For companies operating in the pharmaceutical industry, inspections by the FDA (Food and Drug Administration) represent an unavoidable yet critical process. In recent years, the FDA has been utilizing the Site Selection Model (SSM) to efficiently and fairly select inspection targets. This article explains, in a manner accessible to beginners while maintaining professional standards, how the SSM determines which companies will be subject to inspection.
What is the Site Selection Model (SSM)?
The SSM is a statistical and risk-based model employed by the FDA to identify and prioritize manufacturing facilities (sites) for inspection. Given that inspecting all pharmaceutical manufacturing facilities with equal frequency is impractical, higher-risk facilities must be given greater priority. Against this backdrop, the SSM optimizes inspection targeting based on objective criteria.
The SSM was initially implemented in September 2018 through CDER’s Manual of Policies and Procedures (MAPP) 5014.1. This approach replaced the previous statutory two-year inspection cycle with a risk-based schedule, as codified in Section 510(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) in 2012. The model was subsequently revised in June 2023 (MAPP 5014.1 Rev. 1) to further enhance its effectiveness and incorporate emerging quality challenges.
Basic Components of the SSM
The SSM consists primarily of the following elements:
1. Risk Assessment Indicators
Product Risk Profile
Assessment is based on factors including dosage form (sterile products, oral preparations, etc.), severity of the target disease, and potential impact on patients. For example, injectable sterile products inherently carry higher contamination risks than oral solid dosage forms, while products for life-threatening diseases receive heightened scrutiny due to their critical nature.
Company Inspection History
Past inspection findings of GMP (Good Manufacturing Practice) violations and the status of corrective actions are heavily weighted. The FDA carefully evaluates whether previously identified issues have been adequately addressed and whether similar problems have recurred. Sites with Official Action Indicated (OAI) classifications are removed from routine surveillance inspection planning and are subject to re-inspection as part of the agency’s enforcement efforts.
Manufacturer Size and Activity Status
Production volume, market share, and manufacturing process complexity are also important factors. Large-scale manufacturers supplying critical medicines to the U.S. market or those operating complex multi-step manufacturing processes are typically assigned higher risk scores.
Country/Regional Compliance History
A significant addition in the June 2023 revision of MAPP 5014.1 was the inclusion of compliance history of establishments in the country or region where a facility is located. This change was made pursuant to amendments to Section 510(h)(4) of the FD&C Act by the Food and Drug Omnibus Reform Act (FDORA). If a particular country or region has a history of violations related to exported products, establishments in that jurisdiction may be assigned higher risk scores regardless of their individual compliance history.
2. Data Collection and Analysis
The foundation of the SSM consists of internal FDA databases, reports from manufacturers, and international information sharing (e.g., with the European Medicines Agency and other European regulatory authorities). Large volumes of collected data are used to calculate risk scores through algorithms. The FDA also leverages drug amount reports submitted pursuant to Section 510(j)(3) of the FD&C Act, as amended by the CARES Act, to evaluate patient exposure and inform surveillance planning.
Key data sources include:
- FDA’s Site Catalog of manufacturing establishments
- Historical inspection records and classification outcomes (NAI, VAI, OAI)
- Hazard signals (Field Alert Reports, Biological Product Deviation Reports, MedWatch reports, recalls)
- Information on newly registered sites
- Data from Mutual Recognition Agreement (MRA) partner inspections
- International regulatory intelligence
The Process of Determining Inspection Priority Through the SSM
The SSM is not merely a “checklist” but rather a dynamic and comprehensive risk evaluation system. The typical workflow follows this pattern:
1. Data Input
Risk-related information for each facility is collected and organized by the Office of Quality Surveillance (OQS), a component within CDER’s Office of Pharmaceutical Quality (OPQ).
2. Risk Scoring
The model assigns risk scores to each facility based on empirical evidence collected by the FDA, expert judgment from subject matter specialists, or a combination of both. The scoring process evaluates multiple risk factors simultaneously to generate a comprehensive risk profile for each establishment.
3. Priority Ranking
A Site Surveillance Inspection List (SSIL) is created with facilities ranked by their risk scores, with higher-scoring sites receiving inspection priority. This list is maintained and regularly updated by OQS and is used by the FDA’s Office of Regulatory Affairs (ORA) for planning and conducting inspections.
4. Adjustment by Responsible Officials
While the model’s output is highly influential, responsible officials may adjust priorities based on the latest on-site information, special circumstances, or emerging public health concerns. This human oversight ensures that the model’s statistical outputs are tempered with practical regulatory judgment and situational awareness.
The following types of sites are excluded from prioritization under the SSM:
- Human drug compounding outsourcing facilities registered under Section 503B of the FD&C Act
- Medical gas manufacturing sites
- Excipient manufacturers
- Investigational drug manufacturing sites
- Sites subject to specific alternative inspection protocols
Quality System Effectiveness: A New Inspection Focus
An important evolution in the 2023 revision of MAPP 5014.1 is the enhanced focus on quality system effectiveness. The FDA’s inspection objective now extends beyond mere cGMP compliance verification to encompass evaluation of whether a manufacturer’s quality system results in a robust state of control and promotes a quality culture that allows for exceeding the cGMP standard. In other words, cGMP compliance is viewed as the floor, not the ceiling, and the FDA seeks to identify facilities that demonstrate mature quality management practices.
This philosophical shift aligns with the FDA’s Quality Metrics Feedback Program and Quality Management Maturity (QMM) initiative, which aim to incentivize continuous quality improvement rather than mere minimum compliance. During inspections conducted under this framework, investigators assess:
- Management commitment to quality
- Integration of quality risk management principles
- Robustness of the pharmaceutical quality system
- Effectiveness of corrective and preventive action (CAPA) systems
- Quality culture and employee engagement
Model Governance and Continuous Improvement
The SSM is not a static tool completed upon implementation. It undergoes annual updates to reflect changes in manufacturing environments, distribution systems, emergence of new pharmaceutical technologies, and deepening international cooperation. An annual review and approval process involves joint assessment by CDER and ORA to improve risk factors, weights, and methodology.
This “governance” approach emphasizes validation of the algorithm’s validity and periodic revision of model parameters and evaluation indicators as necessary. For example, the FY2025 SSM incorporated insights from incomplete but growing drug amount reporting data, demonstrating the model’s adaptability to evolving data availability and regulatory intelligence sources.
Recent governance improvements include:
- Enhanced weighting of quality metrics based on empirical outcomes analysis
- Integration of supply chain vulnerability indicators
- Incorporation of emerging technology considerations (e.g., continuous manufacturing)
- Refinement of risk scoring for complex biologics and advanced therapy medicinal products
Inspection Classification and Implications
Following an inspection, the FDA assigns one of three classifications to each facility:
No Action Indicated (NAI)
This classification indicates that no objectionable conditions or practices were found during the inspection. The facility is considered to be in an acceptable state of compliance, and typically no Form FDA 483 is issued.
Voluntary Action Indicated (VAI)
This classification indicates that objectionable conditions or practices were found, but the FDA has determined that the facility can voluntarily correct its deficiencies without formal regulatory action. A Form FDA 483 is typically issued, and the facility is expected to implement corrective actions promptly.
Official Action Indicated (OAI)
This classification indicates that a facility is in an unacceptable state of compliance, and regulatory and/or administrative actions are recommended. Sites receiving OAI classifications are removed from routine surveillance inspection planning and are instead subject to re-inspection as part of FDA enforcement efforts. OAI classifications can significantly impact pending marketing applications and may result in warning letters, import alerts, or consent decrees.
The FDA aims to communicate inspection classifications within 90 days of inspection completion, as committed under the Generic Drug User Fee Amendments II (GDUFA II). These 90-day decisional letters explain what the classification means and how it may impact a company’s application approval prospects.
| Classification | Compliance Status | Form FDA 483 Issued | Typical FDA Action | Impact on Applications |
|---|---|---|---|---|
| NAI | Acceptable | Usually not | None required | No direct impact |
| VAI | Objectionable but correctable | Usually yes | Voluntary correction expected | No direct negative impact if corrected |
| OAI | Unacceptable | May be issued | Regulatory/administrative action | May delay or prevent approval |
Benefits of the SSM and Future Outlook
By utilizing the SSM, the FDA has achieved improved transparency and fairness in its inspection processes, while also providing companies with greater predictability. The application of the model equally to both domestic and foreign establishments promotes parity in inspection frequency, meaning sites with equivalent risk receive equal attention regardless of geographic location.
Future enhancements are expected to incorporate artificial intelligence and machine learning for increasingly precise risk assessment. Industry stakeholders should properly understand the SSM and establish appropriate quality management systems accordingly.
Key trends and future directions include:
Enhanced Data Integration
The FDA is actively expanding its data sources and developing sophisticated visualization tools to enhance decision-making and optimize resource allocation. This includes leveraging real-world supply chain data, adverse event reports, and international regulatory intelligence.
Focus on API Supply Chain
Recent data show that API manufacturers supplying compounding pharmacies represent a disproportionately high percentage of regulatory actions (72% over five years, despite comprising only 18% of API manufacturers). The FDA has prioritized these higher-risk sites for future surveillance, particularly those located in China and India.
International Cooperation
The FDA continues to expand Mutual Recognition Agreements with foreign regulatory authorities, reaching a record 198 MRA partner inspections in FY2024. These partnerships extend the FDA’s oversight capabilities and promote global harmonization of inspection standards.
Emerging Technology Assessment
As pharmaceutical manufacturing increasingly adopts advanced technologies such as continuous manufacturing, advanced analytics, and process analytical technology (PAT), the SSM is being refined to appropriately assess the unique risks and benefits associated with these innovations.
Practical Implications for Manufacturers
Understanding the SSM provides manufacturers with strategic insights for quality system development and inspection readiness:
Align Internal Quality Metrics
Companies subject to cGMP surveillance inspections should consider adjusting internal quality control scoring systems to align with factors incorporated into the SSM. This alignment enables better prediction of conditions the FDA may deem high-risk and allows for more targeted resource allocation.
Maintain Robust Documentation
Given the emphasis on inspection history and 483 responses, maintaining comprehensive documentation of corrective actions, root cause analyses, and quality improvements is essential. Deficient responses to 483 observations can escalate a VAI classification to OAI or trigger warning letters.
Develop Mature Quality Culture
The enhanced focus on quality system effectiveness beyond mere compliance means that manufacturers should invest in building robust quality management systems, fostering quality culture, and demonstrating commitment to continuous improvement.
Monitor Country/Regional Trends
With the addition of country/regional compliance history as a risk factor, manufacturers operating in jurisdictions with heightened regulatory scrutiny should be particularly vigilant in maintaining exemplary compliance records and may expect increased inspection frequency.
Prepare for Inspection Parity
Foreign manufacturers should recognize that the FDA’s commitment to inspection parity means they will receive inspection attention commensurate with their risk profile, regardless of geographic distance. The record-high proportion of foreign inspections (62% in FY2024) demonstrates this commitment in practice.
Conclusion
The SSM brings scientific evidence and objectivity to the FDA’s inspection site selection process, transforming what was once a largely frequency-based system into a sophisticated risk-based approach. This evolution benefits both regulators and industry by focusing limited resources on areas of greatest potential public health impact while providing a more predictable regulatory environment.
By understanding the SSM’s structure, risk factors, and operational implications, pharmaceutical industry professionals—from beginners to experienced practitioners—can better navigate the regulatory landscape, optimize quality system investments, and ultimately contribute to ensuring the availability of high-quality medicines for patients. As the system continues to evolve with enhanced data analytics, international cooperation, and quality culture emphasis, staying informed about SSM developments remains essential for regulatory compliance and business success.
For those seeking to deepen their understanding of the SSM and related FDA policies, key resources include CDER MAPP 5014.1 (Rev. 1), the FDA’s annual Reports on the State of Pharmaceutical Quality, and the agency’s Inspection Classification Database, all of which are publicly available on FDA.gov and provide valuable insights into how the agency conducts pharmaceutical quality oversight in an increasingly globalized industry.
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