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

Beyond?Panel Discussion

Ravi S. Harapanhalli, Ph.DLouis Marzella, MD

Ravindra Kasliwal, Ph.DWendy Sanhai, Ph.D.

Topics

• PET Regulatory framework

• GMPs and FDA’s jurisdictions

• Salient features of 21 CFR 212

• Questions and answers

GMPs Simplified

"Prove it"

"Say what you do"

"Do what you say"

"Improve it“

Continuous Improvement

Innovation

"Unable to prove"Why?

"Corrective and Preventive Actions"

If it is not documented, it does not exist!

Quality Systems Approach to Inspections

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.

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

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>

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12999-13010.• Draft Guidance on the Content and Format of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

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

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.

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

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

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

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

Critical Components of Process Capability: Centering and Spread

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?