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Draft Guidance for Industry: CGMPs for Phase 1 INDs. Joseph C. Famulare, Director Division of Manufacturing & Product Quality Office of Compliance, CDER, FDA Advisory Committee for Pharmaceutical Science Manufacturing Subcommittee 20-21 July 2004. Background.

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draft guidance for industry cgmps for phase 1 inds

Draft Guidance for Industry: CGMPs for Phase 1 INDs

Joseph C. Famulare, Director

Division of Manufacturing & Product Quality

Office of Compliance, CDER, FDA

Advisory Committee for Pharmaceutical Science

Manufacturing Subcommittee

20-21 July 2004

  • 501(a)(2)(B) requires all drug products be manufactured in accordance with current good manufacturing practice (CGMP)
  • CGMP Regulations, published in 1978 and codified in 21 CFR 210 and 211 primarily directed to commercial manufacturing of approved drugs and biologics
background cont d
Background (cont’d.)
  • Preamble to 1978 CGMP regulations:
    • states that CGMP regulations are applicable to preparation of any drug product for administration to humans or animals
    • indicated FDA’s intent to publish additional regulations specific to investigational clinical studies
background cont d4
Background (cont’d.)
  • The 1991 Guideline for preparation of investigational new drug products:
    • does not adequately cover all manufacturing situations
    • does not fully address Agency expectation that an incremental approach to CGMP compliance is acceptable for investigational products
background cont d5
Background (cont’d.)
  • Draft guidance for Phase 1 INDs and complementing regulation:
    • articulates FDA’s intent to implement an incremental approach to CGMP compliance for clinical investigational products
    • recognizes that some controls and the extent of controls differ between investigational and commercial manufacturing, as well as phases of clinical studies
guidance development principles
Guidance – Development Principles
  • Developed by Agency workgroup (CDER, CBER, ORA) composed of compliance staff, CMC reviewers, and inspectors
  • Utilize risk-based approach
    • available knowledge
    • emphasis on safety
  • General CGMP
  • Draft Guidance
    • Applies to investigational new drug and biological drug products used during phase 1 clinical studies
    • Specifically addresses phase 1 studies designed to assess tolerability or feasibility for further drug development work
      • Some phase 1 studies are excluded (e.g., drug metabolism, structure-activity relationships, food interaction)
scope cont d
Scope (cont’d.)
  • Draft Guidance:
    • provides direction for special production situations (i.e. microdose, multi-product, multi-lot) and specific product types
    • intended to serve as a companion to other guidance describing chemistry, manufacturing and control info submitted in Phase 1 INDs, and CGMPs for the manufacture of APIs (ICH-Q7A)
recommendations for complying with cgmp requirements
Recommendations for complying with CGMP Requirements
  • Utilize appropriate quality control (QC) standards, i.e.:
    • well defined procedures
    • adequately controlled equipment
    • accurate recording of all data
  • Application of QC standards leads to implementation of CGMPs consistent with good scientific methodology
recommendations for complying with cgmp requirements cont d
Recommendations for complying with CGMP Requirements (cont’d.)
  • Use available technology and resources to facilitate product development, CGMP compliance, and lessen CGMP burden, i.e.:
    • disposable equipment and process aids
    • prepackaged water for injection (WFI) and sterilized containers
    • contract manufacturing and testing facilities
recommendations for complying with cgmp requirements cont d11
Recommendations for complying with CGMP Requirements (cont’d.)
  • Prevent contamination and cross-contamination:
    • evaluate production environment to identify potential hazards
    • ensure that substances (i.e. chemicals, adventitious agents) from previous or concurrent research or production are removed
general cgmp requirements
General CGMP Requirements
  • Personnel:
    • education, experience and training, (or any combination of the three) to perform assigned functions, e.g. training to include GMPs outlined in guidance
general cgmp requirements cont d
General CGMP Requirements (cont’d.)
  • Quality Control Function:
    • is established for every producer of IND products
    • responsibilities are documented in writing and include:
      • examination of components, containers, closures, in-process materials, packaging and labeling materials
      • review and approval of production and testing procedures, acceptance criteria
      • review of completed production records for release or rejection of each clinical batch
    • is the responsibility of all staff involved in production
    • in operations with limited staff– QC function may be carried out by the same person performing production (with periodic review by another qualified person)
general cgmp requirements cont d14
General CGMP Requirements (cont’d.)
  • Facilities:
    • adequate work areas for intended tasks
    • water of appropriate source and quality
    • adequate air handling to prevent contamination and cross-contamination
general cgmp requirements cont d15
General CGMP Requirements (cont’d.)
  • Equipment:
    • in proper working condition, maintained calibrated, cleaned and sanitized at appropriate intervals
    • appropriate for intended function
    • should not contaminate or be reactive, additive or absorptive with product
    • identified and documented in production records
general cgmp requirements cont d16
General CGMP Requirements (cont’d.)
  • Control of Components:
    • written procedures describing handling and control of components
    • written, specified attributes or acceptance criteria
    • COA or other documentation for components to ensure conformance with specified attributes
    • records of receipt, quantity, supplier’s name, lot number, expiration date
general cgmp requirements cont d17
General CGMP Requirements (cont’d.)
  • Production and Documentation:
    • records including laboratory and production data detailing components, equipment and procedures used
    • records of changes in processes and procedures
    • appropriate microbiological control for production of sterile processed products
general cgmp requirements cont d18
General CGMP Requirements (cont’d.)
  • Laboratory Controls:
    • tests conducted using established written procedures under controlled conditions
    • scientifically sound analytical procedures
    • properly calibrated and maintained analytical lab equipment
    • initiate stability study to support use of product in clinical investigation
general cgmp requirements cont d19
General CGMP Requirements (cont’d.)
  • Container Closure and Labeling:
    • Package to protect product from alteration, contamination and damage during storage, handling and shipping
    • Controlled labeling to preclude mix-ups
  • Distribution:
    • Describes the transport of the IND product from the point of production to the patient/subject for consumption
general cgmp requirements cont d20
General CGMP Requirements (cont’d.)
  • Recordkeeping
    • Retain records related to quality and operation of production processes including:
      • Equipment maintenance and calibration
      • Production records and related analytical test records
      • Distribution records
      • All quality control functions
      • Component records
    • Retain records for 2 years after approval of marketing application or until 2 years after shipment and delivery of the product is discontinued and FDA is notified
special production situations
Special Production Situations
  • Screening/Microdose INDs
  • Multi-Product Facilities
  • Biological and Biotechnological Products
  • Sterile/Aseptically processed products
screening microdose inds
Screening/Microdose INDs
  • The application of CGMPs controls to Screening IND and Microdose studies should be proportional to the scale and scope of the operation.
  • Special provisions for lab scale production are provided in the guidance with respect to QC, facility, equipment, and lab control.
multi product facilities
Multi-product Facilities
  • An area or room can be used for multiple purposes and products, provided that:
    • only one product is produced in an area at any given time
    • appropriate cleaning and change over procedures are in place to ensure there is no carry-over of materials or products or mix-ups
biological and biotechnological products
Biological and Biotechnological Products
  • Additional safeguards
    • Some production systems may warrant additional safeguards to protect personnel (e.g., pathogenic microorganisms, some products made from spore-forming microorganisms, live viral vaccines and gene therapy vectors)
    • Equipment qualification and controls in production assure success of unit operations with safety-related functions (e.g., viral clearance, virus/ toxin attenuation, pasteurization)
biological and biotechnological products cont d
Biological and Biotechnological Products (cont’d.)
  • Retained samples (e.g., drug substance, drug product, intermediates) can be subsequently analyzed and compared to provide assurance of product consistency throughout clinical development.
  • In-process testing and detailed records ensure product consistency for Phase 1 products which are produced in multiple lots
sterile aseptically processed products
Sterile/Aseptically Processed Products
  • Investigational products intended to be sterile require specific precautions, for example:
    • personnel should be properly trained in aseptic techniques
    • aseptic manipulation should be conducted in a Class 100 environment e.g. laminar flow hood
    • controls should be in place to assure appropriate air quality of the aseptic environment