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Overview of USP Chapter

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Overview of USP Chapter Overview of USP Chapter Presentation Transcript

  • Overview of USP Chapter <823> for IND and RDRC Regulated PET Compounding Distributed Manufacturing of PET Radiopharmaceuticals for Multi-Center Clinical Trials Society of Nuclear Medicine Webinar July 28, 2009 Sally W. Schwarz, MS, BCNP Director Clinical PET Radiopharmaceutical Production Washington University St. Louis Department of Radiology
  • US Food & Drug Administration Modernization Act (FDAMA) 1997
    • 1997: US Food & Drug Modernization Act (FDAMA) required revisions to Current Good Manufacturing Practice (cGMP) for PET Radiopharmaceutical (RP) production
    • FDAMA required a new approval path and separate Current Good Manufacturing Practices (cGMPs) for PET from cGMPs for drugs
    • Prior to adoption of final PET cGMP rule, FDAMA requires PET Radiopharmaceutical (RP) production to follow:
      • United States Pharmacopeia (USP) PET RP monographs, if available
      • USP General Chapter <823> for Production of PET RPs
        • USP subcommittee being formed to review
      • 2005: PET CGMP Proposed Rule & Guidance published
      • 2009: Still waiting for final rule
  • Proposed Rule cGMP for PET September 20, 2005
    • The proposed §212.5(b) provides that for investigational and research PET drugs, cGMP would be met by producing PET drugs in accordance with USP General Chapter <823> “ Radiopharmaceuticals for Positron Emission Tomography – Compounding ”.
      • PET Drugs produced under Investigational New Drug Application (IND) (this would apply to Phase 1 and 2) or
      • PET Drugs approved through a Radioactive Drug Research Committee (RDRC)
  • Overview USP Chapter <823>
    • Procedures/Process (Current Chapter 823; revision is planned)
      • Components, Materials and Supplies
      • Written Procedures
          • Acceptance Criteria
        • Compounding
        • Computers & Automated Equipment
        • Verification (3 consecutive runs) & Stability
    • Facilities
    • Quality Control
    • Sterilization & Sterility Assurance
  • Control of Components, Materials and Supplies
    • Establish written specifications
        • Identity, purity & quality of components
        • Appropriate storage
    • Log-in each lot of shipments of components; If no expiration date, must assign one.
    • Determine each batch of components in compliance with written specifications (procedures, tests, and/or certificates of analysis)
    • Store components in controlled access area according to established conditions.
  • Compounding Procedure Verification
    • Written acceptance criteria for identity, purity & quality of each PET drug (If USP monograph exists = minimum acceptance criteria)
    • Written procedures for compounding
      • Master file of Written compounding procedures (Outdated copies retained)
      • Incorporate 0.22 um for parenteral administration; 0.45 um for inhalation
      • Routinely updated at least annually
    • Verification Studies
      • Three consecutive runs are required initially & for any change having potential to alter identity quality or purity
      • Stability testing and expiration dating—meet acceptance
      • criteria at expiry
  • PET Radiopharamceutical (RPh) Compounding Process
    • Inspect compounding area and equipment before use for cleanliness
    • Label final PET RaPh container prior to starting
      • PET drug name and lot number
    • Compound PET RaPh according to written, verified procedure with appropriate written batch record
      • Use appropriate components
      • Responsible individual initials—including each critical step
      • Raw analytical data
      • Signature & date of individual assuming overall responsibility
  • FDA Audit Inspectional Observations (FDA-483)
    • Failure to audit procedures (SOPs) on regular basis & update
    • Failure to investigate failed batch & deviations (should be in writing)
    • Failure to train personnel to perform assigned tasks
    • Found production equipment:
      • Not qualified
      • Not calibrated
      • Not properly maintained
  • Quality Control Procedures
    • Written QC procedures
    • Verification of QC equipment and procedures used
    • System suitability testing must be confirmed on installation of QC equipment and after repair
      • HPLC, GC, analytic instruments
    • Check correct operation on scheduled basis
    • Maintenance performed—written scheduled basis
    • Dose Calibrators:
      • Assay bulk radioactivity and dispensed dosages
      • Perform applicable tests
  • Quality Control Requirements
    • Pre-Release:
    • PET RaPh
      • T 1/2 ≥ 20 minutes (on Batch); T 1/2 <20 minutes ( on QC Sub Batch)
      • Post-filtration integrity test of 0.22  m sterile filter (e.g. Bubble Test)
      • pH
      • Visual inspection
      • Radiochemical purity /identity ***
      • Radionuclidic identity
      • Specific activity
      • Residual solvent analysis, and other toxic chemicals
      • BET (20 min gel clot, or other recognized procedure)
    • Post-Release:
    • Sterility
      • may inoculate test, within 24 h following preparation
  • Endosafe PTS ® System
    • PTS ® is a software-driven spectrophotometer for measuring and documenting endotoxin.
    • Unique cartridge containing dry, pre-calibrated reagents.
    • Each cartridge contains duplicate channels for analysis of sample and positive control.
    • PTS ® is particularly suited for PET RaPh because test requires
      • ~17-20 minutes
      • Requires < 0.1 mL of diluted product
      • NO preparation of endotoxin standards.
  • FDA Audit Inspectional Observations (FDA-483)
    • Lack of assurance that QC test results are reliable & accurate
      • QC equipment;
        • Not qualified
        • Not calibrated
        • Not maintained
      • No equipment suitability performed (USP Chapter <621>)
      • Inadequate reference standards used
    • Inadequate QA/QC oversight
      • Failure to investigate failed batch
      • Failure to update procedures
  • Qualification of Filtration Process
    • Sterile Filters:
      • COC examined and maintained for each lot of filters
      • COA obtained from the company listing microbial retention challenge
      • Each lot of filters must be tested for integrity : Acceptance Criteria
    • After PET drug production, filter tested for integrity pre-release e.g. Bubble Point Test
    • The bubble point pressure is the pressure at which bubbles first appear from a submerged inlet tube in the receiving vessel.
    • Nitrogen gas flow increased until the bubbles appear (e.g. most filters must reach > 50 psi. *
    Nitrogen Gas * Pressure depends on the filter used
  • Facility Environmental Controls
    • Work area is clean
    • Aseptic hood located in low traffic area
    • Clean laboratory clothing worn
    • Aseptic techniques used
    • Disinfect final product septum with sterile 70% alcohol
  • Aseptic Technique Training Requirements
    • Didactic training: pass written exam
    • Training in proper garbing & gloving with documented visual observation audits
    • Media-Fill Test Procedures
      • New preparer: Pass 3 separate Media-Fill Procedures
      • Annually for personnel who currently prepare (compound) PET RaPh
  • PET RaPh Final Product Vial Assembly Performed In Aseptic Hood
    • PET RaPh final product containers must be assembled in Class 100 environment (LFH or Isolator)
    • Gloved hands are disinfected before entering hood
    • Daily disinfection of surfaces before use
    • Microbiological Testing periodically e.g. weekly (per FDA, NOT monitoring)
      • Contact plate-surfaces
      • Settle plate/dynamic air sampler
      • Airborne, nonviable particle count
      • less often
  • FDA Audit Inspectional Observations (FDA-483)
    • Frequency of environmental monitoring—contact plates, touch plates
      • Weekly is not acceptable
      • Should “monitor” environment for each set-up of final product vial
      • Can assemble all final product vials for the day, and keep them in LAF
      • Use of non-sterile disinfectant to sanitize LAF
      • No media fill testing performed
  • Microbiological Testing of Finished Product
    • Innoculated no later than 24 hours after compounding
    • If sterility test fails, an investigation must be initiated to identify the cause
  • FDA Audit Inspectional Observations (FDA-483)
    • Lack of assurance that PET drug is sterile
      • No growth promotion testing of media performed
      • Must have validation data for hold time (eg. 24 hours); assure still have viable product
      • Inadequate incubation temperature control
      • Automatic sterility re-test without investigation
  • Class 100 (ISO Class 5) PET Dose Drawing Station
    • Chapter <823> supersedes Chapter <797> for PET RP compounding, but upon release of PET RP as finished drug product, further manipulation such as dispensing , contents of Chapter <797> apply.
    PET Dose Drawing Device In Class 100 Environment Shielded Dose Calibrator
  • Thank-you! [email_address]