FDA Inspection Priorities: Fact-Checked and Enhanced

Due to the COVID-19 pandemic, FDA inspections (routine inspections) in Japan have been in a state of suspension. The author has attended many FDA inspections over the years. On those occasions, questions such as “Why was our company selected for inspection?” or “What is the logic behind selecting facilities for inspection?” are frequently heard.

In routine inspections, the FDA employs a risk-based approach model called the Site Selection Model (SSM) to calculate scores for all facilities in its catalog. Based on these scores, the facilities to be inspected annually are determined. The SSM aims to allocate limited inspection resources most effectively and prioritize facilities with higher public health risks.

The FDA’s Site Selection Model calculates risk scores by considering the following key factors. Let us examine each factor in detail.

Product-Specific Risk

Different types of products have different levels of risk based on characteristics such as dosage form, route of administration, or whether the product is intended to be sterile. For example, a manufacturing facility that produces sterile injectable drugs has a higher inherent product risk than a facility that manufactures oral capsules. This is because the manufacturing process for sterile products is complex, and contamination can pose significant health risks to patients. Similarly, facilities handling biological products or highly potent active pharmaceutical ingredients (HPAPIs) are also classified as high-risk.

Facility Type

Risk levels vary depending on the operations conducted by the facility. Facilities that manufacture drugs or active pharmaceutical ingredients (APIs) have higher risk than facilities that only package drugs. The more complex the manufacturing process, the higher the possibility of quality problems occurring. Additionally, API manufacturing facilities are particularly important because they directly affect the quality of the final product. Furthermore, contract manufacturing organizations (CMOs) and facilities manufacturing for multiple clients also receive attention due to the breadth of their impact.

Patient Exposure

The more products a facility manufactures, the more likely patients are to encounter products manufactured at that facility. This refers to both the number and types of products manufactured. Facilities that manufacture many products have a higher exposure factor than facilities that manufacture few products. Additionally, the volume of products distributed in the market and the number of patients using the products are also considered. In particular, facilities manufacturing widely used essential medicines or drugs with limited alternatives have higher priority due to the magnitude of their impact.

Inspection History

Facilities that did not meet established quality standards when previously inspected are considered higher risk than facilities that met standards in the past. In FDA inspections, three classifications are used: NAI (No Action Indicated), VAI (Voluntary Action Indicated), and OAI (Official Action Indicated). Facilities that received OAI or VAI determinations have shorter intervals until the next inspection and higher priority. Additionally, facilities that received Warning Letters or Import Alerts are placed under even stricter surveillance.

Time Since Last Inspection

As the time since a facility was last inspected increases, the risk that it may not meet established quality standards increases, and the need for re-inspection similarly increases. The FDA generally aims to inspect domestic facilities every two years and foreign facilities every four years, but through the risk-based approach, this frequency is adjusted based on the aforementioned factors. As the inspection interval lengthens, the period during which changes or deterioration in the facility’s quality system cannot be detected extends, causing the risk score to increase.

Hazard Signals

Events such as product recalls or manufacturer or patient reports of quality issues related to the facility increase the risk score compared to facilities with few or no major hazard signals. Specifically, this includes adverse event reports, product complaints, trend analysis of quality information, and information sharing from foreign regulatory authorities. Additionally, serious adverse events reported to the FDA’s MedWatch (Drug Safety Reporting System) and trends identified in Annual Product Quality Reviews (APQR) are also considered. Furthermore, deficiencies in the pharmaceutical quality system (PQS), increased deviations, and change control issues also serve as important signals.

Other Considerations

In addition to the main factors above, the FDA may also consider the following additional elements.

Facilities manufacturing products related to drug shortages may be inspected preferentially from the perspective of ensuring supply stability. Additionally, facilities manufacturing newly approved products (NDA/ANDA) or facilities with significant changes to manufacturing processes are also subject to Pre-Approval Inspections (PAI) or early post-approval inspections.

From the perspective of international regulatory harmonization, consistency with guidelines from PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme) and ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) is also emphasized. In particular, the concepts of ICH Q9 (Quality Risk Management), Q10 (Pharmaceutical Quality System), and Q12 (Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management) form the foundation of the FDA’s risk-based inspection approach.

After the COVID-19 pandemic, the FDA has also introduced new inspection methods such as remote inspections and hybrid inspections, which have improved the flexibility and efficiency of inspections. However, for high-risk facilities such as sterile product manufacturing facilities, on-site inspections continue to be emphasized.

Summary

The FDA’s Site Selection Model is a scientifically-based, transparent system and an important tool for utilizing limited resources most effectively. Manufacturers can minimize inspection findings and contribute to public health by understanding these risk factors and striving for continuous quality improvement and compliance maintenance. In particular, establishing robust quality systems, appropriate deviation management, effective CAPA systems, and management engagement in quality are important.