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Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
Qa & Gmp 29 May2010
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Qa & Gmp 29 May2010


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  • 1. Regulatory and QA Considerations for Drug Product Development Louise Johnson, M.S. Chinese American Biopharmaceutical Society Meeting June 5, 2010
  • 2. Core Principles
    • Patient safety guides FDA’s review of CMC information during development
    • CMC development proceeds simultaneously with clinical development
    • Data generated during development builds upon early work and should be planned to compose a complete NDA CMC section that supports product approval
  • 3. Topics
    • CMC goals in development
    • Standards for product quality
      • Good Manufacturing Practice (GMP)
      • Quality Assurance (QA)
    • Quality Assurance and Quality Control
    • CMC Information for Original INDs
    • CMC Information as Development Progresses
    • NDA Planning
  • 4. CMC Development Goals
    • Manufacture the drug product in a manner so that you can assure its identity, strength, quality, and purity*
    • Create documentation of your processes so that you can demonstrate to FDA that you understand the critical characteristics of the product and the process and can reliably manufacture a high quality product
    • * FD&C Act Section 505(d)(3)
  • 5. Standards Used to Ensure Product Quality
    • GMP – Good Manufacturing Practice (21 CFR 210 and 211)
      • A standard for the production and testing of a pharmaceutical or device to ensure product quality
      • Required for human use
      • Not required for animal studies
        • However, there are GLP requirements for study material
      • Described in the Food, Drug & Cosmetic Act and FDA regulations
    • Quality Assurance (QA)
      • All those planned and systematic production processes that are established to ensure the investigational product is fit for the intended purpose
    • Quality By Design (QbD)
      • A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management
      • Provides a basis for risk management and increased regulatory flexibility after NDA approval
  • 6. Principles Underlying GMP
    • Right the first time (can’t inspect quality in)
    • Documentation of all actions and decisions
    • Double checking work & calculations
    • Establish acceptance criteria – specifications
    • Analytical testing to confirm product characteristics
    • Define standard processes for manufacturing and analytical testing in writing
    • Final product release by personnel independent of manufacturing department
    • Personnel qualified by education and training
    • Label, segregate, and control components & equipment
  • 7. Regulatory Affairs Function
    • Act as liaison between the company and FDA
    • Make all regulatory submissions
    • Advise on current regulatory requirements, guidance, and agency activities
  • 8. Quality Assurance Function
    • Responsible for independent, objective assessment of manufacturing systems and operations
    • Responsible for lot release, Certificates of Analysis
    • Manages SOPs, revisions, distribution
    • Provides GMP training
    • Audits facilities, operations, documentation
    • Manages change control
  • 9. Quality Control Function
    • Sample, test, and report results for starting materials, excipients, API, final product
    • Perform line checks
    • Involved in the manufacturing process
  • 10. Example Company Organizational Chart CEO Quality Compliance Manufacturing Quality Assurance Quality Control Clinical & Regulatory Affairs Regulatory Affairs
  • 11. So What CMC Information Is Needed At Each Stage Of Development?
    • Regulations allow great deal of flexibility in the amount and depth of data
    • The type of information needed will depend on
      • Phase of investigation (Phase 1, 2, or 3)
      • Specifics of the human study proposed (dose regimen, duration of dosing)
      • Nature and source of the drug substance (synthetic, animal source)
      • Drug product dosage form (oral, IV)
  • 12. CMC Information for Original IND
    • Sufficient information for evaluation of the safety of the proposed investigational product
    • Data relating the clinical supplies to the drug used in the animal toxicology studies that support the safety of the proposed human study
    • Statement of whether you believe there are signals of potential human risk in:
      • the chemistry of either the drug substance or the drug product or
      • the manufacturing of either the drug substance or the drug product
  • 13. IND for Phase 1 Study
    • Identification of a safety concern or insufficient data to evaluate safety are the only CMC reasons for a clinical hold
    • Special note: While FDA has exempted Phase 1 clinical supplies from GMP regulations, the Federal Food, Drug, and Cosmetic Act still requires clinical supplies to be manufactured under GMP
      • Section 501(a)(1)(B) of the FD&C Act
  • 14. CMC Safety Concern Examples
    • Unknown or impure components
    • Chemical structures of known or highly likely toxicity (structural alert)
    • Unstable throughout the proposed testing period
    • Impurity profile indicative of a potential health hazard or impurity profile insufficiently designed
  • 15. IND – CMC Section
    • Manufacturing
      • Brief description of the composition, manufacture, and control of drug substance, drug product, and any placebo
    • Controls
      • Brief description of analytical methods and acceptable limits for drug substance, drug product, and any placebo
    • Stability
      • Brief description of stability data and analytical methods (can use a representative lot)
    • Labels
      • A mock-up of the investigational product labels for the clinical trial
      • Caution: New Drug - Limited by Federal (or United States) law to investigational use.
  • 16. As Development Proceeds
    • Early discussion of unique CMC issues encouraged
      • End of Phase 2 meeting
      • Pre-NDA meeting
    • Update information previously submitted
      • Annual reports
      • Information amendments
        • Emphasis should be on reporting significant changes that can have a safety-related impact
  • 17. Examples of CMC Modifications That Can Affect Safety
    • Changes in drug substance synthesis
      • material change in one of the bond forming steps
      • change in a solvent used for the last reaction and/or crystallization step
      • change resulting in a different impurity profile
    • Change in method of sterilization
    • Change in the composition and/or dosage form of the drug product
    • Change in the drug product manufacturing process that could affect product quality
    • Change in specifications
    • Change in the drug product container closure system
  • 18. Phase 2 – CMC Information
    • Provide more detailed descriptions of the characteristics of the drug substance and drug product, e.g.
      • Configuration and chemical structure for complex organic compounds
      • Any non-compendial excipients
      • Particle size distribution, polymorphic form
      • Stability of reconstituted products
    • Provide more detailed descriptions of manufacturing processes and any changes to them
  • 19. Phase 3 – CMC Information
    • Augment the elucidation and characterization of drug substance structure
    • Identify, qualify, quantify, and report impurities and degradation products, along with suitable limits
    • Provide detailed step-by-step descriptions of manufacturing processes
      • In-process controls
      • Acceptance criteria
    • Detailed listing of all tests performed on starting materials, excipients, drug substance, drug product
      • Validation information for unique tests
  • 20. Phase 3 – CMC Information continued
    • Stress testing to demonstrate inherent stability, potential degradation pathways, capability and suitability of proposed analytical procedures
      • Different pH levels
      • Presence of oxygen and light
      • Elevated temperatures and humidity levels
      • Thermal cycling
    • Protocol for formal stability program to support NDA
  • 21. Advice for CMC Development
    • Focus on patient safety, re-evaluate as development proceeds
    • Plan experiments to maximize their ability to support clinical studies and subsequent development work
    • Seek feedback from FDA for unique situations
    • Consider implementing a Quality by Design program to increase product understanding
  • 22. References for NDA Preparation
    • 21 CFR 314.50 (d)(1)
    • Guideline for Submitting Documentation for the Manufacture and Controls of Drug Products
    • ICH Quality Guidelines
    • ICH M4 Common Technical Document format
    • FDA’s Manufacturing Web Page
  • 23.
    • Louise C. Johnson, M.S.
    • [email_address]
    • Louise_Johnson
    • On Twitter
    Thank you!