Sally W. Schwarz, MS, BCNP Director Clinical PET Radiopharmaceutical Production Washington University St. Louis Departme

1. Distributed Manufacturing via the SNM Multicenter FLT INDPart I SNM MidwinterClinical Trials NetworkAlbuquerque, New Mexico February 1, 2010 Sally W. Schwarz, MS, BCNP Director Clinical PET Radiopharmaceutical Production Washington University St. Louis Department of Radiology

2. US Food & Drug Administration Modernization Act (FDAMA) 1997 1997: US Food & Drug Modernization Act (FDAMA) required revisions to Current Good Manufacturing Practice (cGMP) for PET Radiopharmaceutical (RP) production FDAMA required a new approval path and separate Current Good Manufacturing Practices (cGMPs) for PET from cGMPs for drugs Prior to adoption of final PET cGMP rule, FDAMA requires PET Radiopharmaceutical (RP) production to follow: United States Pharmacopeia (USP) PET RP monographs, if available USP General Chapter <823> for Production of PET RPs USP subcommittee is in process of reviewing/revising

3. 21 CFR Part 212; Final Rule CGMP for PET December 10, 2009 • Regulation is effective December 12, 2011 • Submission of an NDA or an ANDA required for all FDA approved PET drugs no later than 2 years after the enactment date of the Final Rule • F-18 FDG, F-18 Fluoride, N-13 Ammonia

4. 21 CFR Part 212; Final Rule CGMP for PET December 10, 2009 The rule §212.5(b) provides that for investigational and research PET drugs, CGMP would be met by producing PET drugs in accordance with Part 212, or in accordance with USP General Chapter <823> “Radiopharmaceuticals for Positron Emission Tomography – Compounding,” May 1,2009, 32nd Edition. PET Drugs produced under Investigational New Drug Application (IND) in accordance with Part 312 of this chapter or PET Drugs approved through a Radioactive Drug Research Committee (RDRC) in accordance with Part 361 of this chapter

5. Overview USP Chapter <823> (32nd Edition) • Procedures/Process (<823> revision is planned) • Components, Materials and Supplies • Compounding Procedure Verification • Acceptance Criteria • Compounding Procedures • Computers & Automated Equipment Controls • Verification studies (3 consecutive runs) • Stability Testing & Expiration Dating • PET RaPh Compounding for Human Use • Quality Control • Sterilization & Sterility Assurance

6. Overview USP Chapter <823> (Revision?) • Personnel Qualifications • Responsible Person • Aseptic Training (current) • Control of Facilities & Equipment • Facilities (current) • Environmental Controls • Aseptic Hood • Compounding & QC Equipment • Control of Components, Materials and Supplies • Compounding Procedure Verification • Stability Testing and Expiration Dating • PET RPh Compounding for Human Use • Quality Control • Sterilization & Sterility Assurance • Reprocessing

7. FDA Audit Inspectional Observations (FDA-483) Inadequate training of personnel Failure to train personnel to perform assigned tasks No media fill testing performed

8. A. Personnel Qualifications (add) • Responsible person: designated, qualified & trained person shall be responsible for ensuring that compounding activities are carried out & properly completed by qualified & trained personnel • Aseptic Training (current) • Didactic training: pass written exam • Training in proper garbing & gloving • Documented visual observationaudits of garbing • Media-Fill Test Procedures • New preparer: Pass 3 separate Media-Fill Procedures • Annually for personnel who currently prepare (compound) PET RPh • Any time procedures are changed

9. Cleansing & Garbing • Dedicated shoes or shoe covers • Head covers • Face masks & eye protection • Hand cleansing procedure • Gowns with fitted sleeves (sleeve covers) • Sterile gloves (disinfect before entering, then periodically with sterile 70% IPA ) • Garb exposed in patient car e area can’t cross line of demarcation into compounding

10. Overview USP Chapter <823> (Revision?) • Personnel Qualifications • Responsible Person • Aseptic Training (current) • Control of Facilities & Equipment • Facilities (current) • Environmental Controls • Aseptic Hood • Compounding & QC Equipment • Control of Components, Materials and Supplies • Compounding Procedure Verification • Stability Testing and Expiration Dating • PET RPh Compounding for Human Use • Quality Control • Sterilization & Sterility Assurance • Reprocessing

11. FDA Audit Inspectional Observations (FDA-483) • Aseptic workstation is not suitable for aseptic operations • Use of non-sterile disinfectant to sanitize LAF • Frequency of environmental monitoring—does not reflect the volume of manufacturing operations • Weekly is not acceptable • Should “monitor” environment for each set-up of final product vial • Can assemble all final product vials for the day, and keep them in LAF

12. B. Control of Facilities and Equipment (current) • Facilities • Environmental Controls • Work area is clean • Aseptic hood located in low traffic area • Clean laboratory clothing worn • Aseptic techniques used • Disinfect final product septum with sterile 70% alcohol

13. B. Control of Facilities and Equipment 3. Aseptic Hood (LAF or Isolator) • PET RPh final product containers must be assembled in Class 100 environment (LFH or Isolator) • LFH internal surface is cleaned and disinfected with sterile disinfectant daily before and after use • Gloved hands are disinfected before entering hood

14. PET RaPh Final Product Vial AssemblyPerformed In Aseptic Hood • PET RaPh final product containers must be assembled in Class 100 environment (LFH or Isolator) • Gloved hands are disinfected before entering hood • Daily disinfection of surfaces before use • Microbiological Testing periodically e.g. weekly (per FDA, NOT monitoring) • Contact plate-surfaces • Settle plate/dynamic air sampler • Airborne, nonviable particle count • less often

15. FDA Audit Inspectional Observations (FDA-483) • Frequency of environmental monitoring—contact plates, touch plates • Weekly is not acceptable • Should “monitor” environment for each set-up of final product vial • Can assemble all final product vials for the day, and keep them in LAF • Use of non-sterile disinfectant to sanitize LAF • No media fill testing performed

16. B. Control of Facilities and Equipment (add) 3. Aseptic Hood (cont’d) d) Microbiological monitoring performed periodically • Contact plate-surfaces • Settle plate/dynamic air sampler • Airborne, nonviable particle count less frequently • Frequency of monitoring may be reduced once routine sterility of drug product is established e) Frequency: microbiological testing of the aseptic hood should be performed after each critical aseptic manipulation such as set-up of final product vial and after sterility inoculations

17. B. Control of Facilities and Equipment (add) 4. Compounding Equipment (current) • Equipment used to prepare PET drugs • Properly cleaned • May be processed to remove endotoxin • May be sterilized • Verification of sterilizer performance repeated periodically

18. C. Control of Components, Materials and Supplies • Establish written specifications • Identity, purity & quality of components • Appropriate storage • Log-in each lot of shipments of components; If no expiration date, must assign one. • Determine each batch of components in compliance with written specifications (procedures, tests, and/or certificates of analysis) • Store components in controlled access area according to established conditions.

19. D. Compounding Procedure Verification • Written acceptance criteria for identity, purity & quality of each PET drug (If USP monograph exists = minimum acceptance criteria) • Written procedures for compounding • Master file of Written compounding procedures (Outdated copies retained) • Incorporate 0.22 um for parenteral administration; 0.45 um for inhalation • Routinely updated at least annually • Verification Studies • Three consecutive runs are required initially & for any change having potential to alter identity quality or purity • Stability testing and expiration dating—meet acceptance criteria at expiry

20. E. Stability Testing & Expiration Dating

21. F. PET Radiopharamceutical (RPh) Compounding for Human Use • Inspect compounding area and equipment before use for cleanliness • Label final PET RaPh container prior to starting • PET drug name and lot number • Compound PET RaPh according to written, verified procedure with appropriate written batch record • Use appropriate components • Responsible individual initials—including each critical step • Raw analytical data • Signature & date of individual assuming overall responsibility

22. G. Quality Control • Written QC procedures • Verification of QC equipment and procedures used • System suitability testing (Chromatography <621>) must be confirmed on installation of QC equipment and after repair (HPLC, GC, analytic instruments) • Check correct operation on scheduled basis (system suitability) • Maintenance performed—written scheduled basis • Dose Calibrators: Perform applicable tests • Used to assay bulk radioactivity and dispensed dosages • Accept or reject PET drug • Investigate unacceptable QC tests results • Document outcome

23. Quality Control Requirements Pre-Release: • PET RaPh T1/2 ≥ 20 minutes (on Batch); T1/2 ≤ 20 minutes ( on QC Sub Batch) • Post-filtration integrity test of 0.22 m sterile filter (e.g. Bubble Test) • pH • Visual inspection • Radiochemical purity /identity *** • Radionuclidic identity • Specific activity • Residual solvent analysis, and other toxic chemicals • BET (20 min gel clot, or other recognized procedure) Post-Release: • Sterility • may inoculate test, within 24 h following preparation

24. Endosafe PTS® System • PTS® is a software-driven spectrophotometer for measuring and documenting endotoxin. • Unique cartridge containing dry, pre-calibrated reagents. • Each cartridge contains duplicate channels for analysis of sample and positive control. • PTS® is particularly suited for PET RaPh because test requires • ~17-20 minutes • Requires < 0.1 mL of diluted product • NO preparation of endotoxin standards.

25. FDA Audit Inspectional Observations (FDA-483) • Failure to audit procedures (SOPs) on regular basis & update SOPs • Found production equipment: • Not qualified • Not calibrated • Not properly maintained • Failure to investigate failed batch & deviations (should be in writing)

26. FDA Audit Inspectional Observations (FDA-483) • Lack of assurance that QC test results are reliable & accurate • QC equipment; • Not qualified • Not calibrated • Not maintained • No equipment suitability performed (USP Chapter <621>) • Inadequate reference standards used • Inadequate QA/QC oversight

27. H. Sterilization and Sterility Assurance • Compounding Equipment & Components • Equipment may be processed to remove endotoxin • May be sterilized • requires verification of sterilizer • Environmental Controls • Aseptic Hood • Aseptic Technique • Qualification of the Filtration Process • Microbiological Testing of Finished Products

28. Qualification of Filtration Process • Sterile Filters: • COC examined and maintained for each lot of filters • COA obtained from the company listing microbial retention challenge • Each lot of filters must be tested for integrity : Acceptance Criteria • After PET drug production, filter tested for integrity pre-release e.g. Bubble Point Test • The bubble point pressure is the pressure at which bubbles first appear from a submerged inlet tube in the receiving vessel. • Nitrogen gas flow increased until the bubbles appear (e.g. most filters must reach > 50 psi. * Nitrogen Gas * Pressure depends on the filter used

29. Microbiological Testing of Finished Product • Innoculated no later than 24 (30) hours after compounding • If sterility test fails, an investigation must be initiated to identify the cause

30. FDA Audit Inspectional Observations (FDA-483) • Lack of assurance that PET drug is sterile • No growth promotion testing of media performed • Must have validation data for hold time (eg. 24 hours); assure still have viable product • Inadequate incubation temperature control • Automatic sterility re-test without investigation

31. Class 100 (ISO Class 5)PET Dose Drawing Station • Chapter <823> supersedes Chapter <797> for PET RP compounding, but upon release of PET RP as finished drug product, further manipulation such as dispensing, contents of Chapter <797> apply. PET Dose Drawing Device In Class 100 Environment Shielded Dose Calibrator

32. Thank-you! schwarzs@wustl.edu