FDA Issues Draft Guidance On Remote Interactive Evaluations Of Drug Manufacturing And Bioresearch Monitoring Facilities

By Peter H. Calcott, Ph.D., president and CEO, Calcott Consulting LLC

In October 2023, FDA issued a draft guidance titled Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities: Guidance for Industry. Industry has through December 26 to provide comments.¹

This guidance puts into writing how FDA is operating their remote evaluations program, the logistics of its implementation, and what they expect of industry. The use of remote evaluations is not new to FDA or the industry. It has been common practice for many decades in an informal sense. However, over the last two to three years with the Covid pandemic, it has taken on a more central role in allowing FDA to evaluate industry, sometimes with 100% remote operations. FDA recently published comprehensive documents on the tools used in remote assessments.^2,3 After the Covid pandemic, we can expect to see more of these remote practices in either 100% remote or hybrid approaches.

This guidance describes the program as it is run and the agency’s expectations. But the guidance goes further. It allows us to understand the FDA’s thought process and we can learn from it. We run audit programs in our companies and we are always looking for ways to streamline our operations, making them more effective with fewer resources such as people and money, without impacting effectiveness. Some of the FDA’s experience (and they do conduct many more inspections than we do audits) may be applicable to our programs. But now, back to the guidance.

The guidance is broken down into six major sections. The first two are Introduction and Background, which are designed to lay the framework for the following sections. Then there is a section on Planning a Remote Interactive Evaluation, followed by Conducting a Remote Interactive Evaluation and Concluding a Remote Interactive Evaluation. The final section is on Timeframes Following Completion of a Remote Interactive Evaluations.

Candidates For A Remote Evaluation

In the introduction and background sections, the agency points out that the use of remote evaluations is not new. Often, it has requested documents to review at its centers prior to inspectors’ arrival at the facilities. But they also point out that remote evaluation techniques may be even more useful when issues at a plant are not serious or when compliance is expected to be good. They do point out that a fully remote evaluation would not be appropriate for data integrity issues, after a warning letter, or for a company with a poor compliance record. They also point out that it would not be appropriate for new products and new facilities. In addition, a company that is new to FDA oversight would not be a likely candidate for a remote evaluation. They also point to high-risk geographic areas such as India and China as not being likely to experience remote evaluations. If you are offered the option of a 100% remote assessment, the FDA is telling you something about their perception of your operations.

What type of evaluations would be candidates for a remote evaluation? Clearly, certain types of drug manufacturing inspections are candidates, as are Bioresearch Monitoring (BIMO) inspections. A typical inspection (or audit) gathers evidence to determine whether things are operating well and in compliance with FDA expectations.

I always have used the declaration, “Say what you do, do what you say, prove it, and improve it.” The four parts of this statement refer to evaluating the documents, execution, records, and signs of continuous improvement, respectively. Numbers 1 and 3 can be easily done remotely since they entail evaluation of documentation (documents and records). Numbers 2 and 4 look at physical activity, which is much easier to do live, in person at the scene of the activity. That does not mean it has to be done that way, but it is more difficult to do it well remotely. This now brings risk into the picture. That means if no compliance issues or unknowns are expected, 100% remote evaluation would be considered. If there are compliance risks or unknowns, expect it not to be considered.

In section 3 of the draft guidance, the FDA lays out the types of inspections and categorizes them as to whether remote evaluations will be considered. This includes pre-approval inspections (PAIs) and pre-license inspections (PLIs), which may include new companies, new facilities, or just new products. There is no blanket statement with respect to appropriateness of remote evaluations; rather, it appears it will be on a case-by-case basis. Similarly, post-approval inspections when new technology, operations, validations, and changes have been made will be considered on a case-by-case basis. Routine surveillance inspections, when issues are not obvious, could use remote evaluations if risk warrants it. In a similar fashion, BIMO inspections are also potentially good candidates for remote evaluations. The one type of inspection that would almost never utilize 100% remote evaluation would be follow-up or compliance inspections. These involve an issue that prompted a need for an evaluation and, therefore, an increased risk. That does not mean that document or record review might not be performed remotely. Physical presence at the plant is highly likely after the initial remote assessment.

Fully Remote, Fully On-Site, Or Hybrid?

Based on the type of inspection and the risk, FDA will select the techniques to be used to evaluate the facility: 100% remote, 100% on-site or a hybrid. With this decision made they will notify the company of their plans. In almost all cases, the FDA will contact, as appropriate, the person designated in the filing for documents they request. So, keep the contact person information in the filing up to date. If some form of remote evaluation is contemplated, that person becomes the point of contact for coordination. This includes the scope of the remote evaluations, the timing, and dates of potential inspections.

In this section that details the various types of inspections, the common theme is risk-based approaches and decision-making. The other common thread is that data integrity issues will decrease or eliminate the likelihood of 100% remote evaluation independent of the type of inspection. The FDA cites several examples where documents or records are the focus of evaluation and under many circumstances that can be done easily remotely. But they do point out that this 100% remote evaluation will not be considered an actual inspection. These approaches, which are proposed to the company in writing, can be accepted or not by the company. I believe if you disagree and do not accept the proposal, it is not going to speed things up and will probably cause delays.

Logistics Of Remote Evaluations

In the preparations section, FDA spells out the logistics of this phase. It often starts with a virtual meeting over the internet to coordinate the activities. It would include assessment of the ability of the company to support the remote evaluation through teleconference, live stream video, and screen sharing. This will be determined before the coordinating meeting where details are worked out.

Preparing for the remote coordinating session is conducted to cover the logistics of the activities of the remote evaluations and includes:

1. Objective and scope of the assessment; that is, what is the focus and what will be looked at.
2. Introduction of FDA team involved, including IT support.
3. Identifying the facility-coordinating person at the site.
4. Schedule the date, time, and duration of the remote evaluation.
5. FDA’s expectations for the walkthrough of the facility: the physical inspection of operations.
6. Time zone differences considerations and translation service needs.
7. Methods for sharing information: formats and softwares.
8. Technological limitations: hardware and software configurations.
9. Check the internet connection, bandwidth, and signal strength.

With the logistics and date and time confirmed, the actual remote evaluation can begin. FDA points out it should work like a regular inspection with normal requests such as for documents, records, and other information (e.g., electronic systems), walk through facilities using livestream or prerecorded video, scheduling of interviews and meetings to answer questions or clarify issues, evaluation of CAPAs, and providing verbal updates on observations. Unlike an inspection, no form 482 (Notice of Inspection) will be issued.

Clearly, with the heavy involvement of technology, there are potentially things that can go wrong. FDA recognizes this. They do not expect the systems to work perfectly all the time. They have defined the software systems to be used and because of security, they will require the company to use FDA versions of various software. This should minimize issues. They also advise on the use of certain document formats such as PDF. Their recommendations are not out of line with industry practices. They will try to give as much notice so that documents can be procured and made available.

At the end of the remote assessment, the FDA will issue observations but not a form 483 (FDA has stated it is not an inspection). You must consider this evaluation to be preliminary since this is not an inspection. The final outcome will be governed and controlled at the center. That said, you will have the standard 15 business days to respond to the observations.

So, If The Evaluation Is Not An Inspection, What Is It?

The FDA indicates it is information to allow them to plot the path forward. It can be to support applications, preclude the need for an in-person inspection, support regulatory actions, rank and prioritize facilities from a risk perspective, and justify any follow-up as needed. They may not call the outcome of the remote evaluation a form 483, but in my books it’s more like a pre-483. Just like a form 483-driven inspection, you will get an Establishment Inspection Report (EIR). The final outcome will be issued by the appropriate FDA center (CDER or CBER).

It is likely that the FDA will use these remote evaluations to support their compliance with the PDUFA timelines. Remember, if you fail to respond in 15 days, it will impact your path forward. They state that if you are late, they may not consider your responses in their actions.

The Key Takeaways

What are the take-home messages that we can use to improve our auditing program? After the Covid pandemic, we all shifted to virtual inspections out of necessity. But what is clear is that we will not return to the old business model of only in-person audits. We were in the process of change anyway. Low-risk suppliers of low-risk items were assessed by paper audits (that will continue). We adjusted our audit schedules based on risk (that will continue). Often unofficially, we did perform hybrid audits. That is, many documents were sent for evaluation before auditors went to the plant (that will continue).

I believe that the FDA has solidified a strategy of using both virtual (remote) and hybrid models (remote plus in-person). But under certain circumstances, the fully in-person will still be used. This strategy will be useful for industry to implement similarly across our audit programs.

The strategy we use in our operations should be risk-based.

1. The very low risk can be 100% virtual (paper audits and/or remote evaluations). This could be for suppliers of materials with little impact on product or operation quality. We might also consider this for medium-risk items where the supplier, material, or service has had a good track record of operations and compliance, which decreases the risk.
2. The medium risk can be a hybrid audit with documents (SOPs, policies, protocols, specifications) and records (completed batch records, investigations, certificate of analysis, etc.) assessed remotely. The evaluation of execution and improvements would be assessed on-site in person.
3. The high-risk items, such as new products, new CDMOs, and poorly performing operations at troublesome CDMOs, would be executed with all activity done on-site.

The total virtual has some advantages of cost reduction but that is weighed against time zone differences, the vulnerability of electronic connectivity, and, above all, risk. Electronic connectivity systems are better than they were 20 years ago, but they are not perfect.

But does the hybrid model save resources and money over 100% in-person? The auditor(s) have to visit (so travel time and cost are still incurred). But they do not stay as long, so costs for hotels, local transportation, and food are reduced proportionate to the amount of work transferred to remote assessment. The personnel resources would not substantially change. So, there can be some savings.

References

1. Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities Guidance for Industry FDA October 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/remote-interactive-evaluations-drug-manufacturing-and-bioresearch-monitoring-facilities
2. FDA Issues Guidance on using remote oversight tools to help approve drugs. FDA September 2023 https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-guidance-using-remote-oversight-tools-help-approve-drugs
3. FDA’s Remote Oversight Tools. FDA March 2023 https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/fdas-remote-oversight-tools

About The Author:

Peter H. Calcott, D.Phil., is president and CEO of Calcott Consulting LLC, which delivers solutions to pharmaceutical and biotechnology companies in the areas of corporate strategy, supply chain, quality, clinical development, regulatory affairs, corporate compliance, and enterprise e-solutions. He has also served as an expert witness. He also teaches at the University of California, Berkeley in the biotechnology and pharmaceutics postgraduate programs. Previously, he was executive VP at PDL BioPharma, chief quality officer at Chiron and Immunex Corporations, and director of quality assurance for SmithKline Beecham and for Bayer. He has also held positions in R&D, regulatory affairs, process development, and manufacturing at other major pharmaceutical companies. He has successfully licensed products in the biologics, drugs, and device sectors on all six continents. Calcott holds a doctorate in microbial physiology and biochemistry from the University of Sussex in England. He has been a consultant for more than 20 years to government, industry, and academia.