FDG and its intended regulation by FDA in the USA: Points to Ponder

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: • Drug product component and quantitative composition • Controls for components/raw materials • Reference standards • Manufacturing and testing facilities • Manufacture of drug substance • Manufacture of drug product STOP

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

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

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

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

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

13. B. Controls for components and raw materials (contn) • Reagent, solvents, gases, columns, and other auxiliary • Name • Supplier • 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) • Other ingredients (may not apply) • Name • Purpose • Manufacturer • 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: • Name of these standards • Suppliers info • Specifications, COA, acceptance criteria STOP

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

17. E. Manufacture of drug substance • Batch formula: Name, function, and quantities of each component • Triflate; used as a precursor, 10 mg • F-18 fluoride, radioisotope, 100-2000mCi • 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) • Synthesis and purification of drug • Synthesis and purification equipment • Description of equipment, its components, acceptance criteria, flow diagram: an attachment • Synth and purifi. Unit: make and model • Synthesis and purification operation Step wise description, amount of reagents, solvents, acceptable yields: an attachment • 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) • Post synthesis procedures: • Set up of synthesis units, cartridges • Cleaning and purging procedures • Provided as an attachment STOP

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

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

22. H. Controls for finished dosage • 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) • 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) • Appearance • Radionuclide identity • Radiochemical identity • Radionuclide purity • Radiochemical purity • Radiochemical impurities • Assay (concentration) • Specific activity STOP

25. H. Controls for finished dosage (contn) • pH • K222 concentration • Residue solvents • Chloro-deoxy glucose • Membrane filter integrity • Bacterial endotoxins • Sterility STOP

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

27. J. Microbial validation • Includes procedures that ensure sterility • In manufacturing facility • Synthesis box and its components • Facility environmental controls • Clean room • Aseptic techniques • Final filtration • Finished product microbial testing STOP

28. K. Stability and batch data • Expiration dating period • Stability data (a curve) • 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. Medical Cyclotron 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 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. 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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