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Current Good Manufacturing Practice Requirements for Combination Products

This guidance describes and explains the final rule on current good manufacturing practice (CGMP) requirements for combination products (21 CFR part 4). It clarifies which CGMP requirements apply when drugs, devices, and biological products are combined to create combination products, and provides a framework for manufacturers to demonstrate compliance with applicable CGMP requirements.

  1. Determine which CGMP operating system approach to use (drug CGMP-based or device QS regulation-based)
  2. Establish and document quality system procedures that address:
    • Management responsibility
    • Design controls
    • Purchasing controls
    • CAPA system
    • Testing requirements
    • Stability program
    • Reserve samples
  3. Implement appropriate design controls including:
    • Design planning
    • Design inputs/outputs
    • Design verification/validation
    • Risk analysis
    • Design reviews
    • Design history file
  4. Establish testing programs for:
    • Component acceptance
    • In-process controls
    • Release testing
    • Stability testing
    • Special requirements (sterility, endotoxins etc.)
  5. Document CGMP approach in regulatory submissions and quality system documentation
  6. Ensure appropriate agreements and controls are in place with suppliers and contract manufacturers
  7. Maintain appropriate records to demonstrate compliance with all applicable requirements
  8. Establish procedures for change control and evaluation of post-market changes
  9. Implement appropriate training programs for personnel
  10. Be prepared to demonstrate compliance during FDA inspections

Key Considerations

Human Factors

  • Human factors testing may be required as part of design validation for combination products
  • Should consider user needs and intended uses in design controls

Labelling

  • Must comply with tamper-evident packaging and labeling requirements for OTC combination products
  • Labeling must include appropriate expiration dating based on stability testing
  • Instructions for use must be validated through human factors testing

Biocompatibility

  • Must conduct appropriate biocompatibility testing for combination products with device components
  • Should evaluate interactions between drug/biologic and device materials

Safety

  • Must establish and maintain CAPA procedures
  • Must conduct risk analysis and implement risk controls
  • Must perform appropriate testing to ensure sterility and endotoxin requirements are met
  • Must maintain appropriate reserve samples

Other considerations

  • ISO 14971: Risk Management – Medical Devices
  • ISO 10993-1: Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process
  • ASTM E2709: Standard Practice for Demonstrating Capability to Comply with an Acceptance Procedure
  • ASTM E2334: Standard Practice for Setting an Upper Confidence Bound For a Fraction or Number of Non-conforming Items

Original guidance

  • Current Good Manufacturing Practice Requirements for Combination Products
  • HTML / PDF
  • Issue date: 2017-01-11
  • Last changed date: 2024-11-14
  • Status: FINAL
  • Official FDA topics: Pharmaceutical Quality, Medical Devices, Investigation & Enforcement, Drugs, Compounding, Biologics, Current Good Manufacturing Practice (CGMP)
  • ReguVirta summary file ID: b358619ae189070dd5c1d25a8780b465
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