Overview of the Regulatory Framework
The role of Manufacturing Manager (製造管理者) is stipulated in Article 17, Paragraph 6 of the Pharmaceuticals and Medical Devices Act (PMD Act, commonly known as Yakuji-hou or 薬機法). In response to the revised Good Manufacturing Practice (GMP) Ministerial Ordinance, which came into force on August 1, 2021, the responsibilities of the Manufacturing Manager have undergone substantial transformation with the introduction of the Pharmaceutical Quality System (PQS).
This revision represents the most comprehensive overhaul of GMP requirements in approximately 16 years since the 2005 amendments. The revised ordinance mandates that manufacturing sites establish a “Quality Assurance Organization” (QA department) within the quality unit, with the Manufacturing Manager responsible for overseeing this organization. All pharmaceutical companies were required to appropriately revise their Standard Operating Procedures (SOPs) before the enforcement date of August 1, 2021 to ensure compliance with these new requirements.
Background and Context of the Revision
Drivers for Regulatory Change
The revision of the GMP Ministerial Ordinance was necessitated by several critical factors. Between 2015 and 2020, Japan experienced a series of serious quality violations and fraudulent manufacturing practices by pharmaceutical companies. Most notably, a comprehensive inspection conducted in 2016 revealed that approximately 70% of all approved pharmaceutical products (22,297 products out of 32,466 total items from 646 companies) showed discrepancies from their marketing authorization documents, although none affected product quality or safety requiring prior approval amendments.
Furthermore, in late 2020, a generic pharmaceutical manufacturer was discovered to have contaminated an antifungal medication with ingredients from a sleep-inducing drug, leading to widespread supply disruptions across the industry as additional compliance violations were uncovered at multiple manufacturing sites. These incidents fundamentally undermined public trust in pharmaceutical quality systems and highlighted systemic deficiencies in management oversight and compliance culture.
International Harmonization Imperatives
Japan joined the Pharmaceutical Inspection Co-operation Scheme (PIC/S) in July 2015, committing to align its GMP standards with international best practices. The revised GMP Ministerial Ordinance incorporates essential requirements from the PIC/S GMP Guide and implements the International Council for Harmonisation (ICH) Q10 guidance on Pharmaceutical Quality Systems, which had been referenced in administrative notices since 2010 but had not been fully integrated into binding regulations until 2021.
Detailed Analysis of Revised Responsibilities
Article 5: Core Duties of the Manufacturing Manager
Article 5, Paragraph 1 of the revised GMP Ministerial Ordinance defines the fundamental responsibilities of the Manufacturing Manager. The following requirements represent substantial changes from previous regulations, with Items 1 through 3 being almost entirely new provisions:
Item 1: Pharmaceutical Quality System Management and Oversight The Manufacturing Manager must comprehensively oversee manufacturing management, quality assurance, and testing operations (collectively termed “Manufacturing and Quality-Related Operations”) at the manufacturing site to achieve the quality policy and quality objectives. Additionally, the Manufacturing Manager must ensure that the Pharmaceutical Quality System (PQS) is appropriately operated and maintained.
Item 2: PQS Performance Monitoring and Improvement Recommendations The Manufacturing Manager must confirm the operational status of the Pharmaceutical Quality System and report in writing to the manufacturer (経営者, referring to senior management including representatives and executives responsible for pharmaceutical affairs) regarding whether improvements to the system are necessary.
Item 3: Compliance with Marketing Authorization The Manufacturing Manager must ensure that the Quality Assurance organization manages specifications for raw materials, packaging materials, and products (including intermediates), as well as manufacturing procedures, to prevent any deviations from approved marketing authorization documents.
Item 4: Quality Issue Response and Corrective Actions In cases of quality defects or other situations that may significantly impact product quality, the Manufacturing Manager must confirm that appropriate measures are promptly implemented and monitor their progress. When necessary, the Manufacturing Manager must instruct responsible persons and personnel to take corrective actions (including corrective and preventive actions, or CAPA).
Expanded Responsibilities Summary
The Manufacturing Manager’s core responsibilities now encompass three critical areas:
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Management and Operation of the Pharmaceutical Quality System (PQS): This includes establishing, maintaining, and continuously improving an integrated quality management framework that covers all manufacturing and quality-related activities throughout the product lifecycle.
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Escalation of PQS Improvement Needs to Senior Management: The Manufacturing Manager serves as a crucial communication bridge between site operations and executive leadership, providing evidence-based recommendations for system enhancements and resource allocation.
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Ensuring Alignment Between Marketing Authorization and Manufacturing Reality: This responsibility emphasizes the critical importance of maintaining consistency between approved product specifications, manufacturing processes, and actual production practices—a direct response to the widespread discrepancies identified in the 2016 inspection.
Authority Delegation from Senior Management
Independence and Empowerment
The Manufacturing Manager must possess independent authority and responsibility for all manufacturing and quality-related operations at the site to effectively oversee proper and smooth operations and manage the PQS appropriately. This authority must be formally granted by senior management (executives responsible for pharmaceutical affairs, including the company’s legal representative).
The concept of “independent authority” is particularly significant: it mandates that senior management must not interfere with or obstruct the Manufacturing Manager’s execution of their duties. This provision directly addresses historical issues where economic pressures or production demands led to compromises in quality standards.
Bidirectional Communication Framework
While the Manufacturing Manager has independent operational authority, there exists a structured communication framework between site operations and corporate leadership:
Upward Communication (Site to Management): According to Article 17, Paragraph 7 of the PMD Act, when the pharmaceutical Manufacturing Manager deems it necessary to ensure fair and appropriate manufacturing management, they must submit written opinions to the manufacturer (senior management). This legal obligation provides Manufacturing Managers with protected communication channels to escalate critical quality and compliance concerns.
Management Response Obligation: Article 18, Paragraph 4 of the PMD Act stipulates that pharmaceutical manufacturers must respect the opinions submitted by pharmaceutical Manufacturing Managers and take appropriate measures when necessary for legal compliance. This creates a legally enforceable duty for management to respond to Manufacturing Manager concerns, fundamentally shifting organizational accountability structures.
Managing PQS Operations
Monitoring and Reporting Framework
The Manufacturing Manager must systematically monitor the operational status of the Pharmaceutical Quality System and provide written reports to senior management when improvements to the PQS or allocated resources are necessary. These reports must be prepared under the Manufacturing Manager’s own responsibility and authority, ensuring accountability and professional integrity.
Upon receiving these reports, senior management must, under the leadership of executives responsible for pharmaceutical affairs (including the company’s legal representatives), allocate necessary resources as stipulated in Article 3-3, Item 4 of the GMP Ministerial Ordinance. This establishes a mandatory feedback loop where operational needs drive resource allocation decisions.
Resource Allocation Requirements
Resources (リソース) in this context encompasses three fundamental categories: human resources (personnel), physical resources (materials and infrastructure), and financial resources (capital). To operate the PQS appropriately and achieve continuous quality improvement, organizations must invest in:
1. Competent Personnel Recruitment and Retention Hiring individuals with appropriate qualifications, experience, and capabilities to perform manufacturing and quality-related functions effectively.
2. Comprehensive Training and Development Programs Providing initial and ongoing education and training to ensure personnel maintain and enhance their competencies in accordance with Article 19, 25, and 29 of the GMP Ministerial Ordinance.
3. Equipment, Facility, and System Procurement Acquiring necessary equipment, instruments, facilities, and computerized systems to support manufacturing and quality operations. This includes replacement of aging or obsolete equipment to maintain process capability and data integrity.
4. Infrastructure Maintenance and Modernization Investing in facility upgrades, utility systems, and cleanroom environments to ensure continued compliance with environmental and contamination control requirements.
Management’s Support Obligation
Senior management must provide necessary support for the Manufacturing Manager’s execution of duties through appropriate resource allocation. This support obligation is not merely aspirational but represents a fundamental requirement under the revised GMP framework. The ordinance explicitly recognizes that quality improvement cannot be achieved through motivation or determination alone—it requires systematic investment in capabilities and infrastructure.
Escalating PQS Improvement Needs
Structured Communication Requirements
The pharmaceutical Manufacturing Manager must submit written opinions to senior management when necessary to ensure fair and appropriate manufacturing management, as mandated by the PMD Act. This requirement institutionalizes what might be termed “constructive escalation”—a formal mechanism for Manufacturing Managers to advocate for systemic improvements without fear of retaliation.
Effective communication (コミュニケーション) between site operations and senior leadership is fundamental to maintaining an effective quality system. The information flow must be bidirectional, transparent, and action-oriented. Senior management must respect the Manufacturing Manager’s professional opinions and implement appropriate measures when necessary for legal compliance.
Management Review Process
The revised ordinance introduces the concept of “Management Review” (マネジメントレビュー), derived from ICH Q10 and ISO 9001 quality management principles. Although the term “management review” does not explicitly appear in the Japanese ordinance due to legal terminology constraints, the substantive requirements are fully incorporated through the Manufacturing Manager’s reporting obligations and management’s response requirements.
Management review should occur at planned intervals to ensure the continuing suitability, adequacy, and effectiveness of the PQS. These reviews should evaluate opportunities for improvement and identify necessary changes to the quality system, including quality policy and quality objectives.
Ensuring Compliance with Marketing Authorization
Quality Assurance Organization Responsibilities
The Manufacturing Manager must ensure that the Quality Assurance organization manages specifications for raw materials (原料), packaging materials (資材), and products (including intermediate products) as well as manufacturing procedures to prevent any deviations from marketing authorization documents. This represents a formalization of QA’s gatekeeping function in maintaining manufacturing authorization compliance.
The explicit assignment of this responsibility to a dedicated QA organization reflects international best practices where QA serves as an independent function separate from production operations. This organizational separation provides the objectivity necessary to identify and prevent manufacturing authorization deviations before they occur.
Monitoring and Verification Activities
When quality defects or other situations that may significantly impact product quality arise, the Manufacturing Manager must:
1. Verify Prompt Implementation of Measures Confirm that appropriate departments, including manufacturing and quality assurance, are taking necessary corrective actions without delay.
2. Monitor Progress and Effectiveness Track the status of corrective and preventive actions to ensure they are progressing according to plan and achieving their intended objectives.
3. Direct Additional Actions When Necessary Instruct responsible persons and personnel to implement improvements (including corrective actions and preventive actions, collectively known as CAPA) when initial measures prove insufficient.
This active oversight role transforms the Manufacturing Manager from a passive reviewer to an engaged quality leader who ensures systematic problem resolution and continuous improvement.
Understanding the Pharmaceutical Quality System (PQS)
Conceptual Foundation
The concept of the Pharmaceutical Quality System as defined in ICH Q10 presents significant complexity for many pharmaceutical professionals. The ICH Q10 guideline, titled “Pharmaceutical Quality System,” was officially adopted in June 2008 and provides a comprehensive model for an effective quality management system specifically designed for the pharmaceutical industry.
ICH Q10 describes a comprehensive quality management system that encompasses organizational structure, responsibilities, procedures, processes, and resources required to implement quality management across the entire product lifecycle, including pharmaceutical development, technology transfer, commercial manufacturing, and product discontinuation. The PQS model builds upon and enhances regional GMP requirements by incorporating modern quality management principles.
Core PQS Elements
The ICH Q10 model identifies four specific quality system elements that augment traditional GMP requirements:
1. Process Performance and Product Quality Monitoring System Systematic collection and analysis of data to verify that manufacturing processes remain in a state of control and continue producing products that meet their quality attributes. This includes trending analysis, statistical process control, and performance indicators.
2. Corrective Action and Preventive Action (CAPA) System A structured approach to investigating product and quality problems, identifying root causes, implementing corrective actions to address existing nonconformities, and establishing preventive actions to prevent recurrence or occurrence of potential problems.
3. Change Management System A systematic approach for evaluating, approving, implementing, and monitoring changes that could affect product quality, manufacturing processes, equipment, facilities, materials, or the quality system itself. This ensures that changes are technically justified, documented, and do not introduce unintended consequences.
4. Management Review Periodic structured evaluation by senior management of the PQS to ensure its continuing suitability, adequacy, and effectiveness. Management reviews should assess process performance, product quality, corrective and preventive actions, follow-up from previous reviews, changes that could affect the PQS, and improvement recommendations.
Enablers: Knowledge Management and Quality Risk Management
ICH Q10 identifies two critical enablers that support effective PQS implementation:
Knowledge Management The systematic approach to acquiring, documenting, analyzing, storing, and transferring knowledge and experience related to products and manufacturing processes. Knowledge management provides the foundation for science-based and risk-based decision making throughout the product lifecycle.
Quality Risk Management (QRM) A systematic process for the assessment, control, communication, and review of risks to product quality across the product lifecycle. QRM principles, detailed in ICH Q9, enable proactive identification and mitigation of quality risks and support optimization of manufacturing processes based on scientific understanding. The revised GMP Ministerial Ordinance mandates QRM implementation in Article 3-4.
Implementation Challenges and Industry Response
Complexity of Quality System Concepts
Despite the publication of the revised GMP Ministerial Ordinance, substantial uncertainty exists regarding the depth of understanding among pharmaceutical industry professionals, including SOP authors, consultants, seminar instructors, and book publishers who are now producing educational materials on this topic. The fundamental question remains: how many practitioners truly comprehend “quality system” concepts at a level sufficient for effective implementation?
The proper understanding and operation of quality system concepts require deep familiarity with ISO 9001 Quality Management System standards, which provide the foundational principles for modern quality management. Organizations lacking this foundation may struggle to implement PQS effectively, potentially defaulting to procedural compliance without achieving the cultural transformation necessary for sustained quality improvement.
Relationship Between PQS and ISO 9001
While the GMP Ministerial Ordinance does not explicitly mandate ISO 9001 certification, the concepts embedded in the PQS are directly derived from ISO 9001:2015 quality management principles. These include:
- Customer Focus: Understanding and meeting patient and regulatory requirements
- Leadership: Establishing unity of purpose and engagement at all organizational levels
- Engagement of People: Ensuring competent, empowered, and engaged personnel
- Process Approach: Managing activities as interrelated processes
- Improvement: Continuous enhancement of performance and capabilities
- Evidence-based Decision Making: Making decisions based on data analysis and evaluation
- Relationship Management: Managing relationships with interested parties (including regulatory authorities, suppliers, and contract organizations)
Organizations with mature ISO 9001 quality management systems are generally better positioned to implement PQS requirements, as they possess established frameworks for management responsibility, resource management, product realization, and measurement, analysis, and improvement.
Practical Implementation Considerations
Organizational Structure Requirements
The revised ordinance requires each manufacturing site to establish distinct organizational units for manufacturing management (製造部門, Manufacturing Department) and quality control (品質部門, Quality Department) under the supervision of the Manufacturing Manager. Within the Quality Department, there must be a dedicated organization responsible for quality assurance functions (品質保証に係る業務を担当する組織, Quality Assurance Organization).
For certain categories of manufacturing sites—specifically those engaged only in packaging, labeling, storage, or distribution—the quality assurance and testing functions may be performed by the Quality Department of another manufacturing site operated by the same manufacturer, provided there is no hindrance to proper operations.
Role Clarity and Competency Requirements
The revised ordinance emphasizes that personnel assigned to manufacturing and quality-related positions must possess the capability to perform their duties appropriately and smoothly. This capability assessment should consider the type and content of work performed, practical experience, and training history under Articles 19, 25, and 29 of the GMP Ministerial Ordinance.
Organizations must document the responsibilities and management structure for all personnel engaged in manufacturing and quality-related operations, including the Manufacturing Manager and designated responsible persons. This documentation should include organizational charts illustrating each person’s duties, authorities, and collaborative relationships.
Documentation and Record-Keeping
The PQS must be supported by comprehensive documentation, including a Quality Manual that specifies the pharmaceutical quality system. The Quality Manual should describe the scope of the PQS, quality policy, quality objectives, organizational structure, key processes, and interactions between PQS elements.
Additionally, organizations must maintain detailed procedures, records, and work instructions for all manufacturing and quality-related activities. These documents serve as evidence of PQS implementation and provide the basis for training, consistency, and continuous improvement.
Comparative Analysis: Traditional GMP vs. Enhanced PQS Approach
| Aspect | Traditional GMP Approach | Enhanced PQS Approach (Post-2021) |
|---|---|---|
| Focus | Compliance with minimum requirements | Comprehensive quality management and continuous improvement |
| Management Role | Limited oversight; reactive to problems | Active leadership; strategic quality planning and resource allocation |
| Manufacturing Manager Authority | Primarily site-focused operational responsibilities | Expanded authority with formal escalation rights to senior management |
| Quality Organization | Combined quality control and quality assurance functions | Distinct QA organization with defined gatekeeping responsibilities |
| Change Management | Ad hoc evaluation of changes | Systematic change control system integrated across all operations |
| Risk Management | Reactive problem-solving | Proactive quality risk management throughout product lifecycle |
| Documentation | Procedures and records focused on compliance | Knowledge management system supporting science-based decisions |
| Performance Monitoring | Basic batch-by-batch quality control testing | Comprehensive process performance and product quality trending |
| Management Review | Informal and irregular | Structured periodic reviews with documented outcomes and action items |
| Communication | Vertical, formal communication channels | Bidirectional information flow; transparency between sites and management |
| Cultural Orientation | Procedure-driven compliance culture | Quality-by-design culture emphasizing prevention and improvement |
Future Outlook and Evolving Requirements
Recent Regulatory Developments
Since the initial implementation in August 2021, Japanese regulatory authorities have continued to refine GMP expectations through supplementary guidance documents:
GMP Case Studies (2022 Edition) Released in April 2022 as an administrative communication, this document provides specific implementation examples in Q&A format. It addresses practical scenarios encountered during inspections and provides clarification on interpretation of regulatory requirements. An addendum was published in April 2024 incorporating additional cases.
GMP Inspection Guidelines Established in March 2024 and amended in September 2024, these guidelines standardize the inspection approach used by regulatory authorities and provide transparency regarding inspection focus areas and evaluation criteria.
Quality Issue Recurrence Prevention Initiatives Published in March 2022, this guidance emphasizes enhanced oversight of outsourced activities, strengthened data integrity controls, and improved organizational culture focusing on quality and compliance.
Continuing Evolution of International Standards
PIC/S continues to update its GMP Guide to reflect evolving manufacturing technologies, quality management practices, and data integrity expectations. Notably, recent revisions have emphasized:
- Computerized Systems and Data Integrity: Enhanced requirements for electronic records, audit trails, and controls over data lifecycle management
- Quality Culture: Increased focus on organizational behaviors, leadership commitment, and employee engagement in quality
- Supply Chain Integrity: Strengthened requirements for qualification and ongoing monitoring of suppliers, contract manufacturers, and contract testing laboratories
- Pharmaceutical Quality System Maturity: Movement toward risk-based regulatory approaches that recognize mature quality systems
Implications for Pharmaceutical Organizations
Japanese pharmaceutical companies must maintain awareness of these evolving standards and proactively adapt their quality systems. This requires:
1. Continuous Learning and Professional Development Investment in training programs that build deep understanding of quality management principles, not merely procedural compliance.
2. Technology Modernization Implementation of electronic quality management systems (eQMS), manufacturing execution systems (MES), and data analytics platforms that support real-time monitoring and decision-making.
3. Cultural Transformation Evolution from compliance-driven behaviors to quality-minded behaviors where all personnel understand their role in protecting patient safety and product quality.
4. Cross-Functional Integration Breaking down organizational silos to create seamless collaboration between manufacturing, quality, engineering, regulatory affairs, and supply chain functions.
5. Regulatory Intelligence Establishing systematic monitoring of regulatory developments in Japan and internationally to ensure timely implementation of new requirements.
Conclusion
The 2021 revision of the GMP Ministerial Ordinance represents a fundamental transformation in pharmaceutical quality management in Japan. By formally incorporating the Pharmaceutical Quality System concept from ICH Q10 and strengthening the authority and responsibilities of Manufacturing Managers, the revised ordinance aims to establish robust quality systems that prevent the types of compliance failures that undermined public trust in recent years.
However, effective implementation requires more than procedural compliance—it demands a genuine understanding of quality management principles rooted in frameworks such as ISO 9001 and a commitment to building quality-focused organizational cultures. Manufacturing Managers now serve as critical quality leaders who must not only oversee daily operations but also advocate for systemic improvements and ensure alignment between regulatory commitments and manufacturing realities.
The success of these reforms will ultimately depend on whether pharmaceutical organizations embrace the cultural shift from “performance for inspection” to “performance for patients”—moving beyond minimum compliance to pursue excellence in quality management as a strategic imperative and ethical obligation.
Note: This document provides an educational overview of the revised GMP Ministerial Ordinance requirements. Organizations should consult the official regulatory texts, guidance documents, and qualified regulatory professionals for specific compliance requirements applicable to their operations. The regulatory landscape continues to evolve, and companies must maintain current awareness of all applicable requirements.
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