Amy Scanlin, M.S.
In April 2021 FDA issued Final Guidance for Industry concerning Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency. In an effort to meet designated timelines, including user fee commitments and updates to FDA’s relevant internal databases, remote interactive evaluation “assessments” (RIEs) are being conducted in place of in-person inspections–with the expectation that facilities will demonstrate the same level of transparency and forthrightness as with a formal inspection.
What does the announcement of an RIE mean for the pharma industry, and what can be extrapolated for the larger FDA-regulated industries as a whole?
First, it is clear that FDA is actively re-engaging its oversight responsibilities and incorporating the use of remote tools to the extent possible, all in the vein of ensuring “normal” operations and the protection of public health. We saw this last year when, in April 2020, FDA announced temporary electronic record reviews for the Foreign Supplier Verification Program (FSVP) under the Food Safety Modernization Act (FSMA). Later, in July 2020, FDA resumed prioritized in-person domestic inspections, for all FDA-regulated industries after an approximately four-month hiatus. During the pandemic FDA extended the deadline for tobacco PMTA submissions, extended response due dates for medical device premarket notification submissions, provided flexibility for food labeling and adverse event reporting for dietary supplements and more.
As the far-reaching impacts of COVID-19 stretch across all FDA-regulated industries it is reasonable to assume that the use of RIEs could expand beyond the pharmaceutical industry and into other commodities at some point in the future. To that end, gaining an understanding of the use and structure of RIEs could prove to be a valuable learning opportunity. Additionally, the RIE approach can also allow the FDA to make better use of limited field inspection resources and one could expect to see this “emergency response” program being incorporated into the permanent toolkit of inspections and risk prioritization for the Agency.
RIEs—When are They Used?
So, back to the issue at hand—use of RIE assessments for pharmaceutical industry. First, let’s be clear, the FDA does not intend to use this tool as a formal inspection, but in support of non-mission-critical, non-priority inspections. During the pandemic, RIEs are aimed to minimize risks associated with conducting inspections by reducing the number of FDA staff who travel, and time spent on-site for inspections. Focus will be placed on facilities with acceptable inspection histories, including no obvious issues with data integrity or other concerns that would require a more immediate inspection, and whose specific application considerations and cGMP risks may be sufficiently assessed remotely.
Facilities that have received a warning letter or other enforcement action generally would not be approached for an RIE because FDA usually prefers to conduct an inspection to confirm that corrective actions have been implemented.
As RIEs are an “assessment,” not an “inspection,” FDA clearly stresses that, though no Form 483 Inspection Observations will be issued, a remote assessment’s outcome could prompt an FDA inspection, change the sequence of an inspection and findings gathered could become the target of an inspection, determining its scope, depth, and timing.
It is wise to take RIEs seriously as their outcomes have the ability to move forward the evaluation of a submission, and may be used in place of Pre-Approval, Pre-License, Post-Approval and Surveillance Inspections.
RIEs—What to Expect
FDA will notify of its intent to conduct an RIE by mail, electronic correspondence or phone call sent to the facility (identified through the facility registration number), submission applicant (when appropriate) or U.S. Agent. That notification will include a request for confirmation that the facility is willing and able to participate in a remote interactive evaluation. Such contacts will generally be accompanied with a lengthy list of document and data that will need to be made available to the FDA to facilitate their RIE.
In addition, as with any in-person inspection, FDA expects appropriate staff to be available at scheduled times for interviews and other virtual interactions. The facility should be operational to the extent possible so that FDA may evaluate areas of interest (e.g., manufacturing, laboratory, packaging). Facilities should be prepared for FDA to request and review numerous documents, records, and other information via electronic systems such as livestream and/or pre-recorded video through FDA-hosted IT platforms such as FDA Microsoft Teams, FDA Zoom for Government and FDA Adobe Connect.
As part of an RIE, FDA may evaluate a facility’s corrective actions in response to a previous inspection or evaluation, as well as focus on the current remote interactive evaluation, providing feedback on earlier observations and outstanding issues, etc. It is important to note that FDA will issue neither a Form FDA 483 at the conclusion of a remote assessment, nor a Form FDA 482, Notice of Inspection, to announce or open a remote interactive evaluation.
Similar to an FDA inspection with findings, upon completion of a RIE, FDA will have a closeout meeting with facility management and present a written list of observations, if any, describing and discussing each so that an appropriate response may be developed. However, the observations presented after an RIE are not considered a final Agency action or decision so, as mentioned previously, no Form FDA 483, Inspectional Observations will be issued based upon them.
As with an FDA inspection, FDA encourages facilities to participate in a discussion of findings and provide responses in writing to FDA within 15 U.S. business days of their written communication. These responses will be considered as part of the application’s assessment only if provided to FDA within 15 U.S. business days. It is important to note that the agency may defer consideration of responses or corrective actions in the current review cycle if a response is received after that time.
Facilities may not request FDA to perform an RIE. As FDA says, such decisions are based on “many factors” and applicants and facilities may not have all the relevant information.
What happens if a facility declines a RIE or inadequate technology is available for FDA to conduct its RIE? FDA’s evaluation of an application will likely be hampered as will its ability to make a timely regulatory decision. In cases where inadequate technology is available to support video or other virtual interactions, or if FDA determines that the video or any other virtual interaction during the remote interactive evaluation does not permit sufficient examination of the facility or of a corrective action, FDA may terminate the RIE and instead perform an inspection or use other available tools.
What Can You Do Now?
Prepare–just as you would with an in-person inspection. Now is the time to take a close look at your SOPs, recordkeeping, data integrity, production records and testing data/report and more. Critically evaluate your performance and compliance status, be honest with your internal assessments to identify gaps and areas of known weakness. Beyond that, consider the areas that are affected by Covid-19 impacts, such as vendor audits and qualification, lack of routine updates and reports, etc. Assessing these items with a keen eye, just as FDA will use, can help you to identify gaps, missing or misplaced documentation and any areas that need strengthening. Are your laboratory controls scientifically sound under 21 CFR 211.160(b)? Do you have appropriate computer control of master formula records in compliance with 21 CFR 211.68(b)? What is your GMP training frequency per 21 CFR 211.25(a)? Do you have a named U.S. Agent on file with FDA?
EAS Consulting Group offers in-person and virtual third-party assessments, mock-FDA inspections and GMP training to help you stay ahead of FDA’s GMP compliance requirements. We can also act as your U.S. Agent. Our pharmaceutical team, including over 150 independent consultants, are former FDA investigators, drug reviewers as well as high-level industry executives. Our detailed expertise helps you to assess your compliance and develop mitigation strategies where needed. Contact us to learn more about our Rx services– we look forward to working with you.
Posted in Drugs, Issue of the Month.