Transcript Transition to Inspections: USP, 21 CFR 212, And Beyond?

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.
Topics
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PET Regulatory framework
GMPs and FDA’s jurisdictions
Salient features of 21 CFR 212
Questions and answers
GMPs Simplified
"Prove it"
"Improve it“
Continuous Improvement
Innovation
"Unable to prove"
Why?
"Do what you say"
"Corrective and Preventive
Actions"
"Say what you do"
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• Draft Guidance on the Content and Format of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 finishedproduct 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 finishedproduct 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 finishedproduct 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?