Standard Operating Procedures Required by the Revised GMP Ministerial Ordinance

Introduction

The revised GMP Ministerial Ordinance (Ministry of Health, Labour and Welfare Ordinance No. 90 of 2021), which came into effect on August 1, 2021, has brought significant changes to Japan’s pharmaceutical manufacturing industry. The primary objectives of this revision were to ensure international harmonization as a member of PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme) and to incorporate the concepts of ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) into regulatory requirements.

The 17 Types of Standard Operating Procedures Required by the Revised GMP Ministerial Ordinance

Article 8 of the revised GMP Ministerial Ordinance specifies 17 types of standard operating procedures (SOPs) that manufacturers must establish. These SOPs form the core of the Pharmaceutical Quality System (PQS) documentation framework and serve as the foundation for manufacturing control and quality control.

List of the 17 Types of Standard Operating Procedures

No.	Type of Standard Operating Procedure	Relationship to Previous GMP
1	Procedures for the sanitation control of facilities, equipment, and personnel	Previously: Sanitation Control Standards
2	Procedures for the control of manufacturing processes, manufacturing equipment, raw materials, materials, and products	Previously: Manufacturing Control Standards
3	Procedures necessary for the control of testing equipment and specimens and other appropriate testing	Previously: Quality Control Standards
4	Procedures for stability monitoring	Added in 2013 GMP Implementation Notice
5	Procedures for product quality review	Added in 2013 GMP Implementation Notice
6	Procedures for the control of suppliers of raw materials and materials	Added in 2013 GMP Implementation Notice
7	Procedures for the control of other entities that perform part of manufacturing and quality-related operations, including testing, on consignment from manufacturers	Added in 2013 GMP Implementation Notice
8	Procedures for the control of shipment from manufacturing sites	–
9	Procedures for validation	–
10	Procedures for change control as specified in Article 14	–
11	Procedures for deviation control as specified in Article 15	–
12	Procedures for handling quality information and quality defects as specified in Article 16	–
13	Procedures for handling recalls	–
14	Procedures for self-inspection	–
15	Procedures for education and training	–
16	Procedures for the preparation, revision, and storage of documents and records	–
17	Other procedures necessary for appropriate and smooth manufacturing and quality-related operations	–

Transition from Three Master Documents to Standard Operating Procedures

Under the previous GMP Ministerial Ordinance, three documents were required to be prepared as “master documents” (Sanitation Control Master Document, Manufacturing Control Master Document, and Quality Control Master Document). In the revised GMP Ministerial Ordinance, these have been repositioned as “standard operating procedures.” This change is not merely a change in terminology but reflects an intention to require more practical and specific documentation of operational procedures.

The three previous master documents have been transitioned to procedures as follows:

• Sanitation Control Master Document → Procedures for the sanitation control of facilities, equipment, and personnel (No. 1)
• Manufacturing Control Master Document → Procedures for the control of manufacturing processes, manufacturing equipment, raw materials, materials, and products (No. 2)
• Quality Control Master Document → Procedures necessary for the control of testing equipment and specimens and other appropriate testing (No. 3)

Additional Procedures for PIC/S GMP Harmonization

Four procedures that were added in the GMP Implementation Notice of August 30, 2013, to harmonize with PIC/S GMP have now been formally incorporated into the ministerial ordinance through this revision:

• Procedures for stability monitoring (No. 4)
• Procedures for product quality review (No. 5)
• Procedures for the control of suppliers of raw materials and materials (No. 6)
• Procedures for the control of other entities that perform part of manufacturing and quality-related operations, including testing, on consignment from manufacturers (No. 7)

Standard Operating Procedures for Data Integrity and Quality Risk Management

Why Dedicated Procedures Are Not Explicitly Required

Some may question why the revised GMP Ministerial Ordinance does not explicitly require the creation of dedicated procedures for data integrity and quality risk management. There is a clear rationale for this approach.

Data integrity and quality risk management are not concepts limited to specific departments or specific processes; rather, they are fundamental principles that should be applied horizontally across all departments, all processes, and all procedures. Therefore, instead of establishing specialized organizations to handle these matters or creating independent procedures, it is required that the concepts of data integrity and quality risk management be incorporated into each existing procedure.

Responding to Data Integrity Requirements

Regarding data integrity, Article 8, Paragraph 2 and Article 20, Paragraph 2 of the revised GMP Ministerial Ordinance clearly require continuous assurance of the reliability of procedures and records. Specifically, the following controls are required:

1. Continuous control to ensure that procedures and records to be prepared and stored are not lacking
2. Continuous control to ensure that prepared procedures and records have accurate content
3. Continuous control to ensure consistency with the content of other procedures and records
4. Implementation of corrective and preventive actions when deficiencies, inaccuracies, or inconsistencies are identified
5. Other operations necessary to ensure the reliability of procedures and records

Status of International Data Integrity Guidelines

The original column pointed out that “there is no data integrity guideline in Japan,” and this situation continues today. While Japan has not issued its own data integrity guideline, reference to the following international guidelines is recommended:

• PIC/S PI 041-1 “Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments” (Final version issued July 1, 2021)
• FDA “Data Integrity and Compliance with Drug CGMP Questions and Answers” (Revised December 2018)
• MHRA “GxP Data Integrity Guidance and Definitions” (Revised version March 2018)
• WHO “Guideline on Data Integrity” (Technical Report Series, No. 1033, 2021)

The explanatory notes on the revised GMP Ministerial Ordinance (Notification No. 0428, April 28, 2021, from the Director of the Pharmaceutical Safety and Environmental Health Bureau) also suggest referring to the PIC/S guideline, and in practice, compliance with international guidelines is expected.

As basic requirements for data integrity, each guideline presents the “ALCOA+ (ALCOA CCEA) principles,” which consist of the following elements:

• Attributable: It must be possible to identify who did what and when
• Legible: Data must be clearly readable
• Contemporaneous: Data must be recorded at the time it is generated
• Original: Data must be the original or a true copy
• Accurate: Data must be accurate
• Complete: All data must be included
• Consistent: Data must be consistent without contradictions
• Enduring: Data must be maintained throughout the retention period
• Available: Data must be accessible when needed

Documents for Which Clear Requirements Are Insufficient in the Revised GMP Ministerial Ordinance

Quality Manual

The revised GMP Ministerial Ordinance has made the establishment of a Pharmaceutical Quality System (PQS) a mandatory requirement. In quality management systems such as ISO 9001, the “quality manual” is positioned as the top-level document of the PQS. While the explanatory notes on the revised GMP Ministerial Ordinance suggest that the creation of a quality manual is desirable, there is no statement in the text of the ordinance itself that clearly requires the creation of a quality manual.

Article 6 of the revised GMP Ministerial Ordinance requires the creation of a “quality policy,” but the quality policy and the quality manual are separate documents. In standard practice for quality management systems, the quality policy is typically included within the quality manual.

A quality manual typically includes the following content:

• The organization’s quality policy and quality objectives
• The scope of application of the quality management system
• Organizational structure and responsibilities and authorities
• Interrelationships of processes
• References to various procedures

Management Review Procedure

An indispensable element for making the PQS function effectively is management review. Article 7 of the revised GMP Ministerial Ordinance requires manufacturers (senior management) to conduct periodic management reviews, but there is no requirement in Article 8’s list of 17 types of procedures for the creation of specific procedures for conducting management reviews.

Furthermore, specific requirements regarding how to conduct management reviews are unclear. For example, the following important matters are not specified:

• Who should report to senior management (referred to as “manufacturers” in the ordinance) (i.e., who creates the input)?
• Who must participate in management reviews?
• Should management reviews be conducted in meeting format, or is a circulation format also acceptable?
• What is the appropriate frequency for management reviews?
• What should be documented as the output of management reviews?

In practice, it is recommended that each company establish appropriate procedures by referring to the requirements for management review in ICH Q10 “Pharmaceutical Quality System” and ISO 9001.

Corrective and Preventive Action (CAPA) Procedures

In the revised GMP Ministerial Ordinance, “corrective action” and “preventive action” are defined in Article 2, Items 14 and 15, and their implementation is required in multiple articles (such as Article 11-8 and Article 15-2). Although the CAPA system is an important component of the PQS, it is not explicitly included in the 17 types of procedures in Article 8. In practice, it can be addressed as part of Item 17 “Other procedures necessary for appropriate and smooth manufacturing and quality-related operations,” or incorporated into Item 11 “Procedures for deviation control” or Item 12 “Procedures for handling quality information and quality defects.”

Future Prospects for PQS Development

In the current trend of globalization, further penetration of PIC/S GMP and ICH Q10 is desired. However, as mentioned above, the descriptions regarding PQS are not necessarily sufficient.

Since the implementation of the revised GMP Ministerial Ordinance, the Ministry of Health, Labour and Welfare has provided practical guidance through the issuance of case studies and Q&As. Continued development of the following types of documents is expected in the future:

• Guidance on specific content for quality manuals
• Case studies on how to conduct management reviews
• Practical guidelines for data integrity compliance (Japanese version guideline)
• Best practice examples for PQS development based on international harmonization

Recommended Practical Measures

To appropriately comply with the revised GMP Ministerial Ordinance, the following initiatives are recommended for manufacturers:

1. Review of existing procedures: Incorporate the concepts of data integrity and quality risk management into each of the 17 required procedures
2. Development of a quality manual: Even though not explicitly required by the ordinance, create a quality manual as the top-level document of the PQS
3. Establishment of management review procedures: Document specific management review procedures by referring to ICH Q10 and ISO 9001
4. Utilization of international guidelines: Refer to data integrity guidelines from PIC/S, FDA, MHRA, and WHO and reflect them in practice
5. Implementation of education and training: Provide education to all employees on the requirements of the revised GMP Ministerial Ordinance, particularly regarding data integrity and quality risk management
6. Regular self-inspection: Periodically inspect the implementation status of procedures and revise them as necessary

Conclusion

The revised GMP Ministerial Ordinance represents an important turning point that requires the Japanese pharmaceutical manufacturing industry to establish international-standard quality systems. While the 17 types of procedures form the foundation of this system, to build a truly effective PQS, it is essential not only to formally prepare these procedures but also to permeate the culture of data integrity, quality risk management, and continuous improvement throughout the entire organization.

While monitoring international regulatory trends, the pharmaceutical manufacturing industry is called upon to continuously strengthen its quality assurance systems with patient safety as the top priority.