Transition to Inspections: USP<823>, 21 CFR 212, And Beyond?

1. Transition to Inspections:USP<823>, 21 CFR 212, And Beyond? Panel Discussion Ravi S. Harapanhalli, Ph.D Louis Marzella, MD Ravindra Kasliwal, Ph.D Wendy Sanhai, Ph.D.

2. Topics • PET Regulatory framework • GMPs and FDA’s jurisdictions • Salient features of 21 CFR 212 • Questions and answers

3. "Prove it" "Improve it“ Continuous Improvement Innovation "Unable to prove" Why? "Corrective and Preventive Actions" "Do what you say" "Say what you do" GMPs Simplified If it is not documented, it does not exist!

4. Quality Systems Approach to Inspections

5. FDA Retains Authority to Inspect Research PET drugs and INDs • Although USP Chapter <823>, rather than part 212, constitutes the minimum CGMP requirements for investigational and research PET drugs, FDA retains the authority to inspect facilities where investigational and research PET drugs are produced to verify compliance with either Chapter <823> or part 212.

6. FDA’s Regulatory Framework for PET Radiopharmaceuticals • Radiopharmaceutical INDs (21CFR312) • Exploratory INDs, Traditional INDs • cGMPs for INDs (USP<823>) • RDRC imaging studies (21CFR361) • PET Radiopharmaceutical NDAs (21CFR314) • Predetermined to be safe and effective • FDG F 18 Injection, Ammonia N 13 Injection, • Sodium Fluoride F 18 Injection • Novel PET agents • PET cGMPs for NDAs/ANDAs (21CFR212) • PET Radiopharmaceutical Drug Master Files (21CFR 314.420) • Radionuclide production • Precursors and Final intermediates • Automated radiosynthesis units

7. GMPs for INDs and NDAs • FD&C Act 501(a)(2)(B): • cGMP requirement for all drugs [including INDs] • Incremental approach during IND stages • Enforcement discretion • 21 CFR 210/211 requirements • Commercial manufacture • Phase 2/3 drugs • Not for Phase 1 INDs (Phase 1 IND guidace to be followed) • 21 CFR 212 requirements • NDA and ANDAs for PET radiopharmaceuticals • Not for other radiopharmaceuticals • May be followed for INDs in lieu of USP<823>

8. Guidance on PET Drug Product Submissions • PET Drug Products: Safety and Effectiveness of Certain PET Drugs for Specific Indications • FR: March 10, 2000 (Volume 65, Number 48)], Pages 12999-13010. • DraftGuidance on the Content and Format of NDAs/ANDAs for Certain PET Drug Products • FR: March 10, 2000 (Volume 65, Number 48), Pages 13010-13012. • FDG F 18 Injection, Ammonia N 13 Injection • Sodium Fluoride F 18 Injection • CMC section for the three radiopharmaceuticals may be formatted as described in the draft sample formats. • Other new PET drugs should follow the ICH Common Technical Document (CTD) format

9. Clarity provided in the Final PET Rule • § 212.70(f) – Conditional final release • Conditional release due to equipment breakdown or malfunction? Yes • Include problems related to but not specifically due to actual equipment breakdowns? May be • delete the notification requirements? No • any circumstance under which conditional release would not be permitted even if the release criteria were met? E.g. radiochemical ID, RCP, specific activity? No • § 212.70(e): Sterility testing • Can justify a post-manufacture wait time beyond 24-30 h? Yes

10. Pre-release Endotoxin Testing Requirement • USP <823> mandates it for radionuclides with t1/2> 20.0 • May be difficult for certain C 11 PET drugs. • Requiring a rapid endotoxin testing (20 min test) from kits currently made by only one company may not be appropriate • 212 Requirements: • The product can be distributed under control after a pharmacopeial bacterial endotoxin test is initiated. However, the endotoxin results should meet the acceptance criteria before administering the product to humans.

11. A Science and Risk based Approach for Endotoxin Testing • Good manufacturing history and GMP compliance • Good record of endotoxin test results • Before hot synthesis, a cold synthesis run with endotoxin monitoring to confirm acceptable endotoxin levels in the product. • A commitment to initiate endotoxin testing as soon as practicable and to convey the results of the testing to the physicians on a real-time basis (but before patient administration??) • A requirement in place to retain the patients until the endotoxin results are obtained. • A safety monitoring provision in the clinical study protocol for any endotoxin-related events

12. Final release of PET Product (§ 212.70(c) ) and Appropriate Laboratory Determination • An appropriate laboratory determination is required to ensure that each batch of a PET drug product conforms to specifications, • Is a finished-product testing of each batch a must? Not if …. • Alternative validated QbD and PAT-based criteria are used in lieu of end testing • In-process testing of an attribute that is equivalent to finished-product testing of that attribute • Continuous process monitoring of attributes with statistical process controls and ability to adjust the process • Some combination of these approaches

13. Handling Non-critical Quality Attributes • Radionuclidic purity if potential radionuclidic impurities have a low risk of impacting safety and/or effectiveness • Certain low-level nontoxic impurities • Class 3 residual solvents • Periodic Quality Indicator Tests permitted • Formerly called as skip-lot testing • Contingent upon use of a process that is under a state of control • Testing in addition to specification testing • Method and limits should be established in an application • Frequency of testing will be determined during cGMP inspections • Can be handled and refined by internal quality systems

14. Significance of Process Verification • Section 212.50(f)(1): PET drug production in which every batch undergoes full finished-product testing, process verification is not required. • Section 212.50(f)(2) requires process verification when • the results of the production of an entire batch of a PET drug are not fully verified through finished-product testing • only the initial sub-batch in a series is tested • E.g. N-13 ammonia, alternative laboratory determinations, PQIT

15. Critical Components of Process Capability: Centering and Spread

16. Some Questions • 212 says that final product vial assembly and sterility testing should be done under Class 100 area. Should the PET dose drawings from finished product vial be done under Class 100 hood? • What if radiation dose inhibits microbial growth when spiked drug product is kept for > 30 h?