Understanding Quality Systems in Pharmaceutical and Medical Device Industries

Background: Globalization and the Evolution of Inspection Approaches

As pharmaceutical and medical device companies advance globalization, opportunities to undergo inspections by overseas regulatory authorities, including the U.S. Food and Drug Administration (FDA), have increased. Regulatory authorities, in response to the globalization of supply chains, have increased the number of overseas inspections. However, resources available for inspections are limited, necessitating more efficient and effective inspection methodologies.

In traditional inspections, corrective actions addressing findings identified by inspectors were generally accepted until the next inspection. However, there are limitations to the problems and risks that inspectors can identify during inspections of limited duration (typically 4 to 5 days in Japan, and generally 3 to 5 days overseas). Therefore, merely correcting errors and risks discovered by inspectors is insufficient to adequately protect public health and safety.

Consequently, regulatory authorities such as the FDA have shifted from traditional inspection methods focused on discovering individual errors and risks to a more systematic approach that evaluates whether a company has established a “Quality System” under management governance. This methodology enables regulatory authorities to assess whether companies possess the capability to continuously maintain and improve quality.

Latest Developments in Quality System Regulations for Medical Devices

FDA’s Transition from QSR (Quality System Regulation) to QMSR (Quality Management System Regulation)

The FDA has conducted inspections of medical device companies for many years in accordance with 21 CFR Part 820 (Quality System Regulation, QSR). However, on February 2, 2024, the FDA announced a historic regulatory revision, deciding to replace the QSR with the Quality Management System Regulation (QMSR). This new regulation will take effect on February 2, 2026.

The most significant aspect of this revision is that the FDA has incorporated ISO 13485:2016 (the international standard for medical device quality management systems) by reference. This means that most of the requirements in 21 CFR Part 820 will be replaced by ISO 13485:2016, significantly improving international harmonization. However, the FDA has retained U.S.-specific requirements such as control of records (§820.35) and control of device labeling and packaging (§820.45).

The transition to QMSR implements the following important changes:

• The traditional terminology of Device Master Record (DMR), Device History Record (DHR), and Design History File (DHF) will be consolidated into the unified concept of Medical Device File (MDF) from ISO 13485
• Risk management will be more explicitly integrated throughout the quality system
• Requirements for electronic records and electronic signatures under 21 CFR Part 11 will continue to apply

It is important to note that obtaining ISO 13485 certification does not exempt companies from FDA inspections. Companies must still meet FDA’s additional requirements and undergo periodic inspections.

Quality Systems Approach in Pharmaceuticals

Systematic Inspection Using the Six-System Model

The FDA classifies pharmaceutical manufacturing activities into the following six systems and conducts systematic inspections known as “Systems Inspections.” This approach is based on the FDA guidance “Quality Systems Approach to Pharmaceutical CGMP Regulations” issued in 2006.

System Name	Primary Content
Quality System	Ensures overall compliance with cGMP and internal procedures and specifications. Includes the quality control unit and all review and approval duties
Facilities and Equipment System	Design, maintenance, qualification, and calibration of manufacturing facilities
Materials System	Receipt, storage, handling, and testing of raw materials, materials, and packaging components
Production System	Manufacturing operations, process controls, validation, and in-process testing
Packaging and Labeling System	Control of packaging and labeling operations, identification, and storage
Laboratory Control System	Laboratory facilities, equipment, testing methods, and stability programs

Differences Between Full and Abbreviated Inspections

Systems inspections include two types: full inspections and abbreviated inspections.

In full inspections, a minimum of four systems out of the six are selected and inspected, with the quality system being mandatory. Full inspections are conducted in the following cases:

• When the GMP status of the company is unknown
• When significant changes have occurred at the manufacturing site
• When serious complaints or quality problems have occurred
• In conjunction with new approval applications

In abbreviated inspections, a minimum of two systems out of the six are selected, with the quality system being mandatory as with full inspections. Abbreviated inspections are conducted in the following cases:

• When conducted as routine periodic inspections
• When the previous inspection was satisfactory
• When there have been no serious recalls or quality incidents
• When cGMP compliance is at a satisfactory level

Important Changes Regarding Inspection Frequency

The FDA once aimed to inspect pharmaceutical manufacturing facilities every two years. However, with the enactment of the FDA Safety and Innovation Act (FDASIA) in 2012, the FDA transitioned to a risk-based approach. Currently, inspection frequency is determined based on facility risk assessment. Risk assessment includes the following factors:

• Inherent product risk (complexity and criticality of the product)
• Compliance history
• Records of recalls and GMP violations
• Time elapsed since the last inspection
• Results of inspections by foreign regulatory authorities

For medical devices, however, manufacturing facilities for Class II and Class III medical devices are still legally required to undergo periodic inspections every two years.

ICH Q10: International Harmonization of Pharmaceutical Quality Systems

The International Council for Harmonisation (ICH) finalized the ICH Q10 “Pharmaceutical Quality System” guideline in June 2008. This guideline provides a comprehensive quality system model applicable throughout the pharmaceutical product lifecycle (development, technology transfer, commercial manufacturing, and product discontinuation).

ICH Q10 complements regional GMP requirements and does not impose new regulatory requirements. Rather, it aims to promote science-based and risk-based approaches and drive continual improvement. ICH Q10 is closely related to ICH Q8 (Pharmaceutical Development) and ICH Q9 (Quality Risk Management), and these three guidelines form the foundation of modern pharmaceutical quality management.

The four primary quality system elements defined by ICH Q10 are:

1. Process Performance and Product Quality Monitoring
2. Corrective Action and Preventive Action System (CAPA)
3. Change Management System
4. Management Review

These elements are supported by two “enablers”: knowledge management and quality risk management.

Basic Structure of Quality Systems: Four PDCA Cycles

A Quality System (QS) generally consists of the following four PDCA cycles:

1. Management Process

In the management process, top management establishes quality policy and sets quality objectives annually. Quality objectives must be achievable and clearly defined with specific numerical values and achievement criteria.

Examples of quality objectives:

• Reduce customer complaints by 15% compared to the previous year
• Decrease deviation occurrence rate by 20% annually
• Improve customer satisfaction score by 10 points
• Achieve 100% completion rate for product quality reviews

Additionally, management must conduct periodic management reviews to evaluate the effectiveness of the quality system and provide appropriate directives for quality improvement. Management reviews examine internal audit results, the status of corrective and preventive actions, process performance and product quality monitoring results, and customer feedback.

2. Resource Process

In the resource process, management must allocate appropriate resources (personnel, facilities, funding). Quality improvement activities cannot be effectively executed with verbal directives alone without securing resources.

Examples of specific resource allocation:

• Employment and appropriate deployment of necessary personnel
• Implementation of systematic training programs
• Utilization of qualified external consultants or specialists
• Investment in state-of-the-art manufacturing equipment and testing instruments
• Implementation and maintenance of quality management system software

3. Product Realization Process

In the product realization process, all activities including research and development, design, manufacturing, distribution, and service are conducted in accordance with the Quality Management System (QMS). The objective is to ship products that meet user needs (requirements) to the market and achieve customer satisfaction.

This process includes:

• Product design and development control
• Process design and control
• Purchasing control
• Manufacturing and process control
• Testing and inspection
• Disposition for release

4. Continual Improvement Process

In the continual improvement process, information such as customer complaints, deviations, and quality problems is collected and analyzed, and corrective and preventive actions (CAPA) are implemented to prevent recurrence.

The most important aspect of corrective action is to thoroughly investigate the root cause of the problem and eliminate it to prevent recurrence. It is important to note that “correction” and “corrective action” are different concepts. Correction is an action to eliminate a nonconformity itself, while corrective action is an action to eliminate the cause of the nonconformity and prevent recurrence.

Additionally, it is important to conduct internal audits regularly to proactively discover potential problems (i.e., risks). Internal audits are called “Self Inspection” in English. In Japanese pharmaceutical-related ministerial ordinances, this is translated as “jiko-tenken (自己点検),” but this term may not fully express the original meaning. The essence of Self Inspection is for companies to proactively evaluate their own quality systems from the same perspective and at the same level as regulatory inspectors, discover problems, and make improvements.

In Self Inspection, it is important for companies to continuously discover risks through their own internal audits and implement corrections and preventive actions. That is, rather than waiting for regulatory inspections to identify problems, companies proactively implement improvement activities.

The results of corrective and preventive actions and internal audits are fed back to the management process. Management evaluates this information through management reviews and provides improvement directives or sets quality objectives for the next fiscal year. In this way, the PDCA cycle is completed.

The Essence and Importance of Quality Systems

This entire quality improvement mechanism is called a “Quality System (QS).” The foundation of a quality system is the PDCA cycle. The existence and proper functioning of a quality system means that there is assurance that quality will continuously improve from today to tomorrow, and from tomorrow to the day after.

The entire quality system mechanism is called a “Quality Management System (QMS).” A QMS is a management system for establishing, implementing, and maintaining processes to set quality policy and quality objectives and achieve those objectives.

In inspections by regulatory authorities such as the FDA, they confirm that companies have established effective quality systems and are identifying problems and implementing improvement activities at the same perspective and level as inspectors (Self Inspection), even during periods when inspections are not being conducted. For this purpose, securing and developing excellent internal auditors is of paramount importance. Internal auditors must have a deep understanding of regulatory requirements and international standards such as cGMP, QSR/QMSR, ISO 13485, and ICH Q10, and possess the ability to evaluate their own company’s quality system objectively and critically.

Companies that have established and properly functioning quality systems are considered “reliable” and “trustworthy” by regulatory inspectors. Such companies may experience reduced inspection frequency (evaluated as low risk in a risk-based approach) and are more likely to proceed smoothly through approval processes for new products.

Conclusion

Quality systems are not merely compliance tools for pharmaceutical and medical device companies but strategic foundations for achieving continuous quality improvement and business sustainability. The regulatory environment continues to evolve with the FDA’s transition to QMSR, implementation of ICH Q10, and adoption of risk-based inspection methodologies. While these changes demand greater responsibility and autonomy from companies, they also provide opportunities for efficient quality management and innovation.

Successful companies not only meet minimum regulatory requirements but also build cultures of quality excellence and consistently prioritize patient safety and product quality through continual improvement.