FDA Announces Draft Guidance to Continue Implementing Remote Interactive Evaluations of Drug Manufacturing Establishments and Biomedical Research
The U.S. Food and Drug Administration (FDA or the Agency) recently issued the draft guidance, “Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities” (draft RIE Guidance), describing how FDA may request and conduct voluntary remote interactive evaluations (RIEs) of facilities where drugs (including biologics) are manufactured, processed, packed, compounded, or held, and of drug facilities covered under FDA’s bioresearch monitoring (BIMO) program.
The draft RIE Guidance replaces the similar COVID-19-pandemic-related guidance issued in April 2021, titled, “Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency” (COVID-19 RIE Guidance).1 The draft RIE Guidance only makes a few substantive updates to the COVID-19 RIE Guidance, but issuance of the draft RIE Guidance does confirm that FDA intends to continue requesting, conducting, and utilizing voluntary RIEs.
Voluntary RIEs are a type of Remote Regulatory Assessment (RRA). FDA developed the concept of RRAs early on in the COVID-19 pandemic, after FDA suspended most of its domestic and foreign inspection programs due to COVID-19 health risks and travel restrictions. FDA uses the term RRA to refer to essentially any remotely conducted FDA examination of any FDA-regulated facility and/or its records to evaluate compliance with applicable FDA requirements.2 RRAs may consist of (or include) a request to conduct a voluntary RIE. A request by FDA under Federal Food, Drug, and Cosmetic Act (FD&C Act) section 704(a)(4) for records or other information is also considered by FDA to be an RRA.
In the draft RIE Guidance, FDA reiterates (and as was also stated in the COVID-19 RIE Guidance) that, generally, a drug facility’s participation in an RIE, and the facility’s compliance with FDA requests made during an RIE, are voluntary. FDA has authority under section 704(a)(1) of the FD&C Act “to enter” establishments to inspect them “at reasonable times and within reasonable limits and in a reasonable manner,” and FDA generally has not determined that this grants FDA the authority to conduct mandatory inspections through entirely remote means. The draft RIE guidance also reiterates, however, that FDA may request records or other information, either before or during the RIE, utilizing the Agency’s FD&C Act section 704(a)(4) authority. Section 704(a)(4) authorizes FDA to request records or other information in advance of, or in lieu of, an inspection. In such cases, FDA will specifically request such records or information under its section 704(a)(4) authority (typically via an FDA Form 4003, “FDA Inspection Records Request”). Compliance with a valid section 704(a)(4) request is mandatory. The draft RIE Guidance also reiterates that FDA may request and use voluntary RIEs to supplement mandatory in-person inspections.
The draft RIE guidance, like the COVID-19 RIE Guidance before it, states that FDA will consider the use of RIEs in the context of all FDA drug inspection programs, including:3
- Preapproval inspections
- Postapproval inspections
- Surveillance inspections
- Follow-up and compliance inspections
- BIMO inspections
Depending on the purpose and outcome of the RIE, the information and documentation collected by FDA during the voluntary RIE may be used by FDA to, among other regulatory purposes:
- Support FDA’s assessment of pending applications, including whether to approve an application
- Preclude the need for an inspection in follow-up to a reported concern or defect
- Support a regulatory meeting, warning letter, import alert, recall activities, or enforcement action
- Rank or prioritize a facility for an inspection, particularly a surveillance CGMP inspection
- Justify a follow-up or compliance inspection or any other surveillance activity4
It is important to keep in mind that if an establishment refuses a voluntary RIE request, FDA may consider using other tools for evaluating compliance with FDA requirements (including, potentially, conducting an unannounced mandatory in-person inspection as soon as FDA is able). The draft RIE Guidance also notes (as did the COVID-19 RIE Guidance) that declining FDA’s request to perform a voluntary RIE could impede FDA’s ability to make a timely regulatory decision, which could include deciding whether to approve an application.
As we note above, the RIE Guidance makes only a few substantive updates to the COVID-19 RIE Guidance. However, there are a few revisions in particular that are worth highlighting:
- The COVID-19 RIE Guidance noted that FDA section 704(a) requests for records and other information did not apply to FDA’s BIMO inspection program, but the draft RIE Guidance has deleted that note. This is a good reminder that the Food and Drug Omnibus Reform Act of 2022 (FDORA) extended FDA’s section 704(a)(4) authority to BIMO inspections.
- The COVID-19 RIE Guidance did not discuss drug compounding, whereas the draft RIE Guidance clarifies that FDA may utilize RIEs in the context of drug compounding.
- The COVID-19 RIE Guidance indicated that, after the conclusion of an RIE, FDA would always provide the facility with a copy of the final RIE report. The draft RIE Guidance indicates FDA may not always do so. This change was likely made to be consistent with FDA’s clarification in a subsequently issued related guidance (“Conducting Remote Regulatory Assessments — Questions and Answers” (July 2022)) that (as is consistent with FDA’s practice for mandatory inspections) FDA will provide the establishment with a written copy of the narrative portion of the RRA report following the determination that the RRA is closed as described in 21 CFR 505 20.64(d)(3) (“Records or information compiled for law enforcement purposes”).5
- The draft RIE Guidance contains references to two related draft guidances that FDA issued since issuing the COVID-19 RIE Guidance in 2021:
- FDA draft guidance, “Conducting Remote Regulatory Assessments — Questions and Answers” (July 2022) (the draft guidance mentioned above)
- FDA draft guidance, “Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications” (September 2023)
In particular, the draft RIE Guidance recommends reviewing these July 2022 and September 2023 draft guidances for additional information regarding what criteria FDA may use to determine whether to use an RRA or other alternative tools.
The most important point is that RIEs and other forms of RRAs will be permanent parts of FDA’s inspection and oversight program. Companies should plan accordingly. Companies should have in place standard operating procedures (SOPs) not just for inspections but also for RIEs and other forms of RRAs. These SOPs should include policies and procedures on how to participate in RRAs. Any delays could result in delayed approval of a drug or biologic, making efficiency important. There should also be SOPs on how to respond to any findings that FDA makes during an RIE or other type of RRA.
FDA is currently accepting comments on the draft RIE Guidance, and comments are due to FDA by December 26.
If you have any questions about the content discussed in this Advisory or would like more information, please reach out to one of the authors of this Advisory or to your existing Arnold & Porter contact.
© Arnold & Porter Kaye Scholer LLP 2023 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.
Arnold and Porter’s April 2021 coverage of the COVID-19 RIE Guidance is available here.
See, e.g., FDA Draft Guidance, “Conducting Remote Regulatory Assessments” (July 2022) at p. 6.