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

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Transition to InspectionsUSPlt823gt, 21 CFR 212,
And Beyond?

• Panel Discussion
• Ravi S. Harapanhalli, Ph.D
• Louis Marzella, MD
• Ravindra Kasliwal, Ph.D
• Wendy Sanhai, Ph.D.

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Topics

• PET Regulatory framework
• GMPs and FDAs jurisdictions
• Salient features of 21 CFR 212
• Questions and answers

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GMPs Simplified
If it is not documented, it does not exist!
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Quality Systems Approach to Inspections
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FDA Retains Authority to Inspect Research PET
drugs and INDs

• Although USP Chapter lt823gt, 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
  lt823gt or part 212.

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FDAs Regulatory Framework for PET
Radiopharmaceuticals

• Radiopharmaceutical INDs (21CFR312)
• Exploratory INDs, Traditional INDs
• cGMPs for INDs (USPlt823gt)
• 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

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GMPs for INDs and NDAs

• FDC 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 USPlt823gt

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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

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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

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Pre-release Endotoxin Testing Requirement

• USP lt823gt mandates it for radionuclides with t1/2
  gt 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.

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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

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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

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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

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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

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Critical Components of Process Capability
Centering and Spread
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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 gt 30 h?