Key Points of the Pharmaceutical Quality System in the Revised GMP Ministerial Ordinance

Understanding Quality Systems in Pharmaceutical Regulation

The “Quality System” (QS) required by pharmaceutical regulations and the “Quality Management System” (QMS) required by quality management standards such as ISO 9001 and ISO 13485 are synonymous terms that represent the same concept.

The Pharmaceutical Quality System (PQS) is defined and required by ICH Q10, which is an international harmonized guideline for pharmaceutical quality systems. Previously, compliance with ICH Q10 was voluntary in many jurisdictions. However, the revised GMP Ministerial Ordinance in Japan has made the implementation of the Pharmaceutical Quality System mandatory for all pharmaceutical manufacturers.

The Essence of Quality Systems

A quality system fundamentally represents a “mechanism” for “improving” quality. The Quality System is based on the PDCA cycle (Plan, Do, Check, Act), which forms the foundation of continuous improvement methodologies.

The existence of a functioning Quality System (PDCA) provides assurance that quality will be better tomorrow than today, and better the day after tomorrow than tomorrow. This represents a commitment to ongoing enhancement of product quality and manufacturing processes.

Continuous improvement is paramount in this context. It is not merely a goal but an ongoing operational philosophy that must permeate all levels of the organization.

PDCA Cycle and Prevention of Recurrence

Organizations must establish a system in which the entire company, from top management to all employees, continuously rotates the PDCA cycle, enabling the entire enterprise to spiral upward in quality performance. This concept is sometimes referred to as “spiraling up” and represents organizational maturity and improvement over time.

For this purpose, internal audits and corrective actions are extremely important for strengthening the organizational culture and capabilities. Organizations must not forfeit the opportunity to improve their corporate culture by omitting thorough root cause investigations.

Building a system for recurrence prevention that ensures the same non-conformance does not occur repeatedly is essential. It is not advisable for organizational improvement to simply assume that a simple non-conformance requires only a simple correction without investigating the cause or implementing preventive measures.

When simple non-conformances are not properly investigated and prevented, they tend to recur repeatedly like a game of whack-a-mole, preventing the PDCA cycle from functioning effectively. This undermines the entire quality system and prevents organizational learning.

Corrective and Preventive Actions (CAPA)

In the Pharmaceutical Quality System, organizations must collect customer complaints and other quality information and implement Corrective and Preventive Actions (CAPA) to prevent recurrence. The distinction between corrective action and correction is critical to understand.

What is important in corrective action is investigating the root cause of the problem and eliminating it to prevent recurrence. It must be noted here that “corrective action” and “correction” are different concepts:

Correction: An action to eliminate a detected non-conformance (immediate fix)
Corrective Action: An action to eliminate the cause of a detected non-conformance to prevent recurrence (systematic improvement)
Preventive Action: An action to eliminate the cause of a potential non-conformance to prevent occurrence (proactive risk mitigation)

Internal Audit and Self-Inspection

Organizations must conduct internal audits to proactively discover latent problems, which essentially represent risks in the system. In PIC/S GMP, internal audits are called “Self Inspection,” emphasizing the proactive nature of this activity.

Self Inspection is translated as “自己点検” (jiko-tenken) in Japanese ministerial ordinances and related documents, though this translation may not fully capture the intended meaning. The English term “Self Inspection” more accurately conveys the concept of a systematic, critical examination rather than a simple self-check.

In Self Inspection, it is important for companies to discover risks daily through their own internal audits and to implement corrections and preventive measures proactively. This means actively implementing improvement activities on their own initiative rather than waiting for regulatory inspections to identify issues. This proactive approach is fundamental to maintaining a state of control and demonstrates organizational maturity.

Management Review and Feedback

The results of Corrective and Preventive Actions (CAPA) and internal audits must be fed back to senior management. This feedback loop is essential for ensuring that quality issues receive appropriate attention and resources at the highest levels of the organization.

Senior management, through Management Review meetings, provides improvement directives and establishes quality objectives for the following year. This annual cycle ensures that quality improvement is integrated into the strategic planning process and receives adequate resource allocation.

Four Elements of the Pharmaceutical Quality System

The “Pharmaceutical Quality System” consists of four essential elements, each of which plays a critical role in ensuring product quality and continuous improvement:

Element	Purpose	Key Activities
1. Monitoring System for Manufacturing Process Performance and Product Quality	Ensure processes remain in a state of control	Process performance monitoring, quality attribute trending, statistical analysis, early detection of deviations
2. Corrective Action and Preventive Action (CAPA) System	Systematic investigation and resolution of quality issues	Root cause analysis, impact assessment, effectiveness verification, knowledge management
3. Change Management System	Control and evaluate changes to ensure continued quality	Change classification and risk assessment, impact evaluation, implementation control, post-change monitoring
4. Management Review	Senior management oversight and strategic direction	Annual quality system assessment, resource allocation decisions, quality objective setting, continuous improvement planning

These four elements work together synergistically to create a comprehensive quality system that not only maintains compliance but drives continuous improvement throughout the product lifecycle.

Responsibilities of Senior Management

In PIC/S GMP, the term “Senior Management” is expressed as “製造業者等” (manufacturing entity, etc.) in the revised GMP Ministerial Ordinance, which can be confusing. To clarify, Senior Management refers to officers who have responsibility for pharmaceutical affairs, including the representative of the legal entity that is the manufacturing entity.

Senior Management has the responsibility for establishing and implementing an effective “Pharmaceutical Quality System” (PQS). This responsibility cannot be delegated and represents a fundamental commitment of the organization’s leadership.

State of Control

Senior Management must maintain the organization in a “State of Control.” This concept, defined in ICH Q10, represents a condition where:

Manufacturing processes are performing as expected and producing products of intended quality
Variability in critical process parameters and quality attributes is understood and controlled
The quality system effectively manages risks and opportunities
Product quality is consistently achieved through well-understood and validated processes

Senior Management bears responsibility for critical matters related to the Pharmaceutical Quality System (ICH Q10), including but not limited to:

Establishment of Quality Policy: Defining the organization’s commitment to quality that aligns with business strategy
Setting and Communication of Quality Objectives: Establishing measurable targets and ensuring organizational awareness
Appropriate Resource Allocation and Employee Training: Providing necessary human, material, and financial resources, and ensuring competency through training
Implementation of Management Review: Conducting systematic evaluation of the quality system’s performance
Establishment and Maintenance of Communication Mechanisms: Ensuring effective information flow across the organization

Quality Manual

Senior Management must create a Quality Manual, which serves as the top-tier document of the Pharmaceutical Quality System. The Quality Manual provides an overview of the organization’s quality system and typically includes:

Quality policy statement
Organizational structure and responsibilities
Description of the quality system elements
Reference to supporting procedures and documentation
Scope of application across the product lifecycle

According to the GMP Ministerial Ordinance and ICH Q10, the Quality Manual does not necessarily need to be contained in a single document file; it may consist of multiple document files as appropriate for the organization’s structure.

Quality Policy

Senior Management must establish a Quality Policy that must be consistent with the management policy of the organization. The Quality Policy represents senior management’s commitment to quality and provides strategic direction for quality-related activities throughout the organization.

The Quality Policy should be:

Appropriate to the purpose and context of the organization
A framework for setting quality objectives
Communicated and understood within the organization
Reviewed for continuing suitability
Aligned with business strategy and regulatory requirements

Quality Objectives

Senior Management must have each department establish quality objectives annually under the direction of the manufacturing supervisor (quality assurance department). Quality objectives must be consistent with the Quality Policy and should cascade through the organization.

Quality objectives must be achievable targets with specific numerical values and clear achievement criteria. Specific examples include:

Reduce customer complaints by 3 points (e.g., from baseline metrics)
Decrease deviations by 5 points (measured against established KPIs)
Increase customer satisfaction by 10 points (based on satisfaction surveys)
Reduce batch rejection rate by a specific percentage
Improve on-time delivery performance to a target level
Achieve specific process capability indices (Cpk values)

These objectives should be SMART (Specific, Measurable, Achievable, Relevant, Time-bound) and should drive continuous improvement activities throughout the organization.

Authority and Responsibility of Manufacturing Supervisor

Senior Management must grant the manufacturing supervisor independent authority and responsibility. This independence is crucial for ensuring that quality decisions are made without undue commercial pressure and that the manufacturing supervisor can fulfill their regulatory responsibilities effectively.

The manufacturing supervisor (or Person Responsible for Production and Quality Assurance in PIC/S terminology) must have the authority to:

Approve or reject starting materials, intermediate products, and finished products
Ensure that all manufacturing and quality control operations are properly validated
Authorize investigations when quality issues arise
Implement corrective and preventive actions
Participate in management review and quality system decisions

Resource Allocation

Senior Management must prepare appropriate resources (people, materials, and money). Merely giving verbal instructions such as “work hard,” “do it properly,” or “do it correctly” without preparing resources will make quality improvement impossible to execute.

Specific examples of resource allocation include:

Hiring and retaining qualified personnel with appropriate expertise
Providing comprehensive initial and ongoing training programs
Investing in modern equipment and facilities
Engaging consultants or subject matter experts when specialized knowledge is needed
Allocating budget for quality improvement initiatives and validation activities
Providing time and support for participation in internal audits and improvement projects
Implementing appropriate information technology systems to support quality management

Management Review

Senior Management must conduct Management Review at least once a year. The term “Management Review” is appropriately translated as “経営者による見直し” (examination by management) in Japanese, which accurately conveys the concept of senior leadership’s systematic evaluation of the quality system.

The question then becomes: what exactly should be reviewed? The answer is the “Quality System” itself and the “Resources” allocated to support it. Management Review should evaluate:

Quality System Performance:

Results of audits (internal and external)
Feedback from regulatory interactions
Process performance and product conformity trends
Status of corrective and preventive actions
Follow-up actions from previous management reviews
Changes that could affect the quality system
Results of product quality reviews
Effectiveness of risk management activities

Resource Adequacy:

Sufficiency of personnel, infrastructure, and work environment
Training effectiveness and competency levels
Equipment capability and maintenance status
Technology and system support adequacy
Financial resources for quality activities

Outputs from Management Review:

Senior Management must provide appropriate directives for quality improvement based on the Management Review. These outputs should include:

Decisions and actions related to improvement opportunities
Resource allocation or reallocation decisions
Changes to the quality system or quality objectives
Strategic direction for quality improvement initiatives

Management Review ensures that senior management remains engaged with the quality system, understands its performance, and provides the leadership necessary to drive continuous improvement. This systematic review process is not merely a regulatory requirement but a critical business practice that helps ensure long-term success and sustainability in the highly regulated pharmaceutical industry.

Evolution of GMP Requirements and Global Harmonization

The revised GMP Ministerial Ordinance represents Japan’s alignment with international GMP standards, particularly PIC/S GMP guidelines and ICH guidance documents. This harmonization effort, which culminated in the 2021 revision (enforced in August 2021), incorporated several critical elements:

Formal adoption of ICH Q10 (Pharmaceutical Quality System) as a mandatory requirement
Integration of ICH Q9 (Quality Risk Management) principles
Alignment with PIC/S GMP Chapter 1 on Pharmaceutical Quality System
Enhanced requirements for data integrity
Strengthened supplier management and quality agreements
Formalized product quality review processes
Introduction of stability monitoring programs

This alignment facilitates mutual recognition of GMP inspections and certifications, reduces duplicative inspections, and supports the global pharmaceutical supply chain. For pharmaceutical companies operating in multiple markets, this harmonization reduces complexity and enables more efficient quality system implementation.

The Path Forward: Building a Quality Culture

Successful implementation of the Pharmaceutical Quality System requires more than procedural compliance—it demands a fundamental shift in organizational culture toward what is increasingly termed “Quality Culture.” This involves:

Leadership commitment demonstrated through actions, not just words
Employee engagement and empowerment at all levels
Open communication and transparency about quality issues
Learning from mistakes rather than punishing individuals
Data-driven decision making based on sound scientific principles
Continuous learning and adaptation to evolving best practices
Integration of quality considerations into all business decisions

Organizations that successfully implement the Pharmaceutical Quality System do not view it as a regulatory burden but as a strategic enabler that drives operational excellence, reduces costs associated with quality failures, enhances reputation, and ultimately better serves patients who depend on safe and effective pharmaceutical products.

The journey toward pharmaceutical quality excellence is continuous, requiring persistent effort, adequate resources, and unwavering commitment from senior management. However, the benefits—in terms of product quality, patient safety, regulatory compliance, and business performance—make this investment essential for any pharmaceutical organization operating in today’s global marketplace.

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