RRA, RIE and MRA: FDA’s Evolving Inspection Toolkit Still Has Boundaries

As part of the review of a BLA, NDA, or ANDA, FDA assesses the manufacturing facilities named in the application to determine whether they can perform the proposed manufacturing operations in conformance with CGMP requirements, and whether the data submitted in the application are accurate and complete.  In some cases, FDA determines that information is needed from a pre-approval inspection (PAI) or pre-licensure inspection (PLI) in order to approve or license the product.

Traditionally, this would mean an in-person inspection, but FDA has other options available, as described in the recently published Guidance for Industry on Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications (Alternative Tools Guidance).  While the document provides some meaningful insights, it is largely a repackaging of three existing alternative tools that we’ve blogged about before, now presented specifically in the context of a PAI or PLI:

1. Remote Regulatory Assessment (RRA)
2. Remote Interactive Evaluation (RIE)
3. Mutual Recognition Agreement (MRA)

The first two tools are discussed in relation to each other, and both RRA and RIE are also covered in standalone guidances.  An RRA is an entirely remote evaluation of a facility, which can include a records request under FD&C Action section 704 (a)(4) (21 USC § 374(a)(4)).  An RRA could potentially obviate the need for an in-person PAI/PLI, or could be used to resolve application-specific deficiencies identified during a prior PAI/PLI.

While record requests under section 704(a)(4) are mandatory, an RRA is not itself considered an “inspection”—meaning that no Form FDA 483 will be issued at its conclusion.  As described in the Alternative Tools Guidance, an RRA can also include an RIE during the application assessment.  An RIE could involve, for example, livestreaming a production area so Agency staff can observe a specific manufacturing process.  Unlike RRAs, participation in an RIE is voluntary and largely depends on the facility’s technological capabilities.

The Alternative Tools Guidance addresses inspections conducted by “trusted foreign regulatory partners” (i.e., foreign nations with which FDA has an MRA).  FDA currently has MRAs in place with the European Union, Switzerland, and the United Kingdom.  These agreements allow FDA to legally recognize inspections conducted by those regulators in their respective countries (21 USC § 384e). MRA recognition applies to both same-country inspections (e.g., a Swissmedic inspection of a facility in Switzerland) and third-country inspections (e.g., a Swissmedic inspection of a facility in China).

Under the Food and Drug Omnibus Reform Act (FDORA), enacted December 2022, FDA is required to report the number of routine surveillance and for-cause MRA inspections it has recognized (21 USC § 360(h)(6)(A)(vii).  In FY2023, FDA recognized 199 MRA surveillance inspections; that number increased slightly in FY2024 to 206 inspections.  However, based on the FY2023 and FY2024 data, FDA has yet to recognize any for-cause MRA inspections.  Additionally, while FDORA gave FDA the authority to recognize MRA inspections “in order to facilitate preapproval”, the Agency acknowledges in the Alternative Tools Guidance that it “has not to date recognized PAIs or PLIs conducted by a foreign regulatory authority” (page 8).

Unfortunately,  FDA is not using the Alternative Tools Guidance to announce any plan to expand recognition of MRA inspections.  However, when a facility lacks sufficient FDA inspection history, the Agency may request inspection reports from an MRA partner and use that information to determine whether a PAI or PLI is necessary.  As a longer-term strategy, FDA is also evaluating remote participation in inspections conducted by foreign regulators.

The final section of the Alternative Tools Guidance describes how FDA subject matter experts (SMEs) may participate virtually in a PAI/PLI.  Anyone who has taken part in an FDA surveillance or for-cause inspection knows that investigators often confer with FDA SMEs located off-site.  The new Guidance now provides a framework for remote FDA SMEs to engage directly with the facility staff during a PAI/PLI.  Interestingly, the facility must agree in writing to the use of a remote SME; a firm may decline this request but, as the Guidance notes, doing so may “prolong a decision on an application” ( page 7).

Practically speaking, FDA’s use of alternative tools will be risk-based and remain at the Agency’s discretion.  As the Guidance states, “FDA does not intend to grant requests from applicants or facilities for FDA to use alternative tools” (page 5).  While RRAs may be used to collect information in advance, facilities with no regulatory inspection history or with unresolved compliance issues from prior inspections should still expect an in-person PAI or PLI.