Revised GMP Ministerial Ordinance and Data Integrity Officers

Organizational Structure of Responsible Persons under the Revised GMP Ministerial Ordinance

The Revised GMP Ministerial Ordinance (Partial Amendment of the Ministerial Ordinance on Standards for Manufacturing Control and Quality Control of Drugs and Quasi-drugs, Ministry of Health, Labour and Welfare Ordinance No. 90 of 2021), which came into effect on August 1, 2021, marked the first major revision in 16 years. This revision requires manufacturers to designate twelve responsible persons as “persons designated in advance” in addition to the manufacturing supervisor.

Type of Responsible Person	Legal Basis (Article)
Person responsible for creating and storing pharmaceutical quality system records	Article 3-3, Paragraph 1, Item 5
Person responsible for quality risk management	Article 3-4
Person responsible for managing external contractors	Article 11-5
Person responsible for validation	Article 13
Person responsible for change control	Article 14
Person responsible for deviation management	Article 15
Person responsible for quality information and quality defect handling	Article 16
Person responsible for recall processing	Article 17
Person responsible for self-inspection	Article 18
Person responsible for education and training	Article 19
Person responsible for document and record management	Article 20, Paragraph 1
Person responsible for data integrity	Article 20, Paragraph 2

The appointment of these responsible persons aims to ensure the effectiveness of the Pharmaceutical Quality System (PQS) and align with the international standard PIC/S GMP Guidelines.

Requirements for Data Integrity Officers

Article 20, Paragraph 2 is a critical provision requiring the assurance of Data Integrity (DI).

Article 20: Management of Documents and Records

Paragraph 2

Manufacturing operators, etc. shall cause persons designated in advance to carry out the following operations based on the documents stipulated in Article 8, Paragraph 2, with respect to procedure manuals, etc. and records stipulated in this chapter:

(i) To continuously manage so that there are no omissions in procedure manuals, etc. and records that should be created and stored;

(ii) To continuously manage so that the created procedure manuals, etc. and records have accurate content;

(iii) To continuously manage so that there are no inconsistencies with the content of other procedure manuals, etc. and records;

(iv) In cases where there are omissions in procedure manuals, etc. or records, or when inaccuracies or inconsistencies are found in their content, to investigate the cause and take necessary corrective and preventive measures;

(v) Other operations necessary to ensure the reliability of procedure manuals, etc. and records;

(vi) To create records of the operations in the preceding items and store them.

Explanation in the Implementation Notice

The Implementation Notice (Notification regarding Partial Amendment of the Ministerial Ordinance on Standards for Manufacturing Control and Quality Control of Drugs and Quasi-drugs, Yakusei Kanma Hatsu No. 0428, April 28, 2021, GMP Implementation Notice), in its “Article-by-Article Explanation,” provides the following interpretation of Article 20, Paragraph 2:

Regarding Article 20, Paragraph 2:

This provision stipulates operations related to ensuring the reliability (so-called data integrity) of the pharmaceutical product standard documents and procedure manuals stipulated in Article 8, Paragraph 1 of the GMP Ministerial Ordinance, as well as records stipulated in Chapter 2 of the same ordinance, to be carried out by persons designated in advance by drug manufacturers, etc.

Regarding persons designated in advance, it is required that, depending on the type and content of the documents and records, staff members who are well-versed in ensuring their reliability should be designated in advance as responsible persons, and their duties and authorities, including those specified in the documents pursuant to Article 6, Paragraph 4 of the GMP Ministerial Ordinance, should be appropriately defined.

So-called shadow manuals and duplicate records, etc., are naturally unacceptable. For ensuring the reliability of documents and records related to pharmaceutical manufacturing, reference may be made to PIC/S guidance document PI 041 “Good Practice for Data Management and Integrity in Regulated GMP/GDP Environments,” etc.

Practical Challenges in Ensuring Data Integrity

Ensuring data integrity across all procedure manuals and records is by no means an easy task. Even if one “Data Integrity Officer” is appointed as required by the Revised GMP Ministerial Ordinance and its explanatory notes, it would be extremely difficult to scrutinize and ensure data integrity for all products and all process records.

Recommended Organizational Structure

To establish an effective data integrity assurance system, the following organizational approach is recommended:

It is necessary to deploy multiple data integrity officers throughout the entire GMP organization and establish a steering committee or similar body to continuously monitor the status of data integrity assurance. This is consistent with the requirement in Article 6, Paragraph 2 of the GMP Ministerial Ordinance, which states that “manufacturing operators, etc. shall deploy an appropriate number of responsible persons according to the organization, scale, and types of operations of the manufacturing facility.”

Response to Implementation

The implementation date of the Revised GMP Ministerial Ordinance was August 1, 2021. Each manufacturer needed to complete the appointment of data integrity officers and the revision of Standard Operating Procedures (SOPs). As of now (2025), more than four years after implementation, many manufacturers are working on establishing and operating data integrity systems.

Current Status of Data Integrity Guidelines in Japan

Absence of Guidelines and Reference Documents

As of January 2025, the Ministry of Health, Labour and Welfare has not issued its own guidelines on data integrity in Japan. The explanatory notes only mention reference to PIC/S-related guidance documents.

Position of PIC/S Guidance

An important point must be highlighted here. PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme) is an organization of regulatory authorities, established for the purpose of harmonizing regulatory requirements and inspection standards among member countries. It is decidedly not an organization or guidance for pharmaceutical companies, but rather has the character of guidance for inspectors.

On July 1, 2021, PIC/S issued the final version of its data integrity guidance, “Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments” (PI 041-1). This guidance was finalized after approximately five years, with draft versions progressively published since 2016.

Proper Regulatory Framework

Ideally, member regulatory authorities should develop their own regulatory requirements in accordance with PIC/S requirements and demand compliance from companies.

All the new GMP requirements for the 21st century—“Pharmaceutical Quality System,” “Quality Risk Management,” “Risk-Based Approach,” and “Data Integrity”—are concepts first proposed by overseas regulatory authorities such as the FDA (U.S. Food and Drug Administration).

Issues and Future Prospects for Japanese Regulations

International Status and Regulatory Lag

It is regrettable that Japan, a major pharmaceutical consumer nation and one of the three poles of ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) founding members along with the U.S. and Europe, has not been able to propose new regulatory concepts that are globally applicable.

Furthermore, it is a fact that these concepts have been incorporated into ordinances as a follow-up to overseas developments. The current Revised GMP Ministerial Ordinance was the first revision in 16 years, during which time international GMP standards had evolved significantly.

Need for Guideline Development

Moreover, it is puzzling for pharmaceutical companies to be told to refer to overseas guidelines or PIC/S inspector-oriented guidance. Ideally, Japan should develop its own data integrity guidelines for Japanese pharmaceutical manufacturers, taking into account the Japanese regulatory environment and industry realities.

Future Expectations

The following initiatives are expected from the Ministry of Health, Labour and Welfare and PMDA (Pharmaceuticals and Medical Devices Agency):

The development of Japan’s own data integrity guidelines is needed to provide practical guidance on what specific measures pharmaceutical companies should take. Additionally, Japanese-language explanations and case studies of PIC/S guidance, simplified guides for small and medium-sized manufacturers, and continuous enhancement of Q&As on data integrity are also important.

Furthermore, by establishing forums for dialogue between pharmaceutical companies and regulatory authorities to share practical challenges and questions, it becomes possible to build a more effective regulatory environment.

International Regulatory Trends

Major Regulatory Authority Guidance

Regarding data integrity, the following regulatory authorities have published their own guidance:

Regulatory Authority	Guidance Title	Year Published
MHRA (UK)	GXP Data Integrity Guidance and Definitions	2015 (first edition), 2018 (revised edition)
WHO	WHO Guidance on good data and record management practices	2016 (first edition), 2021 (revised edition, Technical Report Series No. 1033)
PIC/S	Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1)	July 2021 (final version)
FDA (US)	Data Integrity and Compliance With Drug CGMP Questions and Answers	December 2018 (final version)

ALCOA+ Principles

A concept common to these guidance documents is the “ALCOA+” principles. This concept, created by FDA inspectors in the early 1990s, represents the characteristics necessary for data integrity and consists of the following elements:

Initial	English	Japanese	Description
A	Attributable	帰属性	The creator and creation date/time of data can be identified
L	Legible	判読性	Data must be readable
C	Contemporaneous	同時性	Data must be recorded concurrently with the activity
O	Original	原本性	Data must be original or a True Copy
A	Accurate	正確性	Data must be accurate
C	Complete	完全性	Data must be complete (no omissions)
C	Consistent	一貫性	Data must be consistent
E	Enduring	永続性	Data must be retained throughout the retention period
A	Available	可用性	Data must be available when needed

Data Governance and Risk-Based Approach

Importance of Data Governance

PIC/S Guidance PI 041-1 emphasizes the concept of data governance. Data governance is a comprehensive system that ensures data integrity, guaranteeing records that meet the ALCOA+ principles throughout the data lifecycle, regardless of the processes, formats, or technologies used for data generation, recording, processing, storage, retrieval, and use.

Implementation of Risk-Based Approach

In the series of processes for pharmaceutical manufacturing, inspection, and testing, it is practically impossible to comprehensively and exhaustively ensure data integrity based on ALCOA+. The risk-based approach becomes important here.

Rather than applying measures of the same level to all processes equally, it is required to conduct comprehensive risk assessments of processes, operations, and related manufacturers, and to reasonably implement measures to ensure data integrity focusing particularly on high-risk areas.

The important point in this regard is to consider the risk-based approach from the perspective of fulfilling accountability to stakeholders (including patients). It is necessary not only from an internal management perspective but also to be able to explain externally that pharmaceutical manufacturing, inspection, and testing were appropriately conducted based on correct procedures approved by regulatory authorities.

Responsibility of Senior Management

Article 3-3 of the Revised GMP Ministerial Ordinance clarifies the responsibility of senior management (officers responsible for pharmaceutical affairs, including the representatives of corporate manufacturing operators) in establishing the pharmaceutical quality system.

Senior management corresponds to “Senior Management” in the ICH Q10 Guideline and PIC/S GMP Guidelines, and is responsible for establishing and implementing an effective pharmaceutical quality system. This naturally includes establishing a data integrity assurance system.

As can be seen from recent cases of misconduct by pharmaceutical companies in Japan, data integrity issues are not merely field-level problems but are greatly influenced by the quality culture of management. It is essential for senior management to understand the importance of data integrity, allocate appropriate resources, and establish an effective management system to achieve the paramount objective of pharmaceutical GMP—patient protection.

Conclusion

More than four years have passed since the implementation of the Revised GMP Ministerial Ordinance, but ensuring data integrity remains an important challenge for the pharmaceutical industry. The establishment of a system with twelve responsible persons, particularly the appropriate appointment and empowerment of data integrity officers, is required.

Since Japan does not have its own guidelines, it is necessary for each company to establish an effective system appropriate to its own situation while referring to PIC/S guidance and guidance from various countries. However, ideally, Japanese regulatory authorities should develop practical guidelines for pharmaceutical companies, and future responses are anticipated.

Ensuring data integrity is not merely a compliance issue but an important initiative directly connected to the fundamental mission of pharmaceutical manufacturing—protecting patient safety. Under the leadership of senior management, it is required to foster a data integrity culture throughout the organization and pursue continuous improvement.