United States – FDA Requirements

Qualification expectations are defined within both pharmaceutical and medical device GMP regulations, both of which apply to ATMP manufacturers depending on the equipment and systems in use:

• 21 CFR Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals
  • §211.68: Requires calibration and inspection of automated and mechanical equipment.
  • §211.100: Mandates validation of any process affecting finished product quality.
  • §211.110: Emphasizes validated methods to ensure batch consistency and integrity.
• 21 CFR Part 820 – Quality System Regulation for Medical Devices
  • §820.75: Requires validation of manufacturing processes, including qualification of systems and equipment used in production.
• FDA Guidance for Industry: Process Validation (2011)
  • Defines a lifecycle approach: Process Design → Process Qualification (including IQ/OQ/PQ) → Continued Process Verification (CPV).
  • Especially relevant for ATMPs, where process variability and small-scale manufacturing necessitate continuous verification strategies.
• FDA Guidance on Software Validation
  • Applicable when software controls or monitors GMP systems, including automated bioreactors, digital cleanroom monitoring, and electronic batch records (EBRs), all widely used in ATMP facilities.

Europe – EMA and EU GMP Requirements

The EudraLex Volume 4 series outlines GMP principles for medicinal products, with Annex 15 specifically addressing Qualification and Validation:

• Annex 15 – Qualification and Validation
  • IQ: Confirms proper installation according to the manufacturer's specifications.
  • OQ: Demonstrates operational consistency across the full range of expected conditions.
  • PQ: Verifies performance under actual or simulated production conditions.

  Key principles include:

  • Section 3.2: Qualification should follow a risk-based approach, focusing effort on aspects that directly affect product quality or safety.
  • Section 4.1: All qualification activities must be documented, traceable, and justified, with clear linkage to validation efforts.
• EU MDR 2017/745 & IVDR 2017/746
  • Require validation of critical manufacturing processes, including evidence of installation, operation, and performance qualification of systems that impact device safety and performance.
• ATMP-specific Guidance Documents
  • EMA’s Guideline on Human Cell-Based Medicinal Products and Guideline on Quality, Non-Clinical and Clinical Aspects of Gene Therapy Medicinal Products both highlight the need for robust facility and equipment qualification as part of the overall control strategy.

International Standards – ISO Requirements

ISO standards provide a global benchmark for implementing and auditing qualification activities, especially critical for multi-national ATMP developers:

• ISO 13485:2016 – Medical devices – Quality management systems
  • Requires process and equipment validation when verification alone is insufficient.
  • Essential for ATMP manufacturers using custom or hybrid device-equipment systems.
• ISO 14971:2019 – Application of risk management to medical devices
  • Supports science- and risk-based qualification in ATMP settings, particularly for novel bioprocessing technologies.
• ISO 14644 Series – Cleanrooms
  • Defines classification and qualification requirements for cleanrooms and controlled environments, a critical aspect for aseptic ATMP production.
• ISO 11135 / ISO 11137 – Sterilization of healthcare products
  • Mandates IQ, OQ, and PQ for sterilization systems, highly relevant for ancillary equipment and materials in ATMPs.
• ISO 11607-2 – Packaging for terminally sterilized medical devices
  • Ensures packaging processes are validated; applies to cryogenic containers, sterile kits, and transport packaging in ATMP logistics.
• ISO 17664:2017 – Processing of health care products
  • Addresses qualification of cleaning, disinfection, and sterilization systems for reusable equipment in ATMP suites.
• ISO 14155:2020 – Clinical investigations of medical devices
  • Relevant when ATMP trials use specialized medical device systems (e.g., point-of-care cell handling devices).

Key Regulatory Expectations for Qualification

1. Risk-Based Approach
   • Regulatory bodies stress using a risk-based validation strategy to prioritize qualification efforts on critical-to-quality attributes.
2. Comprehensive Documentation
   • All qualification phases (IQ, OQ, PQ) must be pre-approved, executed under controlled conditions, and fully documented with traceable evidence.
3. Change Control
   • A formal change control process is required to assess the impact of modifications on qualification status and trigger requalification when necessary.
4. Periodic Review & Requalification
   • Systems should undergo periodic review and requalification after significant changes, repairs, or according to scheduled maintenance cycles.
5. Training and Competency
   • Personnel involved in qualification must be trained, competent, and authorized, with training records maintained as part of the validation file.