FDA Foreign Inspection Status and Inspection Cases in Japan

Current Status and Latest Trends in FDA’s Foreign Inspection Program

On May 6, 2025, the U.S. Food and Drug Administration (FDA) announced a significant expansion of unannounced inspections at foreign manufacturing facilities. This policy shift is positioned as part of enhanced oversight of foreign facilities manufacturing products intended for the U.S. market, including pharmaceuticals, foods, and medical devices.

Historically, the FDA has provided advance notice for foreign facility inspections. According to fiscal year 2023 data, approximately 90% of foreign facility inspections were pre-announced. This contrasted with domestic manufacturing facilities, which typically undergo unannounced inspections. This double standard has been criticized for years, but with the May 2025 announcement, foreign facilities will now receive the same level of oversight as domestic facilities.

This policy change is based on an Executive Order signed by President Trump on May 5, 2025. The Executive Order aims to promote domestic pharmaceutical manufacturing and enhance inspection of foreign manufacturing facilities. The FDA is required to develop and implement improvements to its risk-based inspection regime for foreign manufacturing facilities within 90 days, ensuring routine reviews of foreign manufacturing facilities that supply medicines to the United States.

Post-COVID-19 Pandemic Inspection Resumption and Backlog

The COVID-19 pandemic led to the suspension of most FDA inspections in March 2020. Regular foreign inspections did not resume until 2022. As of May 2024, approximately 2,000 pharmaceutical manufacturing firms had not been inspected since before the pandemic. This backlog includes over 340 plants in India and China, which are major sources of active pharmaceutical ingredients (APIs) for the U.S. market.

According to FDA guidelines, factories uninspected for five or more years are considered a significant risk and prioritized for mandatory inspection. As of June 2024, the FDA faced 225 vacancies in its inspection workforce—nearly four times the pre-COVID number. Factors contributing to this shortfall include extensive travel requirements (up to 50% of the time), lower starting salaries compared to industry roles, and increased competition from the private sector, where former inspectors can earn more than double their FDA salary.

Changes in Inspection Approach

The FDA is implementing multiple policy changes to improve its inspection program.

First, to maintain inspection independence, the FDA has clarified policies prohibiting FDA investigators from accepting travel accommodations from regulated industry, including lodging and transportation arrangements (taxi, limousine, and for-hire vehicle transit).

Second, FDA Commissioner Makary has indicated a shift in how inspections will be conducted, stating that inspectors will not be “hanging out for three to four weeks” but will instead “get in and out” and conduct more inspections with the same amount of resources.

Furthermore, in 2024, the FDA published a plan to address the pandemic-era inspection backlog. The plan outlines a risk-based strategy to prioritize overdue inspections and mitigate gaps in oversight.

Utilization of Alternative Inspection Tools

During the pandemic, the FDA relied on tools such as record requests, virtual site evaluations, foreign regulator reports, and utilization of Mutual Recognition Agreements (MRAs) to maintain regulatory oversight. However, the FDA emphasizes that these means are not substitutes for onsite inspections.

The Consolidated Appropriations Act of 2023 included a provision for the FDA to conduct additional work on developing the foreign drug inspection program and explore further use of alternative inspection tools.

Mission-Critical Inspections

When deemed mission-critical, the FDA continues to conduct inspections of foreign facilities. This includes significant quality issues, patient safety risks, or other high-priority matters.

Representative FDA Inspection Case in Japan: Takeda Pharmaceutical Hikari Plant

An important example of FDA foreign inspection in Japan is the inspection of Takeda Pharmaceutical Company Limited’s Hikari Plant in Yamaguchi Prefecture.

Background and Context of the Inspection

The FDA inspected Takeda Pharmaceutical’s Hikari Plant from November 18 to 26, 2019. This inspection addressed significant concerns related to the manufacturing of sterile products.

Following the inspection, the FDA issued a Warning Letter (Warning Letter 320-20-37) dated June 9, 2020. This Warning Letter outlined significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals.

Key Citations

The Warning Letter cited significant violations based on Title 21 Code of Federal Regulations (CFR), Parts 210 and 211. The major violations included:

1. Inadequacy of Quality Unit Responsibilities and Oversight (21 CFR 211.22)

The FDA noted that Takeda’s Quality Unit (QU) did not take appropriate steps prior to resumption of aseptic manufacturing after a shutdown that included multiple significant activities that compromised cleanroom control.

Additionally, the Quality Unit failed to conduct adequate investigations of unexplained discrepancies and batch non-conformances. This constituted a violation of 21 CFR 211.192. This regulation stipulates that “any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed.”

2. Inadequate Procedures to Prevent Microbiological Contamination of Sterile Drug Products (21 CFR 211.113(b))

Takeda failed to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including validation of all aseptic and sterilization processes.

Specifically, the aseptic processing simulation (media fill) program was inadequate and lacked assurance that aseptic processing operations are adequately performed to prevent microbial contamination. For example, during media fill execution, the firm removed intact vials with complete container-closure systems and did not incubate them.

3. Particulate Matter Issues and Sterilization Process Deficiencies

The inspection discovered serious particulate matter defects in multiple batches of sterile products. Takeda acknowledged that equipment used for sterilizing injectable product components had been malfunctioning for an extended period but failed to adequately explain why the malfunctioning equipment continued to be used.

The FDA required a comprehensive, retrospective, independent review of all batches manufactured since May 2018 for the impact of undetected particles.

Data Integrity Citations

The Warning Letter cited significant problems not only from a CGMP compliance perspective but also from a data integrity perspective.

During the inspection, falsification of airborne particulate measurement records and other data integrity violations were discovered. The FDA noted the following:

These data integrity violations raise doubts about the product’s sterility assurance. Deficiencies in systems for reconciling uncontrolled test worksheets and laboratory documents undermine the reliability of Takeda’s documentation. Takeda’s Quality Management System (QMS) does not adequately ensure the accuracy and completeness of data supporting the safety, efficacy, and quality of the drugs it manufactures.

FDA Guidance Compliance Requirements

In the Warning Letter, the FDA instructed Takeda to reference the FDA guidance document “Data Integrity and Compliance with Drug CGMP: Questions and Answers” (finalized in December 2018) and establish data integrity practices compliant with CGMP.

This guidance was developed to clarify the role of data integrity in CGMP for drugs. The FDA issued this guidance in response to an increase in findings of data integrity lapses in recent inspections.

The guidance defines data integrity as “processes and systems designed to ensure that data are complete, consistent, accurate, trustworthy, reliable, and available.” It also emphasizes the importance of ALCOA+ principles (Attributable, Legible, Contemporaneous, Original, Accurate, plus Complete, Consistent, Enduring, and Available).

Subsequent Progress of Inspection Results

Takeda immediately implemented a comprehensive Corrective Action/Preventive Action (CAPA) plan in response to the Warning Letter and provided monthly progress updates to the FDA.

On October 13, 2021, the FDA revised the inspection classification of Takeda’s Hikari manufacturing site to Voluntary Action Indicated (VAI). This meant that the FDA determined the conditions in the Warning Letter dated June 2020 had been addressed, and the Warning Letter was closed.

However, Takeda and the FDA agreed to maintain dialogue regarding ongoing commitments, and future FDA inspections and regulatory activities will further assess the adequacy and sustainability of these corrections.

Importance of Data Integrity and Latest Regulatory Requirements

Overview of FDA Data Integrity Guidance

The FDA’s “Data Integrity and Compliance with Drug CGMP: Questions and Answers” guidance, finalized in December 2018, is a comprehensive document clarifying the role of data integrity in pharmaceutical manufacturing.

This guidance was revised to reflect public comments on the draft version from April 2016. The guidance is structured in a question-and-answer format covering 18 topics including data integrity definitions, audit trails, metadata, electronic records and copies, frequency of data review, system access, and investigations.

Fundamental Principles of Data Integrity

The FDA expects all data to be reliable and accurate. CGMP regulations and guidance allow for flexible and risk-based strategies to prevent and detect data integrity issues.

The guidance defines data integrity as “the extent to which data are complete, consistent, and accurate.” This means data are complete, consistent, and accurate throughout the data life cycle, from creation through processing, use, data retention, retrieval, and disposal.

Role of Management

The guidance emphasizes the role of management with executive responsibility. Management is responsible for creating a quality culture where employees understand that data integrity is an organizational core value and are encouraged to identify and promptly report data integrity issues.

The absence of management support of a quality culture can lead to breakdown of quality systems and CGMP non-compliance. The FDA recommends that management ask the following questions to ensure CGMP compliance:

Are controls in place to ensure that data is complete? Are activities documented at the time of performance? Are activities attributable to a specific individual? Can only authorized individuals make changes to records? Are audit trails generated to record changes? Is data maintained securely from data creation through disposition after the record’s retention period?

Audit Trails and Metadata

The guidance defines an audit trail as “a secure, computer-generated, time-stamped electronic record that allows for reconstruction of the course of events relating to the creation, modification, or deletion of an electronic record.”

Audit trails are considered part of the associated records. If the review frequency for data is specified in CGMP regulations, then the frequency for audit trail review should be the same. For example, since 21 CFR 211.188(b) requires review after each significant step in manufacture, processing, packing, or holding, and 21 CFR 211.22 requires data review before batch release, audit trails must be reviewed for each batch before that batch can be released for distribution.

Metadata is defined as “the contextual information required to understand data.” Metadata includes units (such as milligrams), date/time stamps, user IDs, instrument IDs, material status data, material identification numbers, and audit trails.

Invalidation and Exclusion of Test Results

The guidance clarifies that invalidating test results to exclude them from quality unit decisions about conformance to a specification requires a valid, documented, scientifically sound justification.

However, even if test results are legitimately invalidated on the basis of a scientifically sound investigation, the full CGMP batch record provided to the quality unit must include the original (invalidated) data, along with the investigation report that justifies invalidating the result.

Validation of Computerized Systems

The guidance states that workflows such as batch records and control records are an intended use of a computer system, which needs to be checked through validation.

If you validate your computer system but do not validate it for its intended use, you cannot know if your workflow is running correctly. Any changes to computerized master production and control records (MPCRs) or other records, as well as the input of laboratory data into computerized records, must be completed only by authorized personnel.

Training Requirements

The guidance clarifies that training personnel to detect data integrity issues is consistent with a routine CGMP training program.

If an employee provides an internal tip or information regarding a quality issue such as potential data falsification, a company should not handle it informally outside of the documented CGMP quality system.

Access by Inspectors

The FDA guidance clarifies that FDA investigators are allowed to look at electronic records. 21 CFR 211.180(c) and (d) stipulate the authority of investigators to examine and copy records and reports.

Alignment with International Standards

Relationship with ICH Q7 and Q10

The FDA’s data integrity guidance is aligned with ICH Q7 (Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients) and ICH Q10 (Pharmaceutical Quality System).

ICH Q7 stipulates data integrity requirements in API manufacturing, requiring record accuracy, legibility, contemporaneous recording, and originality.

ICH Q10 provides a model for a comprehensive quality management system throughout the pharmaceutical lifecycle, and data integrity is positioned as a critical element of this system.

PIC/S and MHRA Data Integrity Guidance

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) issued “Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments” in 2021. This guidance provides an internationally harmonized approach to data integrity.

The UK Medicines and Healthcare products Regulatory Agency (MHRA) also finalized “GXP Data Integrity Guidance and Definitions” in 2018, which is aligned with FDA and PIC/S guidance.

Practical Implications and Recommendations for Pharmaceutical Companies

Preparation for Unannounced Inspections

The FDA’s May 2025 announcement means that foreign manufacturing facilities are now likely to receive unannounced inspections similar to domestic facilities. This signifies the end of the “cyclical” inspection preparation era for pharmaceutical companies.

Companies need to be inspection-ready every day. This includes implementing strong quality systems, real-time data traceability, and rigorous training protocols for operational and quality teams.

Risk-Based Inspection Targets

The FDA is now deploying a risk-based inspection model that prioritizes:

Facilities with previously identified significant deficiencies, facilities uninspected for five or more years, facilities manufacturing high-risk products (sterile products, injectables, critical medicines), facilities with data integrity concerns, or facilities associated with patient safety risks.

Cultivating a Quality Culture

The FDA emphasizes the role of management with executive responsibility in creating a quality culture where employees understand data integrity as an organizational core value and are encouraged to identify and promptly report data integrity issues.

It is essential to cultivate a site culture where regulatory compliance is embedded in daily operations—not staged for scheduled audits.

Strengthening Inspection Programs

According to the FDA’s 2024 inspectional performance summary, 45% of foreign inspections revealed data integrity concerns or failure to meet basic CGMP standards. This means that despite advance notice, foreign facilities showed serious deficiencies more than twice as often as domestic facilities.

Companies should consider implementing robust visual inspection programs, including alternative inspection technologies (such as x-ray inspections or destructive testing). Such technologies are particularly important for products in opaque containers.

Alignment with Strategic Business Planning

It is equally important to align inspection readiness with strategic business planning. Quality and regulatory leaders must have a seat at the executive table to flag risks, allocate resources, and drive continuous improvement across global networks.

Cooperation with International Regulatory Authorities

The FDA is working closely with international regulatory bodies—including the European Medicines Agency (EMA), Japan’s Pharmaceutical and Medical Devices Agency (PMDA), and Australia’s Therapeutic Goods Administration (TGA)—to share inspectional findings and intelligence.

Companies can optimize their global regulatory strategy by leveraging Mutual Recognition Agreements (MRAs) and maintaining good relationships with multiple regulatory authorities.

Conclusion

The FDA’s expansion of unannounced inspections of foreign manufacturing facilities marks a long-term evolution in regulatory oversight. Built on lessons learned during the COVID-19 pandemic, it aims to enhance domestic manufacturing and align foreign inspection standards with those applied to U.S. facilities.

Pharmaceutical companies need to implement robust quality systems, ensure data integrity, and cultivate a site culture that embeds regulatory compliance in daily operations to adapt to this new inspection environment. Data integrity, in particular, is the foundation of CGMP compliance and essential to ensure patient safety, drug efficacy, and quality.

As demonstrated by the Takeda Pharmaceutical case, even when significant violations are discovered, companies can restore trust with regulatory authorities through comprehensive corrective actions and continuous improvement efforts. However, a preventive approach is always the best strategy, and companies should ensure they are inspection-ready every day.

Ultimately, the FDA’s expansion of unannounced inspections serves the common goal of strengthening the integrity of the global pharmaceutical supply chain and providing safe, effective, and high-quality medicines to patients worldwide.