I would like to discuss the issues surrounding the revised GMP Ministerial Ordinance, which was enforced in August 2021, from a practical standpoint.
Excessively Long Period Since Previous Revision
As much as 16 years have passed since the previous revision. Since the December 2004 revision, the environment surrounding pharmaceuticals has changed significantly, and globalization has progressed rapidly.
In 2013, the GMP Implementation Notice was revised to introduce PIC/S standards. The current GMP Ministerial Ordinance revision has codified the content that was incorporated in this GMP Implementation Notice.
A characteristic feature of regulatory requirements in Japan is the retrospective approach of revising ordinances after allowing practical implementation to take root. Specifically, operation is first initiated through division chief notifications and implementation notices, and after these become established in practice, they are codified as ministerial ordinances. Therefore, once an ordinance is enforced, there is a complete obligation to comply with its requirements from the effective date.
In contrast, Western regulatory requirements adopt a phased approach that incorporates expectations and guidance. Even if complete compliance is not achieved on the effective date, regulatory authorities provide guidance and gradually raise the required level as practices become established in operations. This difference reflects cultural disparities in the relationship between regulatory authorities and industry.
There are many instances where it is unclear what should be complied with and to what extent regulatory requirements extend in Japan. The documents that pharmaceutical manufacturers must refer to are diverse and include the following:
| Document Type | Legal Binding Force | Notes |
|---|---|---|
| GMP Ministerial Ordinance | Strong (Law) | Compliance mandatory |
| GMP Implementation Notice | Medium (Notice) | De facto compliance mandatory |
| Article-by-Article Commentary (Notice No. 0428-2) | Medium (Notice) | Interpretation of ordinance |
| Other Division Chief Notices | Medium (Notice) | Interpretation of specific matters |
| Case Studies and Q&A Collections | Reference | Practical reference materials |
| Foreign Guidelines (PIC/S, etc.) | Reference | Reference recommended |
For example, there are numerous requirements described in the article-by-article commentary that are not explicitly stated in the main text of the GMP Ministerial Ordinance. These are treated as requirements that must be complied with in practice, but their legal status is not necessarily clear.
Additionally, there are many matters for which reference to foreign guidelines such as PIC/S GMP Annex 15 (Qualification and Validation) and data integrity is suggested. Particularly regarding data integrity, no comprehensive Japanese guideline has been issued, and companies have no choice but to refer to guidelines from other countries such as those from the FDA, MHRA, and PIC/S.
Preparation Period Until Effective Date Too Short
Despite being a major revision for the first time in 16 years, the period until the effective date (August 1, 2021) was extremely short at approximately four months. The ordinance was promulgated on April 28, 2021, and was enforced approximately three months later.
As a point of comparison, in the case of the QMS Ministerial Ordinance (Ministerial Ordinance on Standards for Manufacturing Control and Quality Control of Medical Devices and In Vitro Diagnostic Reagents), which was also revised in 2021, a transition period of three years was established (promulgated March 26, 2021, until March 26, 2024). The QMS Ministerial Ordinance was also a large-scale revision to harmonize with the international standard ISO 13485:2016, but sufficient preparation time was secured.
As already explained in this newsletter, requirements related to quality risk management (based on ICH Q9) and data integrity need to be incorporated into almost all existing procedures. Quality risk management must be applied to all aspects of GMP activities, including product development, manufacturing, change control, deviation management, corrective and preventive action (CAPA), and supplier management.
Furthermore, it is necessary to establish a Pharmaceutical Quality System (PQS, based on ICH Q10) and create a quality manual. The pharmaceutical quality system requires restructuring the entire organization’s quality assurance structure, including establishment of quality policy, setting quality objectives, implementing management reviews, and establishing cycles of continuous improvement.
These are tasks that require considerable labor and time. While many manufacturing sites would have liked to wait for the issuance of case studies and Q&A collections, there was no time to wait for these before the effective date. As a result, each company was forced to respond based on their own interpretations within the limited time available.
Lacking Clarity, Difficult to Read, Difficult to Understand
A characteristic of Japanese regulatory documents is the problem that the true intent cannot be understood without reading both the main ordinance text and the article-by-article commentary together. This is because there are not a few provisions whose meaning cannot be understood without referring to the commentary.
Ambiguity Regarding Quality Manual
For example, there is no explicit requirement in the main ordinance text for the creation of a “quality manual.” However, the article-by-article commentary contains descriptions about quality manuals.
The quality manual is fundamental to the quality system and is the highest-level document in the quality system. Why is its creation not clearly required in the main ordinance text? This raises questions from the perspective of harmonization with international standards.
In international standards such as ISO 9001 and ISO 13485, the quality manual is clearly positioned as a core document of the quality management system. In these standards, the quality policy is established by management and incorporated into the quality manual.
However, in the article-by-article commentary, there are descriptions that seem to confuse quality policy with quality manual. The quality policy is the organization’s basic philosophy regarding quality as determined by management, while the quality manual is a document describing the entire quality system. The lack of clarity in this distinction has the potential to cause confusion in practice.
Treatment of Data Integrity
The term data integrity is also not included in the main ordinance text and is only mentioned in the article-by-article commentary. Despite data integrity being an important element of the revised GMP Ministerial Ordinance, its definition and requirements are not explicitly stated in the main ordinance text.
The article-by-article commentary presents the following three points (effectively four points) regarding data integrity:
- Continuously manage to ensure there are no omissions in procedures and records that should be created and stored
- Continuously manage to ensure that created procedures and records have accurate content
- Continuously manage to ensure there are no inconsistencies with the content of other procedures or records
- Take appropriate action when there are omissions in procedures or records, when they are inaccurate, or when there are inconsistencies
However, no comprehensive guidance on data integrity has been issued in Japan. Pharmaceutical companies have no choice but to refer to data integrity guidelines from other countries, such as the FDA guidance “Data Integrity and Compliance With Drug CGMP Questions and Answers (December 2018),” the MHRA guidance “GXP Data Integrity Guidance and Definitions (March 2018),” and the PIC/S guidance “Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1, July 2021).”
These foreign guidelines present detailed requirements based on the ALCOA principles (Attributable, Legible, Contemporaneous, Original, Accurate) and ALCOA+ principles (additionally adding Complete, Consistent, Enduring, and Available).
Insufficient Requirements for Management Review
Management review is a core activity of the pharmaceutical quality system. In ICH Q10, management review is an important process for periodically evaluating the suitability, adequacy, and effectiveness of the quality system and identifying opportunities for continuous improvement.
However, the term management review is not used in the main ordinance text. Furthermore, even in the article-by-article commentary, specific implementation methods and requirements for management review are not sufficiently explained.
In practice, questions arise such as:
- Who should create and report the input information for management review?
- Who must participate in management review (executives of the marketing authorization holder, representatives of the manufacturer, manufacturing supervisors, quality assurance managers, etc.)?
- Is the creation of a management review procedure necessary (it is not included in the 17 required procedures)?
- How should the frequency of management review be determined?
- What should be included in the output of management review?
In the international standards ICH Q10 and ISO 13485, the inputs and outputs of management review are clearly specified. For example, inputs include the status of achievement of quality objectives, product quality review results, change control status, effectiveness of corrective and preventive actions, audit results, and customer feedback.
Ordinance Title Does Not Match Reality
The ordinance title remains “Ministerial Ordinance on Standards for Manufacturing Control and Quality Control of Drugs and Quasi-Drugs.”
However, the ordinance does not present specific “standards.” The modern concept of GMP calls for manufacturers to determine appropriate standards themselves based on quality risk management and justify them, rather than presenting uniform standards. This is called the “risk-based approach.”
Global regulatory requirements no longer prescribe detailed standards but instead guide manufacturers to determine standards themselves based on risk and justify them with scientific evidence. If the revised GMP Ministerial Ordinance also adopts this risk-based approach, the word “standards” should be removed from the ordinance title.
With the current revision, the former three standard documents (sanitation control standards document, manufacturing control standards document, quality control standards document) were renamed to “procedures.” Also, “validation standards” was renamed to “validation guidelines.” These changes indicate a shift in direction from uniform standards to procedures and guidelines adapted to the circumstances of each manufacturing site.
Despite this, why does only the ordinance title remain “standards”? This inconsistency shows a discrepancy between the philosophy of the revision and the ordinance title.
Issues with Organizational Structure
The revised GMP Ministerial Ordinance adopts a two-department system of manufacturing department and quality department. The structure places quality assurance department (QA) and testing/inspection department (quality control department, QC) under the quality department.
However, in international standard thinking, a three-department system of manufacturing department, quality control department (QC), and quality assurance department (QA) is common, and the quality assurance department should have independent authority.
The quality assurance department should not be subordinate to the manufacturing supervisor or quality department head, but should be granted independent authority and not be subject to any organizational pressure or bias. The independence of the quality assurance department is essential for making objective quality judgments.
Under the ordinance’s requirements, the quality assurance department is positioned under the manufacturing supervisor and quality department head, making it a structure where true independence is difficult to secure. This organizational structure creates the potential for the quality assurance department to be susceptible to pressure from the manufacturing department.
Furthermore, because the quality assurance department is placed under the quality department, the role of the conventional quality control (QC) department is limitedly defined as “an organization responsible for testing and inspection operations.” However, the role of the quality control department should include broader quality control activities beyond just testing and inspection, such as establishing sampling plans, out-of-specification (OOS) investigations, analytical method validation, and conducting stability studies.
This ambiguity in definition also contributes to confusion in practice.
Issues with Term Definitions in Article-by-Article Commentary
Normally, definitions of terms should be included in the main ordinance text, but in the revised GMP Ministerial Ordinance, definitions of two terms (“instrument calibration” and “blood products that do not constitute a lot”) are only included in the article-by-article commentary.
From the principle of clarity of laws, definitions of terms related to requirements to be complied with should be included in the main ordinance text. The article-by-article commentary is merely to show interpretation of the ordinance and is not an appropriate place to add new definitions.
While this issue may be a formal criticism, improvement is desired from the perspective of clarifying the hierarchical structure and division of roles in legal documents.
Summary and Expectations for the Future
The revised GMP Ministerial Ordinance is a progressive revision that harmonizes with international standards and incorporates important elements such as introduction of pharmaceutical quality systems, utilization of quality risk management, and ensuring data integrity.
However, from a practical perspective, several challenges remain, including the short preparation period, complexity of document structure, and ambiguity of requirements. In future revisions and issuance of notices, consideration of these challenges and establishment of clearer and more effective regulatory requirements are expected.
In particular, continuous improvement is desired in the following areas:
- Securing sufficient preparation period (transition period of about 3 years)
- Clarification of role division between main ordinance text and article-by-article commentary
- Explicit inclusion of important elements such as quality manual and management review in the main ordinance text
- Issuance of Japanese-specific guidelines on data integrity
- Clarification of organizational structure that ensures independence of quality assurance department
- Further harmonization with international standards (ICH Q9, Q10, ISO standards, etc.)
For pharmaceutical companies, while recognizing these challenges, it is important to understand the intent of the revised GMP Ministerial Ordinance and strive to establish a quality assurance system with patient protection as the top priority.
For other detailed points and issues regarding the revised GMP Ministerial Ordinance, it is recommended to also refer to YouTube videos and other resources.
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