Transition to Inspections: USP<823>, 21 CFR 212, And Beyond? - PowerPoint PPT Presentation

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


A Science and Risk based Approach for Endotoxin Testing Good manufacturing history and GMP compliance Good record of endotoxin test results Before hot synthesis, ... – PowerPoint PPT presentation

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

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.

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

GMPs Simplified
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 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.

FDAs Regulatory Framework for PET
  • 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
  • Radionuclide production
  • Precursors and Final intermediates
  • Automated radiosynthesis units

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
  • 21 CFR 212 requirements
  • NDA and ANDAs for PET radiopharmaceuticals
  • Not for other radiopharmaceuticals
  • May be followed for INDs in lieu of USPlt823gt

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
  • Draft Guidance on the Content and Format of
    NDAs/ANDAs for Certain PET Drug Products
  • FR March 10, 2000 (Volume 65, Number 48), Pages
  • 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
  • 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 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.

A Science and Risk based Approach for Endotoxin
  • 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
  • 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
  • Frequency of testing will be determined during
    cGMP inspections
  • Can be handled and refined by internal quality

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 gt 30 h?
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