The Ministry of Health, Labour and Welfare (MHLW) commenced public comment solicitation regarding the draft partial revision of the “Ministerial Ordinance on Good Manufacturing Practice for Medicinal Products and Quasi-drugs” (GMP Ordinance) on November 27, 2020, and concluded on December 26, 2020.
The revised GMP Ordinance was promulgated on April 28, 2021, and implemented on August 1, 2021.
Originally, implementation was scheduled for October 2018; however, the revision was delayed due to postponements in amendments to the Pharmaceuticals and Medical Devices Act (PMD Act), compounded by the COVID-19 pandemic.
Given that the previous GMP revision occurred in 2005 (Heisei 17), this represents a major overhaul after sixteen years.
Research concerning the revised GMP Ordinance has been conducted through the “Study on International Harmonization of Guidelines for GMP, QMS, and GCTP” (Principal Investigator: Nobuhide Sakurai).
The only published literature regarding the draft revised GMP Ordinance was a presentation titled “Draft GMP Ordinance Revision, PMDA Inspection Cases, and Future Direction” delivered at the 45th GMP Case Study Meeting held on July 12, 2018. This presentation disclosed the draft ordinance text (hereinafter referred to as “Research Group Draft”), concepts, and draft implementation notices.
The revision employs the method of partial amendment rather than comprehensive revision. Consequently, article numbers remain unchanged. Therefore, when adding requirements to existing provisions, article numbers have been expanded (e.g., Article 11, Paragraph 2; Article 11, Paragraph 3).
The author finds it regrettable that the revised ordinance represents a significant retreat from the Research Group Draft. The revised ordinance lacks provisions regarding senior management responsibility and information communication that were present in the Research Group Draft. Notably, requirements concerning “data integrity” (completeness of documents and records) are explicitly addressed, contrary to the author’s initial assessment in 2020.
Correction regarding Data Integrity: Upon reviewing the final revised GMP Ordinance and implementation notices, data integrity requirements have been incorporated. Article 8, Paragraph 2 (Procedures, etc.) and Article 20, Paragraph 2 (Document and Record Management) explicitly address data integrity. The implementation notice (Ministerial Notification No. 0428-2, April 28, 2021) clarifies that these provisions concern data integrity and references PIC/S guidance document PI 041 “Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments.” Therefore, the original statement that data integrity requirements are absent was incorrect based on the promulgated ordinance.
Article 3-2 (Compliance with Approved Matters) likely aims to prevent recurrence of past discovered irregularities.
The most significant additional requirement in the revised ordinance is Article 3-3 (Pharmaceutical Quality System). The “Pharmaceutical Quality System” is mandated by ICH Q10 “Guideline on Pharmaceutical Quality System.”
Due to space limitations, detailed explanation of “quality system” is omitted; however, those seeking comprehensive understanding may refer to the author’s lectures.
The “Pharmaceutical Quality System” fundamentally operates on the Plan-Do-Check-Act (PDCA) cycle. “Senior management”—namely presidents and board members—must establish quality policy and implement a Quality Management System (QMS) within the organization. Senior management bears responsibility not only for business management but also for quality assurance, operating the organization with leadership. Thus, governance is required.
Moving forward, seminars and publications concerning the revised GMP Ordinance are anticipated to proliferate; however, these will vary in quality, necessitating discernment of authenticity. This is because Japanese pharmaceutical companies have historically lacked established concepts of “quality systems,” with limited experienced practitioners.
“Quality systems” (Quality Management Systems: QMS) have internationally established standards through quality management standards such as ISO 9001. The FDA published guidance titled “Quality Systems Approach to Pharmaceutical CGMP Regulations” in September 2006, complementing cGMP.
Article 3-4 (Quality Risk Management) requires adopting a risk-based approach in accordance with ICH Q9. For information regarding risk-based approaches, please refer to the author’s lectures.
Furthermore, Article 4 explicitly separates the quality unit into “Quality Control Department” (QC) and “Quality Assurance Department” (QA). The Quality Assurance Department possesses independent responsibility and authority, implementing quality assurance operations centered on lot release determination. The responsibility of the Quality Assurance Department has increased beyond previous requirements.
Article 8 (Procedures, etc.) explicitly specifies procedure names to be created. The three previously required standard documents—“Manufacturing Control Standards,” “Quality Control Standards,” and “Hygiene Control Standards”—have been abolished, with each now defined as procedures. The author surmises this change may reflect the incompatibility of pre-establishing “standards” when adopting risk-based approaches.
Article 11 (Quality Control) adds “stability monitoring,” “product quality review,” and “supplier management for raw materials, etc.” While these have been required by PIC/S GMP and already reflected in implementation notices, they are now incorporated into the ordinance itself.
Chapter 3, concerning quasi-drugs, has been enhanced with detailed requirements, transitioning from previous quasi-application of pharmaceutical provisions. This likely reflects differing risk profiles between pharmaceuticals and quasi-drugs.
As an aside, in the revised ordinance, Chapter 2, Section 3, concerning sterile pharmaceuticals, Article 25 (Education and Training) is absent. If anyone knows the reason for this omission, the author welcomes enlightenment.
Additional Context: Recent Developments and Industry Trends
Background of the Revision
The 2021 GMP Ordinance revision was driven by multiple factors:
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International Harmonization: Japan joined PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme) in July 2014, necessitating alignment with international GMP standards. PIC/S, established in 1995, promotes harmonized GMP standards and improved inspection quality among regulatory authorities. As of 2025, PIC/S comprises 58 authorities from 52 countries.
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Quality Issues and Corporate Scandals: Between 2015 and 2020, numerous quality issues emerged in Japan’s pharmaceutical industry, including unauthorized manufacturing practices and improper documentation. In 2015-2016, a comprehensive inspection of all 32,466 approved pharmaceutical products revealed that 69% (22,297 products from 479 companies) had discrepancies requiring minor change notifications. More seriously, in December 2020, a generic drug manufacturer incident involving contamination of antifungal medication with sleeping pills exposed systemic compliance failures, leading to supply disruptions across the industry.
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Simultaneous PMD Act Revision: The revised Pharmaceuticals and Medical Devices Act, implemented concurrently on August 1, 2021, mandated establishment of compliance systems (governance structures), reinforcing the GMP Ordinance’s quality system requirements.
Key Provisions of the Revised GMP Ordinance
| Article | Requirement | Description |
|---|---|---|
| Article 3-2 | Compliance with Approved Matters | Ensures manufacturing according to approved specifications |
| Article 3-3 | Pharmaceutical Quality System | Implementation of ICH Q10-based quality management system |
| Article 3-4 | Quality Risk Management | Adoption of ICH Q9-based risk assessment approaches |
| Article 4 | Quality Organization Structure | Explicit separation of QC and QA departments |
| Article 8 | Procedures and Standards | Specification of required procedure documents; abolishment of three standard documents |
| Article 11 | Quality Control Enhancements | Addition of stability monitoring, product quality review, supplier management |
| Article 8, Para 2 & Article 20, Para 2 | Data Integrity | Requirements for maintaining reliability of documents and records throughout their lifecycle |
Data Integrity Requirements
The revised GMP Ordinance incorporates specific data integrity provisions:
Article 8, Paragraph 2 requires manufacturers to establish documented procedures ensuring continuous reliability of pharmaceutical product standards, procedures, and records as specified in Article 20, Paragraph 2.
Article 20, Paragraph 2 mandates manufacturers to:
- Designate responsible personnel for data integrity assurance
- Establish procedures for data lifecycle management
- Ensure data is: Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Available (ALCOA+ principles)
The implementation notice (Ministerial Notification dated April 28, 2021) explicitly references PIC/S guidance PI 041 and clarifies that data integrity encompasses the entire lifecycle from data creation through retention period expiration. The notice emphasizes that data integrity applies equally to paper-based and electronic records.
Organizations must:
- Appoint data integrity responsible personnel with defined roles and authorities
- Implement controls preventing unauthorized data modification
- Maintain audit trails for electronic systems
- Establish backup and recovery procedures
- Conduct periodic data integrity audits
The revised ordinance addresses the paradigm shift from “good faith” assumptions to evidence-based quality assurance, reflecting global regulatory expectations.
Responsible Persons System
The revised GMP Ordinance requires designation of twelve specific responsible persons beyond the manufacturing supervisor:
- Pharmaceutical Quality System record creation/retention responsible person (Article 3-3)
- Quality Risk Management responsible person (Article 3-4)
- External contractor management responsible person (Article 11-5)
- Validation responsible person (Article 13)
- Change control responsible person (Article 14)
- Deviation management responsible person (Article 15)
- Quality information and defect processing responsible person (Article 16)
- Recall processing responsible person (Article 17)
- Self-inspection responsible person (Article 18)
- Education and training responsible person (Article 19)
- Document and record management responsible person (Article 20, Para 1)
- Data integrity responsible person (Article 20, Para 2)
ICH Q10: Pharmaceutical Quality System
ICH Q10, issued as Step 4 guidance in June 2008 and implemented in Japan through ministerial notification in February 2010, provides a comprehensive quality management framework. Key elements include:
Four Pillars of ICH Q10:
- Process performance and product quality monitoring
- Corrective Action and Preventive Action (CAPA) system
- Change management
- Management review
Senior Management Responsibilities (Section 2 of ICH Q10):
- Establish and document quality policy
- Demonstrate visible commitment to pharmaceutical quality system
- Ensure timely communication and escalation processes
- Define roles, responsibilities, authorities, and interrelationships
- Conduct management reviews of process performance and quality system effectiveness
- Allocate adequate resources
Quality Manual: ICH Q10 requires a quality manual as the top-level document describing the pharmaceutical quality system, outlining quality policy, quality objectives, and organizational structure.
Continuous Improvement: The guidance promotes innovation and continual improvement throughout the product lifecycle, emphasizing knowledge management and integration between pharmaceutical development and commercial manufacturing.
Implementation Guidance and International References
The implementation notice encourages reference to:
- PIC/S GMP Guidelines (particularly Part I, Chapter 1 on Pharmaceutical Quality System)
- ICH Q8 (Pharmaceutical Development)
- ICH Q9 (Quality Risk Management)
- FDA Guidance “Quality Systems Approach to Pharmaceutical CGMP Regulations” (September 2006)
- PIC/S PI 041-1 “Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments” (July 2021 final version)
Industry Impact and Challenges
The 2021 revision represents a fundamental shift in Japanese pharmaceutical manufacturing philosophy:
From “Trust-Based” to “Evidence-Based”: Historically, Japanese GMP operated under “good faith” assumptions (性善説). The revised ordinance aligns with international “verification-based” approaches, requiring objective evidence and documentation.
Unannounced Inspections: Regulatory authorities (MHLW and PMDA) now conduct unannounced inspections, detecting non-compliance more effectively and deterring fraudulent practices.
Computerized System Validation (CSV): Data integrity requirements necessitate proper validation of computerized systems, following the “Guideline for Computerized Systems Management for Pharmaceutical and Quasi-drug Manufacturers” (October 21, 2010, Ministerial Notification). This guideline aligns with GAMP 5 and PIC/S CSV guidelines, adopting lifecycle approaches.
Cultural Transformation: Companies must cultivate quality culture emphasizing:
- Transparency and accountability
- Scientific understanding of products and processes
- Risk-based decision making
- Continuous improvement mindset
Current Status (2025)
As of 2025, the pharmaceutical industry continues adapting to the 2021 requirements:
- Ongoing Training: Companies conduct extensive training for all personnel on pharmaceutical quality systems, risk management, and data integrity
- System Modernization: Investment in electronic systems (MES, LIMS, CDS) meeting data integrity requirements
- Governance Strengthening: Enhanced senior management involvement in quality oversight
- Supplier Management: Implementation of comprehensive supplier quality management programs
- International Alignment: Japanese manufacturers increasingly competitive in global markets through PIC/S compliance
The revised GMP Ordinance positions Japanese pharmaceutical manufacturing to meet international standards while protecting patient safety through enhanced quality systems. Companies demonstrating effective implementation of these requirements experience benefits including:
- Reduced quality incidents
- Improved regulatory inspection outcomes
- Enhanced international competitiveness
- More efficient operations through systematic approaches
- Greater stakeholder confidence
Going forward, our company will disseminate accurate understanding of the revised GMP and QMS Ordinances through newsletters, website content, and other channels.
About the Author: The author is a recognized expert in pharmaceutical quality systems and GMP compliance, offering lectures and consultations on the revised GMP Ordinance, ICH Q10 implementation, and quality risk management.
Note: This analysis is provided for educational purposes. Organizations should consult official MHLW publications and qualified experts when implementing revised GMP Ordinance requirements.
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