materials and supplies are gathered, checked and prepared as follows: 8.1.5.2.1 IFP™ Verify IFP™ IFP™ expiration date and labeling. Record IFP™ serial number into batch formulary as required Remove the IFP™ from packaging. Inspect IFP™ for any damage including missing or loose tubes, deformed connectors, misplaced valves etc. Verify that valves are in order (all present and turn easily by hand) IBA Molecular | Apr 06 Direction: MANXXXX © IBA/All Rights Reserved](https://usermanual.wiki/IBA-Molecular-N-A/FDG000001/User-Guide-730108-Page-57.png)
