Which Companies Are Subject to FDA Inspection?

One of the questions frequently asked of this author is: “What types of companies are subject to routine FDA inspections?” The FDA employs a Site Selection Model (SSM) to determine which establishments will be inspected. Through the SSM, FDA calculates risk scores for all establishments in its catalog using risk-based factors.

Risk Factors Used in the Site Selection Model

The FDA utilizes multiple risk factors to prioritize manufacturing sites for routine surveillance inspections. These risk factors are based on Section 510(h)(4) of the Federal Food, Drug, and Cosmetic (FD&C) Act and are applied equally to both domestic and foreign establishments. The primary risk factors include:

1. Inherent Product Risk

Different types of products carry varying levels of risk based on characteristics such as dosage form, route of administration, therapeutic class, therapeutic index or range, and whether the product is intended to be sterile. For example, a manufacturing facility that produces sterile injectable pharmaceuticals presents higher inherent product risk than a facility that manufactures oral capsules. Additional considerations include whether the product has a narrow therapeutic index, the complexity of the formulation, and whether it is an emergency use drug.

2. Facility Type

Risk levels vary depending on the operations conducted at the facility. Establishments that manufacture drug products or active pharmaceutical ingredients (APIs) are considered higher risk than facilities that only package or label drug products, or those that serve solely as control laboratories.

3. Patient Exposure

The greater the volume and variety of products manufactured by a facility, the higher the probability that patients will encounter products made at that establishment. This exposure factor considers both the quantity of products manufactured and the diversity of the product portfolio, including the API load. Facilities that manufacture many different products have a higher exposure coefficient than those that produce only a limited number of products.

4. Inspection History and FDA Compliance History

Facilities that failed to meet established quality standards during previous inspections are considered higher risk than those with a history of compliance. This factor evaluates the establishment’s compliance with current good manufacturing practice (cGMP) requirements. The FDA considers inspection frequency and history, including whether the establishment has been inspected within the last four years, and reviews the classification outcomes of previous inspections (such as Official Action Indicated, Voluntary Action Indicated, or No Action Indicated).

5. Time Since Last Inspection

As the time elapsed since the last inspection increases, so does both the risk that the facility may not meet established quality standards and the need for re-inspection. This temporal factor is a critical component in determining inspection priority.

6. Hazard Signals

Events such as product recalls, Field Alert Reports (FARs), entries in FDA’s Adverse Event Reporting System (FAERS), Biological Product Deviation Reports (BPDRs), MedWatch reports, or reports from manufacturers or patients regarding quality issues associated with the facility result in higher risk scores compared to establishments with few or no major hazard signals.

7. Foreign Regulatory Authority Inspectional History

For foreign establishments, the FDA considers whether the facility has been inspected by a foreign government or agency recognized under Section 809 of the FD&C Act. The FDA has established mutual recognition agreements with certain regulatory authorities, such as those in the European Union, and participates in the Pharmaceutical Inspection Co-operation Scheme (PIC/S) to leverage inspection information from trusted international partners.

8. Regional and Country Compliance History

In June 2023, FDA revised its Site Selection Model to include a new risk factor: the compliance history of establishments in the country or region where the facility is located. This amendment, which implements provisions from the Food and Drug Omnibus Reform Act of 2022 (FDORA), considers the history of violations related to products exported from that country or region that are subject to FDA regulation. This means that a facility with a strong compliance record may still be prioritized for inspection if it is located in a region with a broader history of compliance issues, such as frequent import alerts, warning letters, or product recalls.

Implementation and Evolution of the Site Selection Model

The FDA’s approach to pharmaceutical inspections has evolved significantly over the past two decades. Originally, the FD&C Act required domestic drug manufacturing establishments to be inspected every two to three years on a fixed schedule. However, as the pharmaceutical supply chain became increasingly globalized, FDA resources became strained. The agency was unable to increase its inspector workforce proportionally to keep pace with the expanding number of facilities requiring oversight, both domestically and internationally across countries including Japan, Europe, China, India, and many others.

Recognizing that the fixed biennial inspection schedule was no longer sustainable, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012. Section 705 of FDASIA amended Section 510(h) of the FD&C Act, replacing the fixed minimum inspection interval for domestic sites with a risk-based schedule. This legislative change formalized the risk-based approach that FDA had begun implementing in 2005 as part of its “Pharmaceutical Quality for the 21st Century” initiative, and mandated that FDA inspect establishments in accordance with a risk-based schedule that considers “known safety risks,” regardless of whether they are domestic or foreign.

Under this revised framework, inspection frequency is no longer determined solely by the passage of time, but rather by the overall risk profile of each establishment as calculated through the SSM. The goal is to achieve parity in inspection frequency—meaning equal frequency for sites with equivalent risk scores, regardless of geography or product type.

The Office of Quality Surveillance and Inspection Prioritization

The FDA’s Office of Quality Surveillance (OQS), which operates within the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER), is responsible for maintaining and applying the SSM. The OQS generates the Site Surveillance Inspection List (SSIL), which prioritizes sites for routine surveillance inspections based on their calculated risk scores. The Office of Regulatory Affairs (ORA) is then responsible for planning and conducting the actual inspections based on the SSIL.

Newly registered sites are generally expected to be inspected within a reasonable timeframe after registration. The SSM undergoes annual review by a dedicated work group, and any changes to the model must be approved by the SSM Steering Committee to ensure that the prioritization methodology remains current and effective.

Increased Emphasis on Foreign Inspections

Beginning in fiscal year 2015, FDA conducted more inspections of foreign drug manufacturing establishments than domestic establishments—a significant shift from the agency’s historical focus. This transition reflects the reality that more than 50 percent of drug manufacturers supplying the U.S. market are now located overseas, with substantial manufacturing concentrated in countries such as China and India, as well as continuing operations in Japan, Europe, and Latin America.

The globalization of pharmaceutical manufacturing has meant that APIs and finished drug products are increasingly imported into the United States from foreign sources. To enhance its oversight capabilities, FDA established foreign offices in strategic locations beginning in 2008, including offices in China, Europe, India, and Latin America. These offices employ FDA investigators who conduct inspections locally and facilitate collaborative activities with foreign regulatory authorities.

Despite this increased international presence, FDA continues to face challenges in maintaining an adequate inspection workforce. Foreign inspections require specialized skills, as investigators often work independently in foreign establishments under constrained timeframes and may encounter language barriers or logistical challenges. The Government Accountability Office (GAO) has consistently reported concerns about vacancy rates among foreign-based investigators and has recommended that FDA develop tailored recruitment and retention strategies to ensure a sufficient inspection workforce.

Enhanced Inspection Objectives and Quality Culture

In the 2023 revision of MAPP 5014.1, FDA clarified that beyond verifying cGMP compliance, inspections also aim to gain insight into the effectiveness of a drug manufacturer’s quality system and the organization’s quality culture. The agency has emphasized that cGMP compliance represents the floor, not the ceiling—FDA expects manufacturers to exceed minimum standards and maintain a robust state of control through effective quality systems.

This shift reflects FDA’s evolving philosophy that quality cannot be inspected into products; rather, quality must be built into the design, development, and manufacturing processes. By assessing quality management maturity and quality culture during inspections, FDA seeks to identify establishments that not only meet regulatory requirements but also demonstrate proactive commitment to continuous improvement and patient safety.

Exemptions from the Site Selection Model

Certain types of establishments are exempt from the routine surveillance inspection program under the SSM. These exemptions include human drug compounding outsourcing facilities registered under Section 503B of the FD&C Act, medical gas manufacturing sites, facilities that only manufacture inactive ingredients (excipients), and sites that produce drugs intended solely for use in clinical trials. These establishments may still be subject to other types of FDA inspections, such as pre-approval inspections or for-cause inspections, but they are not included in the SSM’s risk-based prioritization for routine surveillance.

Transparency and Predictability

To increase transparency, FDA has made its Site Selection Model methodology publicly available through MAPP 5014.1, which was first published in September 2018 and revised in June 2023. While the MAPP does not disclose the specific weighting of individual risk factors or the precise algorithms used to calculate risk scores—as these determinations may involve proprietary FDA methodologies or the professional judgment of subject matter experts—it does provide substantial insight into the criteria FDA considers when prioritizing establishments for inspection.

Companies subject to cGMP surveillance inspections can use this information to assess their own risk profiles and predict the likelihood of being selected for inspection. By aligning internal quality control systems with the factors considered in the SSM, manufacturers can better identify potential high-risk conditions and take proactive steps to address them before an inspection occurs.

Despite the implementation of the risk-based model, data from FDA’s inspection dashboard reveals that many establishments continue to be inspected approximately every two to three years, suggesting that the practical application of the SSM may result in inspection frequencies that are not dramatically different from the previous fixed schedule—at least for many moderate-risk facilities.

Conclusion

The FDA’s use of the Site Selection Model represents a sophisticated, risk-based approach to prioritizing pharmaceutical manufacturing inspections in an increasingly complex and globalized supply chain. By considering a comprehensive array of risk factors—including inherent product risk, facility type, patient exposure, inspection history, time since last inspection, hazard signals, foreign regulatory inspectional history, and regional compliance history—the FDA aims to allocate its limited inspection resources most effectively to protect public health.

The evolution from a time-based domestic inspection mandate to a risk-based global inspection strategy reflects both legislative changes enacted through FDASIA in 2012 and the practical realities of pharmaceutical globalization. As the pharmaceutical industry continues to evolve, with more than half of drug manufacturers now located outside the United States, FDA’s commitment to maintaining inspection parity and leveraging international regulatory partnerships will remain critical to ensuring the safety and quality of drugs marketed in the United States.

Manufacturers should remain cognizant of the various risk factors FDA considers, maintain robust quality systems that exceed minimum cGMP requirements, foster strong quality cultures within their organizations, and be prepared for inspection at any time. Understanding the SSM’s methodology can help companies anticipate regulatory expectations and demonstrate their commitment to pharmaceutical quality and patient safety.