The United States Food and Drug Administration (FDA) is using Remote Interactive Evaluations (RIE) to assess regulatory compliance, review submission material, or determine the timing of future inspections. Here, we look at some of the impacts of RIE on GxP laboratories. Although RIE is voluntary, is this an offer that you cannot refuse?
Since the pandemic, changes have occurred in the regulatory oversight of GxP laboratories because of travel restrictions or country access. Instead of an inspection (physical entry to a facility) via remote oversight, assessments and/or evaluations have been used by various regulatory authorities. For example, the United States Food and Drug Administration (FDA) has used Remote Interactive Evaluations (RIE) (1) since 2021 and Remote Regulatory Assessments (RRA) since 2022 (2). For RRA, the FDA requests records and documents to be transferred to them for review, with the process being conducted entirely remotely (2). In some cases, the remote review outcome can be a warning letter and/or an import ban for a company (3–7). In 2024, the FDA provided an update to RRA draft guidance to promote greater consistency in the way RRAs are conducted (8). The FDA has also issued draft guidance on Alternative Tools for assessing drug facilities (9), which references the RRA draft guidance. There is also an agency web page explaining Remote Oversight Tools (10). Any interaction with a facility other than inspection or a record request is considered as RIE (11).
The European Medicines Agency (EMA) has also issued guidance on distant assessments for Good Manufacturing Practices (GMP) (12). These remote assessments and evaluations are not a substitute for inspections, but rather an expansion of regulatory oversight (12).
Recently, the FDA updated the draft guidance for Remote Interactive Evaluations (13), and our focus here is on the interpretation of this document for a regulated spectroscopy laboratory. Where there are gaps in the draft guidance, we have added the experience of the International Coalition of Medicines Regulatory Authorities (ICMRA) on remote regulatory oversight (14). The FDA is a member of and a contributor to ICMRA. In addition, some of our personal experiences of remote audits will also be included where appropriate. Post-pandemic, the FDA are continuing to use RRA and RIE for regulatory oversight in some cases. The various sources cited for remote regulatory oversight are shown in Figure 1, but our focus is on the October 2023 RIE draft guidance, circled in red. In this column, the words “investigator” and “inspector” are equivalent in meaning and relative to a person from a regulatory authority conducting on-site or remote regulatory oversight.
In the next pages, we discuss how RIE could be conducted when evaluating a regulated spectroscopy laboratory and how a laboratory should prepare. The key steps of RIE are shown in Figure 2.
Will you consider yourself lucky to be selected for RIE? The RIE planning phase is shown in yellow in Figure 2 and described below:
This process is shown in orange in Figure 2. The RIE starts with a virtual opening meeting, and the investigator will work through the agenda. Traditionally, an inspection will start with an investigator presenting a Form 482 Notice of Inspection; however, this does not happen in a RIE (13). Live streaming a remote video tour of a laboratory and record and information review is discussed in the next sections.
Personnel and records are the two fundamental elements that need to be synchronized to build transparency and trust with the investigator. This is the same approach that you would take for an inspection.
Are you the next Steven Spielberg? One of the most important portions of a RIE is a virtual video laboratory tour. Based on our experience, a video tour must be interactive and filmed with adequate camera resolution. A pre-recorded slide show is unacceptable because it only gives the laboratory’s perspective and may not be what an inspector wants to see. RIE mentions pre-recorded videos (13) may be used, but these suffer from a lack of investigators’ direction. Table I presents our dos and don’ts for livestreaming. One key point is to rehearse the live streaming laboratory tour and to ensure that there is enough bandwidth throughout the laboratory to handle any requests from the investigator. If there is signal drop out, manage an inspector’s expectations at the opening meeting or, better still, set up a WiFi repeater to extend signal coverage. One problem with a remote tour is that an inspector cannot look into wastepaper bins and desk drawers easily.
The organization needs to identify laboratory SMEs and appoint trained and experienced staff who know the procedures, spectroscopy instruments, and application software. The assigned team needs to be aware of laboratory processes such as sample receipt and storage, sample preparation, instrument analysis, data generation, retention, and integrity and back-up processes. Additionally, they should be trained in handling inspection questions: if you cannot answer, refer to your supervisor or someone who can. There needs to be an individual documenting what the inspector asks for and if the request has been fulfilled.
Table II presents the points that should be considered when the laboratory is sharing documents; again, this is not exhaustive. Preparation is essential so that you don’t end up with a Golden Raspberry instead of an Oscar-winning performance.
Spectroscopists should be skilled in handling the request for remote document reviews because turnaround time is needed and the review process could take longer in comparison to the inspection, as shared by the ICMRA (14).
A review of spectroscopic records could find that IR identity testing is a subjective process, with analysts making a manual comparison rather than using the instrument’s application’s compare function or a spectral library. This could result in a video replay back in the laboratory looking at the electronic records in the application software. Inexperienced use of application software has been seen in remote audits and is an indication of a laboratory failing to keep current (18,19). Just remember Cahn’s Axiom: when all else fails, read the manual.
Will you get a form 483? No, but management gets a list of observations at the close-out meeting.
The close-out session is an opportunity to discuss possible remediation actions. The written response is required to be submitted within 15 business days. The company must treat the violations with the same weight as a 483 form because failure to address them adequately can lead to a warning letter or even an import alert (Figure 2) (3–7). The company gets a copy of the final report after the FDA assesses the response to the RIE observations.
These are marked in blue in Figure 2. The nature of the observations and how the company responds to them determines how the FDA will react. For example, the RIE finds that there are conflicts of interest or shared user identities on a single standalone spectrometer. There are two options. The first is that the laboratory takes a systematic approach and checks all computerized systems and resolves any similar systems. This may be acceptable to the agency. In contrast, just fixing the system where the problem was identified is an unacceptable approach because there may be other systems where the problem exists.
On the positive side, an outcome of a RIE could be that an on-site inspection is avoided or that a submission is approved. On the negative side, a meeting with the FDA, a warning letter, or an import alert for companies outside of the United States could be received. Instead of an Establishment Inspection Report after an on-site inspection, the organization will receive the RIE report.
The draft guidance does not mention the following points:
When it is Remote Interactive Evaluation! Table III shows the comparison between the Drug Inspection and RIE and highlights the differences between the two. Although a form 483 is not issued at the end of a RIE, both have a list of observations that must be addressed by the laboratory management. RIE is equivalent to an inspection as outcomes could be the same: a warning letter and an import alert for foreign companies.
The view of ICMRA on remote inspections is:
Remote inspections are an enabling tool to maintain at least a minimal regulatory oversight during the pandemic. It is not the view that remote inspections would fully replace an on-site inspection programme (14). This is echoed by the EMA guidance (12).
Conducting effective interviews under remote inspection approaches is not as effective as on-site, as inspectors are not able to assess body language fully and identify evasive and nervous behaviors. Due to the potential lack of spontaneous response when working remotely, this also creates some challenges in knowing how well inspectees know their own procedures and follow them (14).
Similar views about RIE and RRA were voiced at a U.S. Congressional hearing in February 2024, that described alternative inspection methods, such as virtual inspections, record reviews, and reliance on home-country regulators, inadequate to oversee foreign drug operations. “These tools are no substitute for in-person inspections, given the risk of coverup and fraud (16).” A possible way to mitigate some of this concern could be the use of the FDA’s risk-based site selection tool (15).
RIE is not going away, as a post on the FDA website last year makes clear (20). The FDA is developing Artificial Intelligence (AI) tools/models in four areas: video transcription of voice, translation to English, document and evidence management, and co-working space. If successful, the translation element could overcome the GAO criticism about the FDA relying on translators paid by the inspected company (16). The coworking space portion appears to be a joint project with the University of Maryland to build a system to manage different documents and evidence and share with Agency co-workers. The system consists of three sub-systems: (a) document classifier; (b) video/audio classifier; and (c) an interactive middleware that connects the trained model at the backend and the input at the frontend (20). Let’s see what happens!
Recently, Baker and others (21) have published their work of a pilot study through using a mixed-reality (hybrid) device to facilitate remote inspections. As preparation, both sides ensured the availability of SMEs and technology platforms and performed practice runs. Two of the authors, who are ex-FDA investigators with a representative from Northeastern University, conducted a one-day mock inspection of a manufacturing facility covering QC, production, and warehouse. Areas captured by the device during a remote facility tour could be pinned and held for future evaluation during the inspection. Accessing the Internet via wireless hotspots was unsatisfactory, especially in production, resulting in poor image quality. Participants from several National Regulatory Authorities, as well as WHO representatives, observed and performed a pilot remote inspection using their own procedures and feedback to the main inspectors. Overall, use of a platform for mixed reality remote inspection is feasible to perform GMP inspections and further testing of improved technology will provide a more seamless experience (21).
We have discussed Remote Interactive Evaluation, where spectroscopists may find the FDA so close yet so far away! RIE is not a substitute for an on-site inspection, but it is an alternative for laboratories with a good compliance history.
Our column highlights the challenges and advantages for laboratories. The fundamental challenge is around spectroscopic standalone system design and ability to share records and data easily with the investigators. Has the spectroscopist who gets the short straw to be interviewed been trained to handle remote evaluation including investigator’s questions?
RIE should be an opportunity to support timely regulatory decisions and laboratories selected should take advantage of this approach.
The authors thank, in alphabetical order, Peter Baker, Chris Burgess, Andrea Chellini, and Andrea Kurz for their critique and constructive comments provided during the preparation of this column. We also appreciate your identification of the additional sources of information.
Mahboubeh would like to thank Bob; his support has been an important part of my journey, and I would like to express my profound gratitude for his mentorship.
(1) FDA Guidance for Industry Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency. 2021, Food and Drug Administration:,Silver Spring, MD.
(2) FDA Draft Guidance for Industry Conducting Remote Regulatory Assessments Questions and Answers. 2022, Food and Drug Administration, Silver Spring, MD.
(3) FDA Warning Letter Dr Retter Ec Wladyslaw Retter. 2022, Food and Drug Administration, Silver Spring, MD.
(4) FDA Warning Letter Nantong Furuida Packaging Products Co., Ltd. 2023, Food and Drug Administration, Silver Spring, MD.
(5) FDA Warning Letter Ningbo Poplar Daily-Use. 2024, Food and Drug Administration, Sliver Spring, MD.
(6) FDA Warning Letter Woorilife & Health. 2023, Food and Drug Administration, Silver Spring, MD.
(7) FDA Warning Letter Patcos Cosmetics Pvt. Ltd. 2023, Food and Drug Administration, Silver Spring, MD.
(8) FDA Draft Guidance for Industry Conducting Remote Regulatory Assessments Questions and Answers. 2024, Food and Drug Administration, Silver Spring, MD.
(9) FDA Draft Guidance for Industry Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications. 2023, Food and Drug Administration, Sliver Spring, MD.
(10) FDA’s Remote Oversight Tools. 2023. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/fdas-remote-oversight-tools (accessed 03-07-2024).
(11) Christensen L.; Chasey. M. Best Practices for Remote Interactive Evaluations and other Alternative Inspection Approaches. in FDA Generic Drug Forum 2023. Food and Drug Administration, Silver Spring, MD.
(12) EMA Guidance Related to GMP/GDP and PMF Distant Assessments. A GMP/GDP Distant Assessment Guidance (Version 1). 2020, European Medicines Agency, Amsterdam, The Netherlands.
(13) FDA Draft Guidance for Industry Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities. 2023, Food and Drug Administration, Sliver Spring, MD.
(14) Reflections on the Regulatory Experience of Remote Approaches to GCP and GMP Regulatory Oversight During the COVID-19 Pandemic. 2021.: https://icmra.info/drupal/sites/default/files/2021-12/remote_inspections_reflection_paper.pdf (accessed 03-07-2024).
(15) Understanding CDER’s Risk-Based Site Selection Model, Manual of Policies and Procedures, MAPP 5014.1. 2018, Food and Drug Administration, Silver Spring, MD.
(16) Lawmakers Voice Concerns over FDA’s Foreign Inspection Program. 2024. https://www.raps.org/news-and-articles/news-articles/2024/2/lawmakers-voice-concerns-over-fda%E2%80%99s-foreign-inspec (accessed 03-07-2024).
(17) McDowall, R. D. Data Integrity and Data Governance: Practical Implementation in Regulated Laboratories; Royal Society of Chemistry, 2019.
(18) Facts About the Current Good Manufacturing Practices (CGMPs). 2021. https://www.fda.gov/drugs/pharmaceutical-quality-resources/facts-about-current-good-manufacturing-practices-cgmps (accessed 03-07-2024).
(19) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use. Official Journal of the European Union 2001, 311, 67.
(20) FDA Analysis and Strategy of Tools to Improve Remote Interactions and Document Management. 2023. https://www.fda.gov/science-research/advancing-regulatory-science/analysis-and-strategy-tools-improve-remote-interactions-and-document-management (accessed 03-07-2024).
(21) Baker, P.; Cathey, T.; Auclair, J. R. Evaluation of a Pilot: Inspection Facilitation and Collaboration Using a Mixed Reality Device. Ther. Innov. Regul. Sci. 2024, 58, 11–15. DOI: 10.1007/s43441-023-00594-2
Mahboubeh Lotfinia works as a Qualified Person and Quality Partner at F. Hoffmann-La Roche and is trained in GMP/GDP audit execution and CSV (Computerized System Validation). ●
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