Japan maintains one of the most rigorous and structured Good Manufacturing Practice (GMP) compliance frameworks globally. Designed to ensure the safety, efficacy, and quality of drugs and quasi-drugs, Japan’s GMP regime is enforced by the Pharmaceuticals and Medical Devices Agency (PMDA), under the Ministry of Health, Labour and Welfare (MHLW). For foreign manufacturers seeking to obtain or maintain market authorization in Japan, understanding and navigating this regulatory landscape is crucial.

This article provides an in-depth overview of the GMP compliance inspection system for foreign drug manufacturers, including inspection types, applicable manufacturing sites, inspection procedures, required documentation, and exemptions.

Introduction to Japan’s GMP Framework

Japan’s GMP compliance requirements are codified in the “Ministerial Ordinance on Standards for Manufacturing Control and Quality Control for Drugs and Quasi-drugs” (Ordinance No. 179 of 2004). Foreign manufacturing facilities that intend to supply drugs to the Japanese market must demonstrate conformity with these standards through inspections conducted or validated by the PMDA. Compliance is a mandatory prerequisite for marketing approval.

Types of GMP Compliance Inspections

Japan’s GMP inspection system categorizes inspections into two broad groups: those based on applications and those initiated independently of any application.

Application-Based Inspections

These inspections are triggered by regulatory filings and include:

New Marketing Approval Applications: Conducted when a manufacturer submits a new drug application.
Partial Change Applications: Initiated when significant changes to previously approved information are proposed.
Post-Approval Change Management Protocol (PACMP): Introduced in August 2021, this framework allows manufacturers to predefine the scope and procedures for post-approval changes, with inspections conducted to confirm implementation.
Periodic Inspections: Conducted every five years post-marketing approval. These ensure ongoing compliance with GMP standards.
Product Category-Based Inspections: Manufacturers may undergo inspections for specific manufacturing process categories. A successful inspection results in a three-year certificate that may exempt the site from routine periodic inspections for products in the certified category. This system, introduced in 2021, enhances international harmonization.

Non-Application-Based Inspections

These are driven by the PMDA’s internal risk assessments:

Routine Risk-Based Inspections: Regularly scheduled based on risk factors such as product type, compliance history, and manufacturing complexity.
For-Cause Inspections: Triggered by specific concerns, complaints, or product quality issues.

Manufacturing Sites Subject to Inspection

GMP compliance inspections may target different categories of manufacturing and testing facilities, based on the nature of the regulatory application or the inspection type.

Application-Based Inspections

For new marketing approvals or PACMP confirmation, inspections are required for:

Manufacturing sites listed in the application.
External testing laboratories cited in the application, unless:
- The site has undergone a recent inspection for the same product or active substance.
- Documentation verifying compliance (e.g., GMP notification and product identity) is submitted.

Periodic Inspections

Every five years, periodic inspections encompass:

All manufacturing stages, including formulation, active substances, intermediates, packaging, labeling, and storage.
Exceptions include:
- Sites holding a valid GMP certificate for a product category.
- Sites already confirmed GMP-compliant for the same active substances with supporting documentation.
- External testing laboratories meeting exemption conditions.

Notably, manufacturers of active substances used in over-the-counter (OTC) drugs (excluding new OTC drugs) are exempt from mandatory inspections.

Inspection Procedures: From Application to Outcome

Application Process

Foreign manufacturers do not apply directly for inspections. Instead, the marketing authorization holder (MAH) in Japan must initiate the application.

Inspection Methods

Inspections are primarily conducted onsite by PMDA inspectors. However, in certain cases, such as:

Low-risk products,
Countries with recognized GMP standards, or
Sufficient existing compliance documentation,

The PMDA may conduct a desktop inspection (document-based review).

Outcome Reporting

Upon completion:

PMDA submits a GMP Compliance Inspection Result Notification to MHLW.
Copies are issued to the MAH and, in the case of onsite inspections, to the foreign manufacturer.
Desktop inspections do not generate inspection result reports for manufacturers.

The inspection flow may vary depending on whether Master Files (MFs) are utilized in the application. These confidential documents, which include details of manufacturing processes and controls, may influence the inspection scope and depth.

Required Documentation for Inspection Applications

All documents must be submitted in Japanese. Summaries may be accepted for large foreign-language submissions. Document requirements vary slightly by inspection type.

For Application-Based and PACMP Inspections

Applicants must submit:

Previous inspection reports or compliance certificates (from within the last two years).
For sites in Mutual Recognition Agreement (MRA) countries (EU countries, the US, and Indonesia are some countries that have MRAs with Japan): certificates based on the MRA.
For Memorandum of Understanding (MOU) countries (EU countries, the US, and China are some countries that have MOUs with Japan): MOU-based certificates.
For all others: WHO certificate or equivalent.
Marketing approval application.
Any additional documents specified by the inspectorate.

For Periodic Inspections

Additional requirements include:

Five-year history of partial change and minor change notifications.
Product recall records (if applicable).
Rationale for selecting representative products if applying for multiple products.
Site master file or equivalent documentation.

For Product Category-Based Inspections

Additional documentation includes:

List of products in the same manufacturing category.
Inspection history of these products.
Summary of compliance issues in the past three years (including global issues such as recalls or import alerts).
Site master file or equivalent.
Statement prepared by the applicant, along with supporting documents

Harmonization with International Standards

Japan’s introduction of PACMP and product category-based inspections reflects a growing emphasis on aligning its GMP framework with global practices. These efforts promote efficiency, reduce inspection redundancies, and provide greater predictability for foreign manufacturers.

By recognizing certifications from regulatory counterparts in MRA or MOU countries and accepting international GMP documentation in lieu of duplicate inspections, Japan is demonstrating regulatory maturity while maintaining rigorous standards.

Key Takeaways for Foreign Manufacturers

Early Preparation: Begin assembling necessary documents – including recent GMP certificates and inspection reports – well in advance of application timelines.
Leverage International Agreements: If your manufacturing site is in a country with an MRA or MOU with Japan, your certification process may be simplified.
Engage a Knowledgeable MAH: Since the MAH serves as the intermediary with PMDA, selecting one with inspection experience and regulatory fluency is critical.
Track Certification Validity: Product category certificates are valid for three years and can help reduce future inspection burdens.
Maintain Robust GMP Systems: Routine and for-cause inspections may occur at any time, so consistent GMP adherence is essential to avoid non-compliance outcomes.

Conclusion

Japan’s GMP compliance inspection framework serves as a gatekeeper for the nation’s high pharmaceutical quality standards. For foreign drug manufacturers, mastering this system is essential not only to gain market entry but to maintain uninterrupted product distribution within one of the world’s most highly regulated drug markets. By understanding inspection types, exemption criteria, and documentation protocols, manufacturers can streamline compliance efforts and build trust with Japanese regulators.

As Japan continues to modernize its approach through systems like PACMP and product category-based certification, opportunities for global harmonization and efficiency gains are expanding – benefiting regulators, industry players, and ultimately, patients.

Written by: Ames Gross – President and Founder, Pacific Bridge Medical (PBM)

Mr. Gross founded PBM in 1988 and has helped hundreds of medical companies with regulatory and business development issues in Asia. He is recognized nationally and internationally as a leader in the Asian medical markets. Mr. Gross has a BA degree, Phi Beta Kappa, from the University of Pennsylvania and an MBA from Columbia University.

Japan’s GMP Compliance System for Foreign Drug Manufacturers