Examining FDA’s New Alternative Tools for Drug Pre-Approval and Pre-License Inspections

In late March 2025, The U.S. Department of Health and Human Services (“HHS”) announced that it would cut 3,500 full-time Food and Drug Administration (“FDA”) positions.   HHS claimed that those cuts would be focused on “streamlining operations and centralizing administrative functions” and “not affect drug… reviewers, nor… impact inspectors.”  

 

The positions that FDA cut, however, supported the efficiency of a multitude of departments including the Office of Pharmaceutical Quality (“OPQ”) and the Office of Inspections and Investigations (“OII”, formerly known as Office of Regulatory Affairs). 

 

OPQ and OII play complementary roles in planning and executing FDA facility Pre-approval and Pre-license inspections (collectively, “PAI”) as part of the New Drug Applications (“NDA”), Abbreviated New Drug Application (“ANDA”), or Biologics License Agreements (“BLA”) approval process. Due to these reductions, inspectors are now tasked with both administrative and investigative work and the increased workload may contribute to even more bottlenecks in the PAI and approval pipeline. 

 

With in-person operations now resumed, FDA faced a choice: return exclusively to on-site inspections or integrate lessons learned from the pandemic into its current practices. It wisely chose the latter by providing inspectors with “alternative tools” pursuant to FDA’s September 2025 final guidance on Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications (“Guidance”).  The Guidance outlines FDA’s framework for assessing drug manufacturing facilities identified in pending NDAs, ANDAs, and BLAs, fundamentally reshaping how pre-approval inspections and evaluations are conducted. Building on strategies refined during the COVID-19 pandemic, the Guidance discusses:

• • Formal remote regulatory assessments (“RRA”);

• • Voluntary remote interactive evaluations (“RIE”);

• • Mutual Recognition Agreements (“MRAs”); and

• • Remote Subject Matter Experts (“SME”) to support PAI on-site inspections using virtual technology, broadening the depth and technical reach of FDA’s review teams for complex manufacturing operations

By virtue of the Guidance, alternative assessment tools have transitioned from temporary, pandemic-era solutions into formal regulatory mechanisms for evaluating whether facilities can meet current cGMP requirements and whether submission data are reliable and complete. The Guidance establishes these tools as routine options for application reviews and introduces new protocols for international collaboration and remote subject matter expertise. Importantly, only FDA decides when and how these tools are used—applicants or facilities cannot request their use, as FDA retains exclusive decision authority based on its own risk-based evaluation.

 

Section 704(a) of the Federal Food, Drug & Cosmetic Act (the “Act”) (21 U.S.C. § 374(a) gives FDA authority to inspect any facility where drugs are manufactured, processed, packed, or held, to verify compliance with current Good Manufacturing Practice (cGMP) and ensure product safety and efficacy. PAIs confirm that facilities can manufacture according to cGMP and that application data are accurate and complete.

 

PAIs are critical steps manufacturers must clear before obtaining FDA approval to market drugs or biologics. These inspections, however, often are an aspect that is a bottleneck in the review process— particularly for products requiring foreign site visits or when submissions cluster toward the end of a fiscal year. Delays can result from FDA resource constraints, staffing changes, or travel limitations. Although FDA has worked to restore normal inspection schedules with the return to pre-pandemic operations, backlogs and limited resources continue to pose challenges.

 

PAIs were traditionally conducted on-site near the end of a NDA, ANDA, or BLA review period. During the COVID-19 pandemic, however, shutdowns forced FDA to carry out these inspections virtually, both for domestic and international facilities. Although response times were slower, FDA was still able to complete virtual PAIs and approve drugs and biologics.

 

Those virtual inspections, however, are not considered formal inspection.  An inspection under Section 704(a)(1) of the Act involves FDA officers or employees physically entering a regulated establishment to examine its compliance at reasonable times and in a reasonable manner. Although the Act does not clearly contemplate remote inspections, it does contemplate leveraging foreign governments to assist FDA with foreign inspections.  Specifically, sections 809 (21 U.S.C. § 384e) and 801(r)(3) (21 U.S.C. § 381(r)(3)) of the Act allows FDA to negotiate agreements with foreign governments or agencies to inspect foreign facilities and use those inspection results as evidence of compliance with U.S. regulatory standards. The United States currently has  “Mutual Recognition Agreements” with the European Union, Switzerland, and the United Kingdom.

 

The Guidance describes RRA as a process in which FDA remotely evaluates a regulated facility or its records to assess compliance, using tools such as records requests, electronic data reviews, and virtual meetings instead of on-site inspections. It formalizes the use of written RRA observation lists (distinct from Form 483) as the official means of documenting and communicating findings from remote assessments supporting pending drug applications. An RIE is a specific subtype of voluntary RRA that emphasizes real-time, interactive engagement. It always involves live video streaming, teleconferencing, virtual facility tours, and scheduled interviews—all conducted remotely. For the purposes of this update, we discuss RRAs and RIEs as separate programs despite RIEs being a voluntary form of an RRA. 

 

A mandatory RRA does not always involve a livestreamed walkthrough of the facility. The core requirement of a mandatory RRA is to remotely review of records, documents, and other compliance materials that FDA is legally authorized to request. However, a mandatory RRA can include interactive or observational components—such as a livestreamed walkthrough—if FDA determines it is necessary and the facility has the capability to provide it but it is not, unlike an RIE, the main emphasis of the remote review. 

 

During a pending NDA, ANDA, or BLA, FDA uses a risk-based approach to determine whether to initiate or request an RRA or RIE or to perform an on-site PAI. Factors that may be considered include:

• • establishment location,

• • inspection history,

• • complexity of product and process, and

• • travel restrictions.

Because RRAs and RIEs are not formal inspections, FDA does not issue a Form 482 during a remote review. FDA sends a cover letter to notify a facility or manufacturer of its intent to conduct a remote review. This letter specifies whether the review is an RRA or RIE and whether participation is voluntary. If the remote review is a mandatory RRA, FDA includes a Form 4003 with the cover letter. For an RIE, the Agency may send only the cover letter.

 

Following the review process of a mandatory RRA, FDA issues a Form 4003a to confirm receipt of the records and may provide letters summarizing observations or stating that no observations were found. The process is formally concluded when FDA sends a closure letter or other official written communication stating that the RRA is closed. Only after the RRA is formally closed and, if applicable, any issues have been resolved, would the pathway to NDA, ANDA, or BLA approval continue. To be sure, the RRA does not itself determine approval but can inform readiness for such regulatory decisions.

 

Similarly, after an RIE is completed, FDA holds a closeout meeting with facility management during which a written list of any observations is presented. Facilities are typically encouraged to respond to these observations within 15 U.S. business days.

 

Participation in an RIE is voluntary, and there are no direct regulatory consequences for declining. FDA notes however that RIEs may be the “quickest means for FDA to assess a facility’s activities,” and thus “declining to participate in an RIE may prolong a decision on an application.”  It can also lead to a formal inspection. 

 

Declining to participate in a mandatory RRA, however, could have devastating outcomes like:

• • delay application action if FDA does not have enough information to make a regulatory determination;

• • result in FDA sending a complete response letter to the applicant if FDA cannot confirm that application deficiencies have been satisfactorily addressed; or

• • carry other potential regulatory or legal consequences.

FDA considers declining participation to include failing to respond, withdrawing participation, or refusing to provide records requested under relevant legal authorities. The following highlights differences between a mandatory RRA versus a voluntary RIE:

 

Feature	Mandatory RRA	RIE
Initiation	FDA can initiate as part of oversight; typically to address deficiencies or instead of in-person.	Initiated by FDA, but participation depends on facility’s technology and willingness.
Participation	Mandatory if FDA requests records under section 704(a)(4).	Voluntary for the facility.
Legal Basis	FD&C Act section 704(a)(4) (21 U.S.C. § 374(a)(4)).	Described in FDA guidance, not a statutory requirement.
Inspection Status	Not considered a formal inspection; no Form FDA 483 is issued.	Not considered a formal inspection; no Form FDA 483 is issued.
Scope	Remote review of records, documentation, and submitted data.	Involves livestreamed observations and interactive video with facility staff.
Outcome	Determines if further inspection or information is needed; may resolve application deficiencies.	Offers real-time process observation; declined participation may slow application review.
Facility Rights	Compliance with records request is required; refusal may affect application approval timeline.	Participation can be declined, but may prolong decision-making on the application.

The crucial difference is that mandatory RRAs may be legally compelled for certain record reviews or compliance activities, while RIEs always require facility consent and focus on real-time interactive evaluation.

 

Under the Guidance, FDA may involve remote SMEs during an on-site PAI when there is a need for an expert who is employed by the Agency with specialized technical knowledge to evaluate a product, process, or facility. In these cases, FDA requests permission from the facility to allow for a remote SME to become involved in the inspection remotely.  

 

There may be several reasons for a facility to deny an FDA request for a remote SME:

• • Facility concerns over data security and confidentiality: Sensitive proprietary manufacturing processes or trade secrets may be exposed through virtual technologies that could be vulnerable to unauthorized access or lack robust security protections;

• • Lack of technical infrastructure: Facility’s lack of technical infrastructure or resources to support real-time, high-quality livestreaming, screen-sharing, or video conferencing, which are necessary for effective remote participation by the SME; and

• • Operational Disruption:  Concerns that remote participation may delay or complicate the inspection, particularly if technology problems arise.

Though voluntary, declining an FDA request for a remote SME may result in significant delays to market approval.  Without a remote SME, FDA may not be able to adequately assess specific technical or compliance issues. So FDA may need to schedule a traditional, fully on-site inspection or pursue other oversight mechanisms, extending the overall timeline for review and product approval.

 

There is also a risk that declining remote SME participation could signal a lack of transparency or cooperation to FDA, potentially raising additional questions or scrutiny about the facility’s processes and readiness for approval.

MRAs are intended to improve efficiency, reduce redundant inspections, and allow FDA to focus resources on higher-risk facilities.  While FDA has not yet recognized foreign government inspections for PAIs, the Guidance indicates a clear intention to increase regulatory flexibility and efficiency by leveraging MRAs in future assessments of drug manufacturing facilities.  These MRAs cover pharmaceutical GMP inspections and do not grant marketing authorizations, label approvals, tariff/trade preferences, or cover medical devices.

During FY2024, FDA reported an increase in the total number of drug quality assurance inspections (both remote and in-person), with foreign sites seeing a particularly large uptick—bolstered by both direct FDA remote tools and partnerships with trusted overseas regulatory agencies.  Through the Guidance, FDA may save or reserve financial and personnel resources for the highest risk products manufactured by the highest risk facilities. 

 

For Drug Manufacturers and Applicants

• • FDA PreCheck Program: Remote FDA assessments of facilities not yet constructed or operational for pending NDAs, ANDAs, or BLAs.

• • Heightened readiness: All facilities named in pending applications must be continuously prepared for inspection or remote assessment, including having secure document exchange and virtual access capabilities at the time of application submission.

• • Accelerated timelines: Alternative tools may enable FDA to meet user fee performance goals, reducing regulatory delays and expediting market access for critical and innovative medicines.

• • Increased accountability: Facilities must respond promptly to mandatory RRA requests for records (usually within 15 business days), or risk regulatory delays, adverse letters, or enforcement actions for noncompliance.

• • Loss of petitioning rights: Applicants and facilities cannot request or insist on the use of alternative tools; FDA alone decides when remote assessments are used, requiring acceptance of agency decisions on evaluation approach.

For Regulatory Agencies and Global Partners

• • Greater collaboration: Enhanced collaboration with trusted foreign regulators, leading to harmonized standards, reduced redundant inspections, and broader international recognition of facility assessments;

• • Deeper expertise: Ability to integrate remote subject matter experts, permitting broader technical evaluations and expertise exchange without travel or resource constraints; and

• • Improved transparency: Written observation reports from RRAs set clear expectations for facilities and provide actionable feedback, even outside formal inspections.

Practical Challenges and Considerations for Stakeholders

As FDA expands the use of alternative tools—such as RRAs and RIEs with foreign partners—stakeholders face new operational and compliance challenges. These requirements demand a higher level of digital preparedness, inspection readiness, and rapid response capabilities than ever before. The following considerations and best practices offer practical recommendations to help manufacturers and applicants successfully navigate and meet the agency’s evolving expectations under the Guidance.

• • Maintain continuous inspection and assessment readiness for all facilities in applications with up-to-date records, compliance documents, and trained staff;

• • Be prepared for both in-person and remote FDA assessments;

• • Develop protocols and policies on RRAs and SMEs, where there is an internal review and approval process regarding the substantive information that is disclosed to FDA, and how such information will be disclosed. Facilities should ensure that only the minimum necessary responsive information is disclosed;  

• • Invest in secure digital infrastructure and engagement tools for document management, teleconferencing, and virtual site access, and ensure policies are in place to maintain such infrastructure and engagement tools;

• • Train staff on remote meeting protocols, document handling, and efficient response to FDA electronic record requests;

• • Communicate proactively with FDA, including disclosure of operational, technical, or scheduling limitations for remote assessment;

• • Coordinate technology and personnel for remote interactive evaluations and hybrid inspections involving remote SMEs; and

• • Preserve trade secrets even under the codified protection of 21 CFR § 20.61 and 18 U.S.C. § 1905.  Consider internal policies that prohibit recordings within facilities which are intended to protect trade secrets.  There may be a need to revise such policies to create an exception for RRAs and SMEs if authorized by the facility’s management.

FDA’s embrace of tools like RRAs, RIEs, MRAs, and virtual engagement with remote SMEs, signals a major step forward in how it allocates it resources and timely approves NDAs, ANDAs, and BLAs. This shift enables a more flexible, risk-based, and collaborative approach, helping FDA work around resource constraints, travel limits, and operational disruptions while still drawing on specialized expertise and maintaining strict quality and accountability standards.

That said, relying more heavily on digital and virtual inspections comes with its own set of challenges—chief among them the need for strong data security, advanced technology, and a state of continual readiness on the part of each facility. Facilities must move quickly to invest in secure systems, keep compliance records current, and prepare staff to handle both in-person and remote reviews seamlessly.

 

For more information contact J. Mason Weeda (mweeda@ofwlaw.com) or Michael Goodman (mgoodman@ofwlaw.com).

 

The information contained in this post is provided for general informational and educational purposes only and should not be construed as legal advice on any subject matter. No reader should act or refrain from acting on the basis of any information included in this post without seeking appropriate legal or professional advice based on their particular facts and circumstances. Posting or engaging with this content does not create an attorney–client relationship. All views expressed are those of the author and do not necessarily reflect the views of any organization, employer, or affiliate.