Evolution from COVID-19 Response to Permanent Oversight Tool
The COVID-19 pandemic, which began affecting the world in early 2020, imposed severe constraints on pharmaceutical regulatory authorities’ inspection activities. The U.S. Food and Drug Administration (FDA) was compelled to develop new oversight methods as an alternative to traditional on-site inspections while ensuring the safety and quality of drugs under travel restrictions and social distancing requirements.
On June 2, 2020, FDA presented testimony to the Senate Finance Committee titled “COVID-19 and Beyond: Oversight of the FDA’s Foreign Drug Manufacturing Inspection Process.” This testimony detailed FDA’s approach to foreign establishment inspection processes during COVID-19. At that time, FDA had temporarily postponed most routine domestic and foreign facility inspections, conducting only those deemed “mission critical” (inspections necessary for approval of COVID-19 therapeutics or vaccines, inspections related to drugs in serious shortage, etc.).
During the pandemic period, FDA utilized alternative inspection methods including records requests (under Section 704(a)(4)), information sharing with foreign regulatory authorities, and sampling and testing at U.S. borders. However, FDA initially did not consider these alternative methods equivalent to formal inspections.
Institutionalization of Remote Regulatory Assessments (RRAs)
Remote evaluation methods developed as pandemic responses were subsequently formalized as permanent regulatory oversight tools. FDA issued its first draft guidance “Conducting Remote Regulatory Assessments: Questions and Answers” in July 2022, published a revised version in January 2024, and finalized the guidance on June 26, 2025.
A Remote Regulatory Assessment (RRA) is an examination of an FDA-regulated establishment and/or its records conducted entirely remotely without FDA staff being physically present on-site. RRAs are positioned as tools that complement, but do not replace, traditional inspections. However, records requests under the Foreign Supplier Verification Program (FSVP) are exceptionally considered equivalent to inspections.
Types of RRAs and Legal Basis
RRAs are broadly categorized into two types.
Mandatory RRAs are those where establishment participation is required by legal authority. These include records requests conducted in advance of or in lieu of inspections for drugs, devices, and biologics under Section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), and FSVP records requests under Section 805. The Food and Drug Omnibus Reform Act (FDORA, 2022) expanded the scope of Section 704(a)(4) to include device and bioresearch monitoring (BIMO) establishments.
Voluntary RRAs are conducted when establishments consent and are not mandated by statute or regulation. If an establishment refuses to participate in a voluntary RRA, FDA does not consider the refusal itself a violation of the FD&C Act. However, refusal may delay regulatory decisions (such as approval application reviews), and FDA may consider whether additional oversight activities (such as on-site inspections) are necessary for that establishment.
RRA Implementation Process
RRAs typically begin with FDA contacting the establishment’s designated representative. FDA reviews manufacturing records, electronic data, and other documentation, and may also conduct virtual interviews or review livestreamed facility walkthroughs.
Upon completion of an RRA, FDA “may” hold a closeout meeting to present and discuss a written list of RRA observations with the establishment’s management. FDA encourages establishments to submit written responses to RRA observations received at a closeout meeting within 15 business days, similar to the timeframe for responding to Form 483 following traditional inspections.
Importantly, because RRAs are not formal inspections, FDA does not issue Form FDA 482 (Notice of Inspection) or Form FDA 483 (Notice of Inspectional Observations). Instead, FDA will “ordinarily” prepare a written report summarizing the information reviewed, conditions and practices found, and any observations identified during the RRA.
RRA reports and observations are subject to disclosure under the Freedom of Information Act (FOIA) with appropriate redactions, similar to inspection-related materials.
Combination of RRAs and On-Site Inspections
RRAs are utilized in various contexts. When conducted prior to Preapproval Inspections or Pre-licensing Inspections, they assist in assessing risks identified during application review. They may also be implemented as follow-up activities after inspections to verify establishment corrective actions.
FDA may combine information gained from RRAs with observations from on-site inspections. When reviewing multiple applications, FDA has discretion to consolidate records requests under a single Form FDA 4003.
Regulatory Actions Based on Remote Assessments
During and after the pandemic period, FDA has taken regulatory actions based on records-based remote assessments. The Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) have issued Warning Letters for GMP violations discovered through remote assessments.
Specific Case: Colombian API Manufacturer
On April 16, 2020, FDA requested record submissions under Section 704(a)(4) from a Colombian Active Pharmaceutical Ingredient (API) manufacturer (Proquimes S A Productos Quimicos Especializados S.A.). However, the company was unable to submit certain critical records. Major deficiencies included:
- Failure to establish and perform process validation demonstrating the ability to consistently produce APIs with predetermined quality characteristics
- Failure to establish and perform equipment qualification for equipment used in API manufacturing
- Failure to validate cleaning processes for equipment used in manufacturing
- Inadequate testing of incoming raw material lots used in manufacturing APIs imported to the U.S. to ensure material identity
In response to these significant GMP regulation violations, FDA imposed an import restriction measure (Import Alert 66-40) on the company’s products on December 3, 2020. Subsequently, FDA issued a Warning Letter on April 13, 2021. FDA strongly recommended that the company review guidance documents on cGMP regulations and engage a cGMP consultant to assist in achieving compliance with cGMP requirements.
The import restriction measure continues until the company corrects all observations and full compliance with cGMP requirements is confirmed.
Timeline from Remote Assessment to Warning Letter Issuance
In early remote assessments, Warning Letters tended to be issued approximately 8-12 months after records requests. However, this timeline varies depending on individual case complexity, company response, and FDA priorities.
From March 2020 to February 2022, FDA issued approximately 172 manufacturing-related Warning Letters to drug and biologics manufacturers (March-December 2020: 85 letters; all of 2021: 87 letters). In approximately 17% of these cases, data integrity (failure to ensure data accuracy and integrity) was cited as a specific violation.
Latest Regulatory Developments and Future Outlook
Introduction of Remote Interactive Evaluations (RIEs)
In October 2023, FDA issued draft guidance titled “Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities.” This represents more detailed remote assessment methods specific to drug manufacturing facilities and BIMO facilities.
Remote Interactive Evaluations (RIEs) are positioned as a special form of RRAs, incorporating interactive elements such as live video streaming, virtual interviews, and real-time records review. RIEs apply to all drug inspection programs including Preapproval Inspections (PAI), Pre-licensing Inspections (PLI), Postapproval Inspections, Surveillance Inspections, Follow-up/Compliance Inspections, and BIMO inspections.
Importantly, Form FDA 482 (Notice of Inspection) is not issued prior to RIE initiation. FDA uses risk management methods/tools to select facilities for RIEs but does not accept RIE requests from applicants and will not establish a request-based program.
Expansion of RRA Scope
The final guidance clarifies that RRAs are applicable across all FDA-regulated products, specifically including human and animal drugs, biologics, medical devices, food, and tobacco products.
As a 2025 development, FDA has indicated that a forthcoming proposed rule amending 21 CFR Part 1271 (applicable to human cells, tissues, and cellular and tissue-based products (HCT/Ps)) will establish requirements for submission of records or other information in advance of or in lieu of inspections and require participation in remote interactive evaluations if requested.
Recovery of Inspection Activities
Following the significant inspection reduction due to the pandemic, FDA’s inspection activities have gradually recovered but have not fully returned to pre-pandemic 2019 levels as of January 2025. Foreign establishment inspections in particular showed approximately 79% decrease compared to 2019 as of 2022, demonstrating slower recovery compared to the approximately 35% decrease for domestic establishments.
The Government Accountability Office (GAO) continues to urge FDA to address inspection delays and backlogs. FDA is addressing this challenge through utilization of innovative alternatives such as RRAs and RIEs, and risk-based approaches to inspection prioritization.
International Cooperation and MRAs (Mutual Recognition Agreements)
FDA is strengthening cooperation with foreign regulatory authorities such as the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Inspections conducted by certain European regulatory authorities are considered equivalent to and may be substituted for FDA inspections. However, FDA positions other alternative tools (records review, sampling and testing, etc.) as providing useful information but not being fully equivalent to formal inspections.
Industry Impact and Preparation
Companies are recommended to make the following preparations to effectively respond to RRAs and RIEs.
Regarding technology infrastructure, it is necessary to establish livestreaming-capable equipment, document management and retrieval systems, and secure data transfer means. From a document management perspective, standard operating procedures (SOPs) and records documenting quality systems and/or demonstrating compliance with FDA requirements should be maintained in electronically accessible formats.
Communication strategies with FDA are also important. When receiving records requests, rather than simply submitting documents, it is effective to request preliminary discussions with FDA to explain document background and context. Records should be accompanied by appropriate explanations and context to prevent misunderstandings.
Furthermore, for responding to RRA observations, it is recommended to prepare comprehensive written responses including root cause analysis and corrective and preventive actions (CAPA) within 15 business days.
Importance of Data Integrity
In remote assessments, data integrity issues tend to receive greater attention. Companies need to ensure the following:
- Appropriate access controls in electronic records systems
- Complete audit trails recording data changes, deletions, and additions
- Complete retention of raw data
- Protection of data from unauthorized changes, access, or omissions
Impact on Global Supply Chain
In a situation where over 58% (as of October 2022) of drugs for the U.S. market are manufactured at foreign facilities, RRAs and RIEs have become critical tools for FDA to efficiently oversee the global pharmaceutical supply chain.
The current U.S. administration emphasizes an “America First” approach, and Executive Order 14293 issued on May 5, 2025, calls for facilitating the restoration of a robust domestic pharmaceutical manufacturing base. How FDA will utilize RRAs and RIEs going forward to ensure foreign manufacturing facilities receive the same level of oversight as domestic facilities while simultaneously promoting domestic pharmaceutical manufacturing is of great interest.
Conclusion
The COVID-19 pandemic brought permanent transformation to pharmaceutical regulatory authority oversight methods. FDA’s Remote Regulatory Assessments (RRAs) and Remote Interactive Evaluations (RIEs) evolved from emergency response measures to permanent regulatory oversight tools, officially institutionalized through the finalization of guidance in June 2025.
These methods are positioned not as replacements for traditional on-site inspections but as complements. Companies need to effectively respond to RRAs and RIEs by establishing appropriate technology infrastructure, document management systems, and FDA communication strategies to demonstrate continuous GMP compliance.
Going forward, FDA is expected to ensure the safety and quality of the global pharmaceutical supply chain by strategically combining on-site inspections, RRAs, and RIEs using risk-based approaches. For companies, adapting to these new regulatory environments and maintaining flexible yet robust quality management systems has become essential for securing competitiveness and market access.
Comment