FDA revises compliance guide on pre-approval inspections
The US Food and Drug Administration (FDA) revised its compliance program guide (CPG) for preapproval inspections (PAIs) for new drugs. This update emphasizes a risk-based approach to making decisions about the necessity of inspections and clarifies the agency’s use of alternative methods instead of relying solely on onsite inspections.
The updated document will take effect on 10 August 2026 and replaces an earlier version that went into effect in October 2022. (RELATED: FDA addresses alternative inspection tools, expectations for nitrosamine assessment in updated CPGs, Regulatory Focus 17 October 2022)
The guide outlines four key objectives of a PAI: to assess a manufacturer’s readiness for commercial manufacturing, to evaluate the manufacturer’s compliance with the application, to conduct a data integrity audit that encompasses all PAIs, and to ensure a commitment to quality in pharmaceutical development.
An introduction to the CPG outlines the changes. It states that the guide has been “revised to further strengthen the risk-based strategy to make a prompt decision on the need for inspections and promote efficient conduct of the inspections. Additionally, the roles and responsibilities have been updated.”
The document states that “FDA employs a risk-based strategy to determine the need, timing, and conduct of a PAI in support of the regulatory action on an application. The risk-based approach, such as leverage of inspection history and utilization of alternative tools streamlines FDA’s oversight of pharmaceutical manufacturing establishments and operations and enables prompt and efficiency evaluation of establishments readiness to conduct manufacturing operations as described in the application.”
The revision also adds new text that emphasizes the agency’s risk-based approach to inspections in the section titled “Risk-Based Inspection Determination.”
It states that, “In performing the quality assessment, the IQA [Integrated Quality Assessment Team] team takes a holistic and a risk-based approach to determine the need for PAIs of facilities listed in the application by assessing: a) Understanding product and manufacturing (process and facility) risks. The manufacturing operations and activities of the facility, as described in the application, should be assessed in relation to those previously evaluated or inspected at the facility (e.g., profile codes). Information demonstrating the facility's capability to conduct oct operations in compliance with CGMP (e.g., compliance status, inspection history) is evaluated.”
The update also includes a new flow diagram illustrating how FDA makes a risk-based inspection determination to decide whether a PAI is necessary or not.
The flow diagram illustrates that FDA takes various factors into account when deciding whether to inspect a facility. Key considerations include the facility’s profile code status, compliance history, inspection history, product characteristics (including whether the drug is novel or complex), manufacturing operations and activities, and the presence of hazard signals, such as recalls, complaints, field alert reports (FARs), and MedWatch reports.
The update also includes a new section outlining the use of alternative tools to support PAIs. The newly added section states that “FDA can use alternative tools to support evaluation of establishments and regulatory decisions regarding applications, such as the following: (1) requesting existing inspection reports and other information from trusted foreign regulatory partners through Mutual Recognition Agreements (MRAs) and other confidentiality agreements; and (2) conducting remote regulatory assessments, including (a) requesting records and other information directly from establishments and other inspected entities related to the application under section 704(a)(4) of the FD&C Act (21 U.S.C. 374(a)(4)), and (b) conducting remote interactive evaluations where appropriate. With regards to this compliance program, a request of records under section 704(a)(4) can be used in lieu of or in advance of a PAI to support assessment of an application.”
The revision references FDA's guidance for industry regarding alternative tools for assessing drug manufacturing facilities mentioned in a pending application from September 2025.
The update also clarifies new roles and responsibilities related to sample-related testing requirements. According to the previous guidance, the Division of Pharmaceutical Analysis in the Office of Testing and Research (OPQ/OTR/DPA) in the Office of Pharmaceutical Quality (OPQ) and the ORA laboratories were responsible for testing samples collected for method verification and profiling.
Under the revision, testing of collected samples for method verification and profiling is now the responsibility of the Office of Pharmaceutical Quality Research (OPQR) in OPQ, along with the laboratories in the Office of the Chief Scientist/Office of Analytical and Regulatory Laboratories (OCS/OARL).
The updated CPG also deletes references to FDA’s Office of Regulatory Affairs (ORA) and replaces this with the Office of Inspections and Investigations (OII); the update also deletes references to COVID-19.
