Good Manufacturing Practice (GMP) compliance is required for drug registration approval in Japan. The Pharmaceuticals and Medical Devices Agency (PMDA) conducts GMP inspections at foreign manufacturing sites to verify adherence to Japan’s GMP ordinance (MHLW Ordinance No. 179, 2004). This article provides an overview of Japan’s GMP inspection types, scope, and procedures, with special focus on requirements for foreign manufacturers.

Types of GMP Compliance Inspections

PMDA conducts several kinds of inspections based on the product lifecycle, risk analysis, and regulatory submissions.

1. Application-Based Inspections

These occur when manufacturers seek:

• New marketing approval
• Approval for partial changes to existing products
• Confirmation of a Post-Approval Change Management Protocol (PACMP)

If the PMDA determines during review that an inspection is necessary, the relevant manufacturing sites and external testing laboratories will be subject to GMP inspection.

Exemptions:
A site may skip inspection if GMP for the same product or active substance has already been confirmed, and the applicant submits:

• A copy of the previous GMP compliance notification, and
• Documentation verifying product identity.

2. Periodic Inspections (Every Five Years)

All manufacturing sites listed in the marketing approval file, including formulation, APIs, intermediates, packaging, labeling, and storage, are inspected every five years.

Exemptions:

• Sites holding a valid GMP certificate for product category-based inspection, effective for three years. This system, introduced for international alignment in 2021, allows periodic inspection to be omitted for products in that category (except initial periodic inspections for new drugs).
• Sites already confirmed compliant for the same active substance, with the appropriate documentation submitted.

3. Product Category-Based Inspections

This newer system categorizes manufacturing processes and issues a three-year certificate per category. If a product falls within a category covered by the certificate, periodic inspection may be waived. This approach aligns Japan’s system more closely with international practices.

4. Inspections Not Based on Applications

PMDA may also conduct:

• Routine inspections based on risk analysis
• For-cause inspections triggered by quality issues, adverse events, or regulatory concerns

These inspections do not depend on marketing applications.

5. Exclusions

Manufacturers of active substances for OTC drugs (excluding new drugs) are not required to apply for GMP compliance inspection.

Manufacturing Sites Subject to Inspection

The scope of inspections differs depending on the inspection type, but generally includes:

• Formulation sites
• Active substance / API manufacturers
• Intermediate manufacturers
• Packaging and labeling sites
• Storage/warehouse locations
• External testing laboratories

Eligibility for exemptions depends on previously confirmed GMP compliance and whether the site holds a valid product category certificate.

Inspection Process for Foreign Manufacturers

1. Application Procedure

Foreign manufacturers cannot apply directly. Instead, applications must be submitted by:

• The Marketing Authorization Holder (MAH),
• A holder of exceptional approval for foreign manufacturers, or
• An applicant seeking exceptional approval (who must also appoint an MAH).

2. On-site vs. Desktop Inspection

The default method is an onsite inspection conducted by PMDA at the foreign site.

However, PMDA may opt for a desk-top (document-based) inspection depending on:

• Product risk
• GMP standards and enforcement practices in the country
• Information from the pre-submitted documentation
• Previous compliance history

Desk-top inspections enhance efficiency while maintaining oversight for lower-risk scenarios.

3. Reporting and Documentation

After completing the inspection:

• PMDA prepares a GMP Compliance Inspection Result Notification and submits it to the Ministry of Health, Labour and Welfare (MHLW).
• The MAH receives a copy of the notification.
• A GMP Compliance Inspection Result Report is issued to the foreign manufacturer if an on-site inspection was conducted. For desktop inspections, this report is not issued.

4. Use of Master Files (MFs)

The flow of GMP inspection may differ depending on whether Master Files are used for APIs or intermediates. PMDA provides model process flows in its training materials.

Japan’s GMP inspection system is comprehensive and multi-layered, ensuring rigorous oversight throughout the product lifecycle. Foreign manufacturers are subject to the same expectations as domestic sites and must work closely with their marketing authorization holders to navigate the process. Recent initiatives, such as PACMP inspections and product category-based certifications, demonstrate Japan’s commitment to streamlining regulatory oversight while maintaining alignment with international standards. Ultimately, a manufacturer’s compliance history and product risk profile determine whether PMDA conducts onsite or document-based inspections. Clear, accurate documentation remains critical, particularly when seeking inspection exemptions, as it helps minimize redundant reviews and ensures smoother interactions with regulators.