Guidance Breakdown: Alternative Tools for Assessing Drug Manufacturing Facilities Identified in Pending Applications
The FDA explains how it'll use alternative tools—§704(a)(4) records requests, RIEs, and inspections supported by remote SMEs—to assess facilities named in pending applications.
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The FDA recently published finalized guidance explaining how it intends to use “alternative tools” in advance of, in place of, or to support pre-approval (PAI) and pre-license inspections (PLI) when assessing facilities named in pending NDAs, BLAs, ANDAs, and supplements.
The guidance fulfills PDUFA VII and BsUFA III commitments, and codifies lessons from the COVID-19 era into routine operations.
Importantly, it does not apply to postapproval surveillance inspections, follow-up/compliance (for-cause) inspections, or bioresearch monitoring inspections. Those programs are expressly out of scope.
The guidance mentions Executive Order 14293 regarding prioritizing alternative tools for U.S.-located facilities.
We've distilled the key points from the guidance and a few suggestions in light of it.
Watch our popular interview with former FDA investigator Chris Smith for some more insider insight into PAI prep:
Scope and purpose
The guidance establishes explicitly that the FDA will use alternative tools to help determine whether facilities named in a pending application can perform the proposed manufacturing operations in conformance with CGMP, the application, and (depending on the statutory pathway) ensure identity, strength, quality, and purity (FD&C Act §505) or safety, purity, and potency (PHS Act §351).
The guidance applies to foreign and domestic facilities. The FDA notes it may decide that a PAI/PLI isn’t needed if sufficient information is otherwise available.
Definitions and alternative tools
“Alternative tools” (as used here) are methods the FDA may use in advance of, in lieu of, or to support an inspection of a facility identified in a pending application.
The guidance focuses on three categories:
1. Remote Regulatory Assessments (RRAs)
These can include two specific types of RRAs:
Section 704(a)(4) FD&C Act records requests (mandatory to fulfill) for any records/information FDA may inspect under §704. The FDA may set timelines (often 15 U.S. business days, up to 30 when translation is requested; shorter deadlines are possible for time-sensitive needs). Refusal or insufficient responses can delay action, trigger a complete response if deficiencies can’t be resolved, or have other regulatory consequences.
Remote Interactive Evaluations (RIEs) using livestream video, teleconferences, or screen-sharing. Participation is voluntary, and the FDA does not issue Form FDA 482 to open an RIE. The agency is clear that it can terminate an RIE if it cannot adequately evaluate the facility and may instead inspect or use other tools. Declining an RIE can prolong the FDA’s decision. The FDA is clear that it does not conduct an RRA and an inspection simultaneously.
Read our other breakdown for a deeper look at the FDA’s newest RRA guidance:
2. Info from trusted foreign regulatory partners
The FDA may request existing inspection reports and related information from partners under MRAs or other arrangements to understand facility history and coverage of proposed operations.
Although the FDA has not recognized PAIs/PLIs conducted by foreign authorities under the FD&C Act §809, it does collaborate with regulatory authorities and assesses shared inspection information to support application decisions.
The guidance also mentions that the FDA is piloting collaborative hybrid inspections where a foreign authority is on-site and the FDA participates remotely (via virtual participation), to make things more efficient and less redundant when multiple regulators share a mutual interest.
3. PAIs/PLIs supported by FDA remote subject-matter experts
When specialized expertise is needed and on-site attendance isn’t feasible, the FDA may augment an on-site inspection team with remote FDA SMEs via virtual technologies.
Facility agreement is voluntary here, but declining may prolong application decisions. The FDA says it will generally notify the facility when pre-announcing/initiating the inspection and request confirmation of willingness and technical capability for a virtual connection.
Remote SME interactions are not recorded. The on-site team remains responsible for verifying, documenting, and determining observations (e.g., what appears on a Form FDA 483).
The FDA’s risk-based decision framework
The FDA says it decides case-by-case when to use alternative tools, considering factors such as:
Inspection history (FDA or trusted partners) and whether proposed operations are the same or sufficiently related to those previously inspected.
Whether application-specific risks (product/process/facility) can be adequately assessed via alternative tools.
Urgent public health or drug shortage considerations.
Travel limitations (e.g., pandemics, natural disasters).
Regulators say they intend to prioritize using alternative tools when a facility is U.S.-located and use is appropriate to support a PAI/PLI decision.
Operational expectations for applicants and facilities
Let’s quickly run down what the guidance lays out in terms of expectations on industry teams.
1. Be inspection-ready at the time of submission.
Because the FDA may inspect and/or use alternative tools at any point in the assessment cycle, all drug substance and drug product manufacturing, packaging, and control sites named in the application should be inspection-ready at the time of submission. The FDA will not grant requests from applicants or facilities to use an alternative tool. Those decisions are the FDA’s, based on the totality of factors. The FDA references Form FDA 356h and related identification of manufacturing establishments. Make sure the right facilities are correctly listed and ready!
2. If you receive a §704(a)(4) records request (RRA), treat it as mandatory and respond within the FDA’s stated deadline.
Again, that deadline is often 15 U.S. business days, or 30 U.S. business days when translation is requested.