[ 18 F]FALLYPRIDE FOR INJECTION: MASTER BATCH RECORD

Transcription

1 Approved by: Initials Date: Victor W. Pike, Ph.D Chief, PET Radiopharmaceutical Sciences, NIMH Batch # FAY- Date Hot-cell # 5, Automated Method 1. General notes: [ 18 F]Fallypride for Injection is prepared by an automated method with a GE TRACERlab FX FN module, through nucleophilic displacement of a tosylate leaving group by no-carrier-added [ 18 F]fluoride ion in dry acetonitrile. Endotoxin and sterility tests are performed on all samples. 2. Components: Cyclotron material: [ 18 F]fluoride ion production Item Reagent Specifications Manufacturer Lot # Quantity 1 [ 18 O]water 95 atom % Rotem Industries Others ml Reagents: [ 18 F]fluoride ion-kryptofix potassium carbonate solution Item Reagent Specifications Manufacturer Lot # Expiry Quantity date 1 Kryptofix Anhydrous Aldrich mg 98% 2 Potassium Anhydrous Aldrich mg carbonate 99.99% 3 Acetonitrile Anhydrous Aldrich 4 5 ml 99.8% 4 Water De-ionized MΩ; Millipore; 0.5 ml In house 5 Stock solution: Kryptofix potassium carbonate SOP # GP011 In house 80 ± 20 µl Document 2. [ 18 F]Fallypride for Injection: Master Batch Record Page 1 of 1

2 Reagents: production of [ 18 F]Fallypride for Injection Item Reagent Specifications Manufacturer Lot # Expiry date Quantity 1 Tosylate precursor > 95% ABX Advanced Biochemical Compounds 2.5 ± 0.5 mg 2 Acetonitrile Anhydrous Aldrich ml 99.8% 3 Acetonitrile HPLC grade Burdick & Jackson ~ 500 ml per 1 L of HPLC eluent 4 HPLC water HPLC grade EMD Science ~ 500 ml per 1 L of HPLC eluent 5 Fallypride SOP # GP103 In house 1 4 L preparative HPLC mobile phase 6 Fallypride SOP # GP103 In house 1 4 L analytical HPLC mobile phase 7 Stock sodium SOP # GP105 In house ml acetate buffer (0.25M; ph = 5.5) 8 Triethylamine (TEA) 99.5% Aldrich 0.6%TEA/L solvent (v/v) 9 Ammonium formate % Aldrich (Cat. # ) 5 mm 10 Ethanol, absolute USP Warner- 100 ml Graham 11 Sodium Chloride Injection, USP APP 9 ml Document 2. [ 18 F]Fallypride for Injection: Master Batch Record Page 2 of 2

3 Inert components: [ 18 F]Fallypride Item Component Specifications Manufacturer Lot # Expiry date Quantity 1 Preparative HPLC Luna (21.2 x 250 Phenomenex Serial # 1 column mm; 10 µm; 100 Å ) 2 Guard column Luna (21.2 x 50 mm; 10 µm; 100 Å) Phenomenex Serial # 1 3 Analytical HPLC Prodigy (4.6 x 250 Phenomenex Serial # 1 column mm; 5 µm) 4 C18 Sep-Pak Plus Waters 1 5 Sterile empty vial Sterile, nonpyrogenic APP 1 (10 or 30 ml) 6 Filter (Millex GV; Sterile, nonpyrogenic Millipore µm; 25 mm) 7 Filter (Millex GV Sterile, nonpyrogenic Millipore µm; 4 mm) 8 Syringe Luer, sterile Norm-Ject 1 (1 ml size) 9 Syringe Luer, sterile Norm-Ject 1 (10 ml size) 10 Needles 18 G x 31/2 B-D 3 11 Needle 20 G 11/2 B-D 1 12 Needles 18G11/2 B-D 5 13 Activated charcoal 4260AC Ommifit 4260ac As needed Radiosynthesis equipment Item Equipment Manufacturer Model Serial # Checked 1 Synthesis apparatus General Electric TRACERlab FX FN HPLC pump Beckman Coulter System Gold 126 solvent model UV absorbance detector Beckman Coulter System Gold 166 detector Radioactivity detector Bioscan Flow-Count Document 2. [ 18 F]Fallypride for Injection: Master Batch Record Page 3 of 3

4 Summary Records of [ 18 F]Fallypride for Injection - Work Sheet Reaction substances record Item Quantity Comments EOB (End of bombardment) Time: Starting radioactivity of [ 18 O]water-[ 18 F]fluoride ion mci at Volume of [ 18 O]water-[ 18 F]fluoride ion µl Stock Kryptofix potassium carbonate solution µl Tosyl-fallypride mg Acetonitrile µl TRACERlab FX FN Pressure performance record Item Initial During reaction Comments Compressed air pressure kpa kpa Nitrogen pressure kpa kpa Pressure of reactor kpa kpa Radioactivity record (mci at ) Item Reagent Radioactivity measurement 1 Cyclotron run # 2 Starting radioactivity at 3 Radioactivity in reactor of TRACERlab FX FN at 4 Radioactivity in final formula at 6 Overall yield of production Chemist Initials Batch # FAY- Date Date Document 2. [ 18 F]Fallypride for Injection: Master Batch Record Page 4 of 4

5 3. Pre-synthesis Procedures 1. Clean GE TRACERlab FX FN Module and Hot-Cell Follow the program "CLEAN BOX" (SOP # MP101). Clean and dry the GE TRACERlab FX FN module on the day of preparation or the day before. All the reagent vessels and transfer lines of the module should be washed with acetone and dried under nitrogen flush. 1.2 Inspect hot-cell compounding/dispensing area for cleanliness. Remove extraneous materials and labels. Spray ethanol to clean this area. 1.3 Inspect and set if necessary charcoal trap in the module 2. Prepare [ 18 F]fluoride ion-kryptofix potassium carbonate solution 2.1 Add stock solution of Kryptofix and potassium carbonate ( µl) to V-Vial (1 ml size). 2.2 Take V-Vial to the Cyclotron Facility (CC, NIH) to collect [ 18 F]fluoride ion in 18 O-water. The fluorine-18 radioactivity should be between 100 and 250 mci in the 18 O-water ( 500 µl). 3. Verify the integrity of the glassy carbon reaction vessel assembly (containing small magnetic bar stirrer) in the TRACERlab FX FN module. Follow SOP # MP202 and record the data in the sheet of Summary Records of [ 18 F]Fallypride for Injection run: 3.1. Check vacuum pressure (gauge, kpa) Check compressed air pressure (kpa) 3.3. Check nitrogen pressure (kpa) 4. Prepare the preparative HPLC System 4.1 Start the HPLC computer software, enter the necessary information and select the right method Fally_Production 4.2 Verify that mobile phase bottles are in the right position on the Beckman System Gold Delivery module The solvent bottle of 0.6% TEA connects to the B1 line (marked red) The solvent bottle of HPLC water connects to A1 line (marked red) The above connections should match the set-up in the method Fally_Production. 4.3 Set acetonitrile w 0.6%TEA /HPLC water (30: 70 v/v) as initial conditions. Equilibrate the Luna preparative column with preparative mobile phase at 2 ml/min. 4.4 Check the pump pressure while increasing the flow rate to 9 ml/min, then reduce to 2 ml/min if the pump pressure is satisfactory Pump the HPLC mobile phase through the preparative column at a low flow rate (1 2 ml/min) and maintain this until purification time. Document 2. [ 18 F]Fallypride for Injection: Master Batch Record Page 5 of 5

6 5. Prepare at the clean bench a Sterile Filtration/Collection Unit, using sterile technique: 5.1. Attach a membrane filter unit (GV; 25 mm; 0.2 µm) to a sterile disposable needle (18 guage) and insert it completely into a sterile, empty collection vial (10 ml or 30 ml size if needed) Attach a Chemovent needle or a combination of needle and syringe driven filter (4 mm) to the collection vial Attach a prepared label for [ 18 F]Fallypride for Injection with the current batch number and date. 6. Open the TRACERlab FX FN Computer Controlling System ("Admin" and "Tracerlab") and Select synthesis method: "Fallypride". Click Synthesis-Start to start preparation of the synthesis. 7. Enter all the needed information (including date, radiotracer, batch #, human preparation #) into the corresponding method of the HPLC computer software program. 8. Check that you have the correct UV absorbance wavelength (254 nm) and the correct settings for the gamma detector (diode/20k/2/rate). 9. Place the solvents and precursor solution in the corresponding module support vials: Support vial 1: acetonitrile (0.5 ml) Support vial 2: used as port (1 ml V-vial w 100 µl [ 18 F]fluoride ion-kryptofix potassium carbonate) Support vial 4: dry acetonitrile (0.7 1 ml) plus tosyl-fallypride (2 ± 0.5 mg). Support vial 5: dry acetonitrile (0.5 ml) Support vial 6: dry acetonitrile (1.5 ml) Support vial 7: sterile saline solution ( ml) Support vial 8: Ethanol for Injection (1 1.5 ml) Support vial 9 sterile water (8 ml) Large 10 ml V-vial 0.5 ml sterile water with 0.6%TEA. Large bulb vessel: HPLC water (90 ml) and sodium acetate solution (250 mm; ph 5.5; 10 ml; see SOP # GP105). 10. Check that the line for delivery of the complex goes through valve V2 and into the reactor vessel (glassy carbon). 11. Place acetonitrile (0.5 ml) in a syringe (3 ml size) connected to an external line going into the "complex" vial (for recovery of [ 18 F]fluoride ion-kryptofix potassium carbonate left in transportation vial and its addition to the reaction vessel). 12. Activate one C-18 Sep-Pak Plus with ethanol (10 ml) and then sterile water (10 ml) and place in its corresponding connection site in the module. 13. Place the small double-necked round bottom flask to receive the ethanolic eluted from the Sep- Document 2. [ 18 F]Fallypride for Injection: Master Batch Record Page 6 of 6

7 Pak in its corresponding location in the module. 14. In a lead pot place a sterile empty vial (30 ml size) fitted with a vent needle/filter and a second needle and Millev GV filter for sterilization of the final product. 15. Place enough dry-ice-acetone mixture in the vacuum trap. 16. Check that the nitrogen and compressed air valves close to the hot-cell are open (also check the nitrogen cylinder). 17. Assure that you have change syringes and needles and the used de-pyrogenated reaction vessel (with magnetic stirrer), HPLC collection bulb, 10 ml V-vial, Product vial, sterile 15 ml vial etc. 18. Get at hand a standard solution of fallypride for the validation of HPLC analysis system. 4. [ 18 F]Fallypride synthesis and purification 1. Preparation of [ 18 F]/K222/K 2 CO 3 complex (Kryptofix [ 18 F]fluoride-potassium carbonate) Using the dose calibrator (Biodex AtomLab 300) set at F-18, determine the amount of radioactivity that will be transferred to the clean glassy carbon reaction vessel (20 ml size). Record the data in the summary record sheet: EOB, starting radioactivity of [ 18 F]Fluoride and volume of [ 18 O]water Connect one vent needle, one needle and line from external syringe containing acetonitrile (0.5 ml) and one spinal needle and line going from the radioactive solution through V2 to reactor vial. Make sure that spinal needle is all the way down to the bottom of the radioactive solution. 2. Starting the preparation and transferring the [ 18 F]/K222/K 2 CO 3 complex. 2.1 Start the TRACERrLab automated software program. Select Synthesis: "Fallypride" in method box, click Synthesis-Start in main menu bar, follows process instructions. Organize "Instrument screen", "Program" and "Graphics" in the computer screen. 2.2 The program had already started turning the vacuum pump ON and transferring the [ 18 F]/K222/K 2 CO 3 complex from the V-vial (1 ml) into the reaction vessel; then MESSAGE BOX comes out. At this moment add acetonitrile (0.5 ml) from the outside syringe into the transport F-18 vial (pushing with air until the line is empty and the vial is full). Press Enter or click OK when done. 3. [ 18 F]Fallypride synthesis step 1: remove water from the [ 18 F]/K222/K 2 CO 3 complex 3.1 The reactor temperature will be increased first to 65 ºC and later to 88 ºC (T1 + 3 min) and then back to 60 ºC. At this point, the contents of V5 are added and the temperature cycle starts again: heat at 65ºC, then at 88ºC and finally at 60 ºC (drying process). Document 2. [ 18 F]Fallypride for Injection: Master Batch Record Page 7 of 7

8 4. [ 18 F]Fallypride synthesis step 2: [ 18 F]Fallypride reaction. Check V4 and reaction temperature. 4.1 Once drying is complete, V4 will open and the tosylate precursor in acetonitrile (1 ml will be added to the reaction vessel and the mixture heated at 105 ºC for 30 min. At the end of the reaction, the reaction vessel will be cooled to 35 ºC and the first part of the Program will finish. 4.2 A message will show saying "End of synthesis, Hit OK to continue to next Program". Hit CONTINUE. 5. Prepare Beckman HPLC system for purification. 5.1 Verify that the HPLC is in Preparative and in LOAD mode and that the detectors are in the right settings. 5.2 Check that method setting of Beckman HPLC instruments is correct. 5.3 Set the flow rate to 9 ml/min. Wait for pressure to go up. 5.4 Click Single run in Beckman HPLC software to start acquisition and wait the acquisition Box appears. 5.5 Check that the injector is in inject position 6. [ 18 F]Fallypride purification step 1: transferring the initial reaction mixture. 6.1 Second program continues purification process. The reaction mixture will be transferred to the V-vial (10 ml size) containing water with 0.6% TEA (0.5 ml) for pre-dilution before HPLC injection. 6.2 Check that the injector transfer needle in V-vial (10 ml) is far above the level of the solution. 6.3 Check that valve 6 will open and the acetonitrile (1.5 ml) is added to the reaction vessel. 7. [ 18 F]Fallypride purification step 2: loading and injection 7.1 After transferring, a message box will appear "System now ready to load Loop. Hit OK when completed". System will load the reaction mixture solution from T-vial (10 ml) into HPLC loop automatically. 7.2 At this moment, a new message box will appear System now ready to inject. Hit OK when the loading is completed. 7.3 Watch the T-vial (10 ml) closely. When the loading of solution is completed, hit OK. 7.4 At same time hit OK to start the HPLC run in Beckman software. 8. [ 18 F]Fallypride purification step 3: HPLC separation and product collection. 8.1 In GRAPHICS observe the UV and radioactivity traces on the data acquisition systems. 8.2 When the desired peak starts to come out, click on the collect arrow. Record the R t. as min. Document 2. [ 18 F]Fallypride for Injection: Master Batch Record Page 8 of 8

9 8.3 The mobile phase containing the product will be added to the bulb vessel containing sterile water for dilution (90 ml) and of sodium acetate buffer (10 ml) for dilution and neutralization. 8.4 At the end of collection click on the end collection arrow (the mobile phase will go into the waste reservoir). 5. [ 18 F]Fallypride for Injection Formulation 1. The program will continue and the diluted fraction will be passed through the solid phase cartridge (C-18 Sep-Pak) for concentration. This process is programmed for 6.5 min. 2. After passing through C-18 Sep-Pak, valve V9 will open and C-18 Sep-Pak will be washed with sterilized water. 3. After the water wash, V8 will open and the product will be eluted from the C-18 Sep-Pak with 1 ml ethanol into the two-necked round bottom flask. 4. Program will stop to allow sampling of the ethanolic solution. The message "Take QC sample and hit OK to proceed with filtration" will appear. Take sample for QC if needed. 5. The program can be continued hitting OK. Valve 7 will open and saline solution will be added to the round bottom flask containing [ 18 F]Fallypride for Injection through the 0.22 µm Millex filter for filtration and sterilization. 6. After filtering product, the program will complete. When the message reaction completed comes out, remove sterile filter and measure the radioactivity of the product vial, which contains the final [ 18 F]Fallypride for Injection. Radioactivity of [ 18 F]Fallypride for Injection: mci at. 7. Sampling for QC: The 1 cc sterile polypropylene syringe is used to withdraw a 1 ml sample of the formulated [ 18 F]Fallypride for Injection in a certified laminar flow sterile cabinet. The 1 ml sample is transferred to a sterilized depyrogenated tube labeled with the information final [ 18 F]FALLYPRIDE, batch number and the date. The vial is stored in a lead pig. This aliquot will be used for the following QC tests: radioconcentration, radiochemical purity, specific radioactivity, ph, residual solvents, and bacterial endotoxins (LAL test). Synthesis comments: Document 2. [ 18 F]Fallypride for Injection: Master Batch Record Page 9 of 9

10 The approved procedure has been followed without any deviation. Chemist Initials Batch # FAY- Date Date Document 2. [ 18 F]Fallypride for Injection: Master Batch Record Page 10 of 10