Sally W. Schwarz, MS, BCNP Director Clinical PET Radiopharmaceutical Production

1. Distributed Manufacturing via the SNM Multicenter FLT INDPart IISNM MidwinterClinical Trials NetworkAlbuquerque, New MexicoFebruary 2, 2010 Sally W. Schwarz, MS, BCNP Director Clinical PET Radiopharmaceutical Production Washington University St. Louis Department of Radiology

2. §212.10 Personnel and Resources: What personnel & resources must I have? • Sufficient personnel with necessary education.. • *Responsibilities & assigned duties clearly identified in written policies • *Small PET drug production—producing 1-2 batches of a PET drug daily or weekly—may employ 2 people for production and quality assurance (QA) • One individual can be designated to perform production and QA (highly qualified person) • Conventional drugs (Part 211) normally require second-person checks at various stages—for small PET drug operation, can perform documented self-checks *Guidance: PET Drugs—CGMP December 2009

3. §212.20 Quality Assurance: What activities must I perform to ensure drug quality? • Production operations: • ensure that each PET drug meets the requirements of the act (safety, identity & purity) • PET drug meets required quality & purity (b) Materials: examine & approve or reject components…in-process materials…finished dosage forms to ensure compliance with procedures specifications (c) Specifications & processes: approve or reject before implementation..specifications, methods, procedures (d) Production records: review production record to determine whether errors have occurred, investigate and take action (e) Quality assurance: establish & follow written QA procedures

4. § 212.30 Facilities and Equipment: What requirements must my facilities & equipment meet? (a) Facilities: adequate to ensure orderly handling, prevention of mix-ups & prevention of contamination (b) Equipment procedures: • Clean • Suitable for intended purpose • Properly installed, maintained & capable of producing valid results • Document activities (c) Equipment: not reactive, additive or absorptive to alter the PET drug

5. §212.40 Control of Components, Containers & Closures: How must I control components used for PET drug & containers , closures I package them in? • Written procedures • Written specifications • Examination & testing • Establish minimum standards for controlling components containers & closures. • If you conduct finished-product testing which ensures correct components have been used, may rely on COA from suppliers. Need justification why identity testing is not required. • Components be handled and stored to prevent contamination, mix-ups & deterioration • Keep a record of each shipment of components

6. § 212.50 Production & Process Controls: What production & process controls must I have? • Written control Procedures: document all key process parameters are controlled & deviations are justified • Master production & control records • Name and strength of PET drug • Name & amount of other active pharmaceutical ingredient (API) • Components • Identification of all major pieces of equipment used • Statement on minimum percentage yield allowed • Batch production & control record created for each new batch

7. § 212.60 Laboratory Controls: What requirements apply to laboratories where I test components, in-process materials & finished PET drug products? • Written procedures • Established specifications & standards • Analytic methods, sensitive, specific, accurate & reproducible • Equipment suitable for purpose, and • Complete record of all data e.g. a print-out of the chromatogram with calculated amounts of each component analyzed • Test results and relation to acceptance criteria • Initial or signature of analyst and date performed

8. § 212.61 Ensure Stability Through Expiry What must I do to ensure the stability of my PET drug products through expiry? • Establish written stability testing program • Program used to establish storage conditions and expiration time • *Parameters to evaluate: • Radiochemical identity & purity (including levels of radiochemical impurities • Appearance • pH • Stabilizer effectiveness • Chemical purity • * Perform stability testing at highest radioactive concentration • * Withdraw sample from the intended final container/closure *Guidance: PET Drugs—CGMP December 2009

9. Finished Product Testing *Guidance: PET Drugs—CGMP December 2009 *Noncritical attributes (perform periodic quality indicator test [PQIT]): perform on predetermined interval rather than every batch • Radionuclidic purity • Low-level nontoxic impurities • Class 3 residual solvents

10. § 212.70 Finished Product TestingConditional Final Release • If you cannot complete one or required finished-product tests for a batch of PET drug due to malfunction involving analytical equipment, you may approve conditional final release • Determine all acceptance criteria are met • Retain reserve sample • Promptly correct malfunction, & complete omitted test • May not approve if the malfunction involved performance of radiochemical identity/purity

11. § 212.71 If PET Drug Does Not Conform to Specifications? • Reject nonconforming product • Investigation • Correction of problem • Reprocessing

12. § 212.80 Packaging and Labeling: What are the requirements associated with labeling & packaging PET drug products? • Suitably packaged and labeled to protected from alteration, contamination and damage *1. Label to prevent mix-ups *2 . Due to Radiation exposure : label empty product vial prelabeled ( e.g. product name, batch number, date) *3. Outer shielded container labeled *4. Label identical to the container shield label can be incorporated into the batch production record

13. § 212.110 Records: How must I maintain records of my production of PET drugs? • Record availability: maintain at drug production facility or other accessible location to allow inspection by the FDA • Record quality: legible, stored to prevent deterioration, readily available for review & copying by FDA • Record retention period: 1-year from date of final release, or conditional final release

14. § 212.70 Finished Drug Product Controls & Acceptance: What controls & acceptance criteria must I have for my finished PET drug products? • Establish specifications for each PET drug • Establish & document Test Procedures accuracy, sensitivity, specificity & reproducibility • PET Drug conforms to specifications PET drug batch (sub-batch) may not be released until appropriate laboratory determination is compete (except sterility), is reviewed & approved by appropriate releasing authority • Sterility testing: innoculate within 30 hours post production Can exceed 30-hour requirement due to weekend, by demonstrating that the longer period does not affect the sample *Verification can be accomplished by innoculation of USP organism (e.g. E coli) and demonstrate no loss (little) in viability