1. FDG and its intended regulation by FDA in the USA: Points to Ponder Pradeep K. Garg, Ph.D. Director, PET Center Wake Forest University Health Sciences Winston Salem, NC; USA STOP

2. PET Center Three major domains:  Radiopharmaceutical area: Chemist  Imaging and data acquisition: Technologist  Reading scans and reporting: Physician STOP

3. Radiopharmaceuticals Among several choices: FDG is widely accepted and dominates the market share STOP

4. FDG regulations In US:  Expectation is to be compliant with cGMP  FDA requiring CMC  FDA differentiates between small and large manufacturers STOP

5. cGMP current Good Manufacturing Practices Broad coverage, covers four major areas  Safety  Purity  Strength  Quality STOP

6. CMC: The full form Chemistry, Manufacturing, and Controls Section STOP

7. CMC CMC covers following points: CMC covers following points: A. Drug product component and quantitative composition B. Controls for components/raw materials C. Reference standards D. Manufacturing and testing facilities E. Manufacture of drug substance F. Manufacture of drug product STOP

8. CMC (contn..) G. Containers/closures H. Controls for the finished dosage form I. Analytical test procedures J. Microbial Validation K. Stability and Batch Records L. Vials and outer packaging labels STOP

9. A. Drug product component and quantitative composition 1. Drug substance: i. Name/description: 2-Deoxy-2[ 18 F]fluoro D- glucose, FDG. ii. Composition/mL: 10-20mCi at 9:30AM (EOS) iii. Composition/batch: 100-250mCi at 9:30AM (ESO) 2. Other ingredients: i. Name/description: Sodium chloride injection, USP ii. Composition/mL: 1 mL iii. Composition/batch: 10-12 mL STOP

10. B.Controls for components / raw materials 1. Organic substrates: 2. Target material (radioactive fluoride) 3. Other ingredients 4. Reagent STOP

11. B.Controls for components and raw materials (contn) 1. Organic substrates: i.Component name: 1,3,4,6-Tetrafluoro methanesulfonyl-D-mannopyranose (triflate) ii.Supplier: Name and address iii.Is this further purified: yes/no, if yes, how? iv.Acceptance specs: Tests and criteria i.Appearance, Identity (nmr, ir), Purity (mp hplc). v. v.COA vi. vi.Identity test: test procedure and criteria in SOP vii. vii.Storage condition: refrigerator, room temp, dry glove box,.. STOP

12. B.Controls for components and raw materials (contn) 2. Target Material (O-18 water): i.Name of Material ii.Manufacturer/supplier iii.Specifications iv.Identity test to release lot: as attachment v.COA vi.Recycled: yes/no, if yes: i.Procedure as attachment ii.Acceptance specs vii.*If F-18 purchased: supply all this info on it STOP

13. B. Controls for components and raw materials (contn) 3. Reagent, solvents, gases, columns, and other auxiliary i. Name ii. Supplier iii. Grade, quality, COA, and acceptance criteria The above info is needed for all materials used in the manufacturing STOP

14. B. Controls for components and raw materials (contn) 4. Other ingredients (may not apply) i. Name ii. Purpose iii. Manufacturer iv. Specifications STOP

15. C. Reference standards Items:  2-Fluoro-2deoxy-D-glucose  2-Chloro-2deoxy-D-glucose  Kryptofix 222 On each of these items, supply: i. Name of these standards ii. Suppliers info iii. Specifications, COA, acceptance criteria STOP

16. D.Manufacturing and testing facilities 1. Name of PET facility and address 2. Contact person name 3. Contact person phone number STOP

17. E. Manufacture of drug substance 1. Batch formula: Name, function, and quantities of each component i. Triflate; used as a precursor, 10 mg ii. F-18 fluoride, radioisotope, 100-2000mCi 2. Radionuclide production  F-18 produced at site? Yes/no ; if yes:  Cyclotron  make and model, operating parameters, specifications on target body (volume, material, windows info, acceptance criteria on windows and body…) STOP

18. E. Manufacture of drug substance (contn) 3. Synthesis and purification of drug i.Synthesis and purification equipment  Description of equipment, its components, acceptance criteria, flow diagram: an attachment  Synth and purifi. Unit: make and model ii.Synthesis and purification operation Step wise description, amount of reagents, solvents, acceptable yields: an attachment iii.In process control Number of azeotropic evaps, temp for heating precursor, delivery rates, pressure for air and gases, hydrolysis temp, time for each steps, etc: a master production and control record section STOP

19. E. Manufacture of drug substance (contn) 4. Post synthesis procedures: i. Set up of synthesis units, cartridges ii. Cleaning and purging procedures iii. Provided as an attachment STOP

20. F. Manufacture of drug products 1. Production operation General procedures provided as an attachment Master production and traceable control records provided as an attachment 2. Reprocessing of drug product  Yes/no, if yes, circumstances (Attachment) 3. Packaging and labeling  Detail descriptions as an attachment STOP

21. G. Containers and closures 1. Using USP Type 1 glass, grey butyl stopper, and aluminum crimp seal i. Manufacturer name and address ii. Catalog number and description iii. DMF # (attachment #) STOP

22. H. Controls for finished dosage 1. Sampling procedure  Produced as multidose or aliquot in multiple vials  If multi-vials, sampling procedure to assure unbiased representation STOP

23. H. Controls for finished dosage (contn) 2. Regulatory specs, procedures and testing schedules  Provide:  Test, acceptance criteria, procedure, and test schedule Each batch should meet these criteria during entire shelf life STOP

24. H. Controls for finished dosage (contn) Regulatory specs (itemized) 1. Appearance 2. Radionuclide identity 3. Radiochemical identity 4. Radionuclide purity 5. Radiochemical purity 6. Radiochemical impurities 7. Assay (concentration) 8. Specific activity STOP

25. H. Controls for finished dosage (contn) 9. pH 10. K222 concentration 11. Residue solvents 12. Chloro-deoxy glucose 13. Membrane filter integrity 14. Bacterial endotoxins 15. Sterility STOP

26. I. Description of Analytical test procedures 1. For each (major) tests described, provide:  Test, STP #, Attachment #, Page number STOP

27. J. Microbial validation 1. Includes procedures that ensure sterility i. In manufacturing facility ii. Synthesis box and its components iii. Facility environmental controls iv. Clean room v. Aseptic techniques vi. Final filtration vii. Finished product microbial testing STOP

28. K. Stability and batch data 1. Expiration dating period 2. Stability data (a curve) 3. Post approval commitment  Annually, minimally one batch tested for the following tests  List these tests STOP

29. L. Vials and outer label  Copies of proposed vial description and outer packaging and label  As an attachment STOP

30. PET Center  Scanner  Cyclotron  Chemistry Laboratories  Radiopharmacy  Offices  Personnel STOP

31. Scanner Several options, but does not necessarily affects our task at hand:  CTI-Siemens HR+  GE Advance  CTI CT/PET  GE CT/PET  Philips PET and CT/PET STOP

32. Cyclotron Is an important factor in preparing this document Several to choose from:  CTI RDS 111; 11 MeV  GE 10MeV or 18.5 MeV  IBA (various)  Others… STOP

33. Are deutrons as common and important? Acceleration Capability Particle + v/s –ve ions Single particle (Protons) v/s dual particles (proton & deuteron) Energy Nuclear Reaction Target Material and Design Medical Cyclotron STOP

34. Isotope Production Issues may not be pertinent to FDG book, but would impact on what document we prepare  Small Medical Cyclotron (<15 MeV)  C-11  N-13  O-15  F-18  Large Cyclotron (>15 MeV)  Br-75, Br-76  Ga-68  I-122 STOP

35. Cyclotron Target Yields These factors would influence the details for the document  Dependent on: 1. Nuclear Reaction 2. Target Design Physical (silver, tantalum, HP, LP, HV) STOP

36. Radiochemistry Laboratories  Hot Cells  Fume Hoods  Laminar flow Hood  HPLC  GC  Synthesis Modules  Dose drawing station STOP

37. 18 F Chemistry Process Control Modules  Issues:document should apply to all modules  Choice of module  CTI CPCU  GE  Coincidence  Choice of chemistries  Acid v/s base hydrolysis  Single v/s two pot synthesis STOP

38. Other Issues We may want to emphasize on radiation safety factor as guidance (FDA does not cover it)  Radiation Exposure from 1 mCi unshielded  General Nuclear Medicine clinic  0.02 – 0.22 mR/h at 1 meter  PET clinic  0.58 mR/h at 1 meter (5.8 R/h at 1 cm)  Patient handling STOP

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