Fundamental Differences Between System Inspections and Process Inspections
System Inspection
System inspection represents an innovative inspection methodology that the FDA introduced in the late 1990s and early 2000s. It is a comprehensive approach that systematically evaluates the entire quality system, marking a paradigm shift by “refocusing GMP compliance assessment from specific products to facility-wide evaluation.” This groundbreaking methodology fundamentally changed how regulatory authorities assess pharmaceutical manufacturing quality.
Key Characteristics:
System inspection provides an integrated evaluation of the facility-wide quality assurance system. It verifies whether the quality system has been appropriately designed, implemented, and maintained. The primary objectives include reducing the frequency of routine periodic inspections and enhancing the efficiency of pre-approval inspections. Fundamentally, system inspection investigates whether a company has established a “Quality System” under management governance and executive responsibility.
Process Inspection
Process inspection represents the traditional approach that focuses on specific manufacturing processes or operational procedures, verifying that processes are executed according to written procedures.
Key Characteristics:
Process inspection centers on an “inspection methodology for discovering errors (risks)” in individual manufacturing processes. It confirms compliance with specific operational procedures and emphasizes problem identification at the process level.
Understanding System Inspection Through GMP Subsystems
System inspection evaluates six subsystems described in the FDA’s “COMPLIANCE PROGRAM GUIDANCE MANUAL PROGRAM 7356.002” as interrelated components. This six-system framework is “globally recognized” and has been internationally adopted as the standard approach.
1. Quality System
Role: The central system that oversees the other five subsystems.
Key Evaluation Items:
The quality system encompasses quality policy and quality manuals, change management systems, deviation management systems, CAPA (Corrective Action and Preventive Action) systems, and the overall framework that forms the foundation of quality assurance.
FDA Definition: “This system assures overall compliance with cGMPs and internal procedures and specifications.”
The quality system serves as the integrating mechanism for all other subsystems and is mandatory in both full and abbreviated inspection options.
2. Facilities and Equipment System
Role: Comprehensive management of physical infrastructure affecting product quality.
Key Evaluation Items:
This system includes management of the manufacturing environment, equipment qualification (installation and operational), instrument calibration and preventive maintenance, cleanliness management, cleaning and cleaning validation (where applicable), and lifecycle management throughout the equipment lifespan.
The facilities and equipment system ensures that the physical infrastructure supports consistent product quality and GMP compliance.
3. Materials System
Role: Management of the entire chain from raw material procurement to usage.
Key Evaluation Items:
Essential elements include supplier management, incoming testing systems, inventory control, traceability, and raw material storage management.
This system ensures that all materials used in pharmaceutical manufacturing meet appropriate quality standards and are properly managed throughout their lifecycle.
4. Production System
Role: Evaluation of the mechanisms supporting all manufacturing activities.
Key Evaluation Items:
Critical components include manufacturing instruction creation and approval processes, process control systems, record integrity, operator training and education, and overall manufacturing system effectiveness.
Important Note: The focus is not on verifying individual processes but on evaluating the integration and effectiveness of the overall manufacturing system.
5. Packaging and Labeling System
Role: Management of areas directly connected to final product quality and patient safety.
Key Evaluation Items:
This system covers packaging material management, packaging operation management systems, ensuring labeling accuracy, and quality assurance of packaging and labeling processes.
Proper packaging and labeling are critical for ensuring that patients receive the correct product with accurate information.
6. Laboratory Controls System
Role: Foundational system supporting quality control operations.
Key Evaluation Items:
Key elements include analytical method validation, instrument management systems, data integrity, laboratory independence, and ensuring reliability of quality control operations.
The laboratory controls system provides the analytical foundation for demonstrating product quality and compliance.
System Inspection Implementation Methodology
Inspection Options
Abbreviated Option:
- Application Conditions: Applied when a company demonstrates good compliance history
- Coverage Scope: Quality system plus at least one other system (minimum 2 systems total)
- Purpose: Efficient inspection execution
Full Option:
- Application Conditions: Applied when compliance history is unfavorable or company information is insufficient
- Coverage Scope: Quality system plus at least three other systems (minimum 4 systems total)
- Purpose: Comprehensive system evaluation
Fatal Flaw Scenario (Critical Deficiency Scenario)
Critical Feature: A stringent scenario where observation of a significant deficiency in any single system can result in the entire facility’s operations being deemed inadequate.
Impact:
This scenario may lead to immediate inspection termination, demonstrates stricter standards compared to traditional inspections, and emphasizes the impact on the entire system rather than isolated issues.
Implementation in Japan
Introduction Background
- Implementation Year: 2005 (Heisei 17)
- Foundation: Ministry of Health, Labour and Welfare Scientific Research “Study of GMP Inspection Policies and Methods”
- System Name: “Research Related to GMP Inspections by Regulatory Authorities: Implementation Standards for System Inspection System”
Current Implementation Status
Current administrative GMP compliance investigations are conducted based on this system inspection system and implementation standards.
PMDA Implementation Standards:
- In a single investigation, at least two subsystems including the quality subsystem are investigated
- When investigating an entire manufacturing site, at least four subsystems are investigated
This approach aligns with international standards while maintaining Japan’s regulatory requirements and quality expectations.
Characteristics and Benefits of System Inspection
Evaluation of Inter-System Integration
System inspection evaluates how the six subsystems interconnect with each other and form an integrated quality assurance system as a whole.
Evaluation Examples:
- How changes in the materials system are communicated to the production system and laboratory controls system
- Appropriateness of information sharing and coordination among systems
- Functionality as an integrated quality assurance system
Differences from Traditional Inspections
Advantages of System Inspection:
System inspection identifies coordination deficiencies between systems that traditional process inspections often overlook. It provides comprehensive understanding of quality system weaknesses, achieves more efficient and effective inspections, and provides guidance for continuous improvement.
International Adoption Status
Position as a Global Standard
The system inspection approach has been “established as a globally recognized concept,” is widely accepted especially by U.S.-based companies, and is frequently used in GMP audits by overseas companies through audit plans based on six subsystems.
This framework shows close alignment with the ICH Q10 Pharmaceutical Quality System (PQS) concept, which provides a harmonized approach to pharmaceutical quality systems throughout the product lifecycle.
Position in Modern GMP Inspections
In modern GMP inspections, this system approach has become mainstream and is emphasized for the following reasons:
Comprehensiveness: Provides integrated evaluation of the entire quality system
Efficiency: Reduces duplicate inspections and enables effective problem discovery
Prevention: Enables problem prevention at the system level
International Harmonization: Aligns with global standards
Continuous Improvement: Promotes continuous improvement of the entire system
Summary
System inspection represents an innovative approach that has evolved from traditional process inspection and has become the standard methodology in modern GMP inspections. Through comprehensive evaluation using six subsystems, it ensures the effectiveness of the entire quality system and functions as a critical mechanism supporting the provision of safe, high-quality pharmaceuticals to patients.
The shift from product-specific to facility-wide quality system evaluation represents not just a change in inspection methodology, but a fundamental transformation in how pharmaceutical quality is conceptualized and assured. By examining the integration and interaction of multiple quality subsystems, regulatory authorities can better assess a manufacturer’s overall capability to consistently produce quality products and maintain a state of control throughout all operations.
For pharmaceutical manufacturers, understanding and implementing robust systems that align with this inspection approach is essential for regulatory compliance, operational excellence, and ultimately, patient safety. The system inspection methodology encourages companies to adopt a holistic view of quality management, promoting proactive problem prevention rather than reactive problem-solving, and fostering a culture of continuous improvement across all aspects of pharmaceutical manufacturing operations.
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