As onsite pharma FDA inspections resume in earnest, the agency will use state advisory level rating systems for the areas where manufacturing sites are located to help determine whether to inspect onsite at any given location.  The agency is also considering how to best perform remote drug inspections for circumstances in which onsite agency presence is not critical.  The conduct of FDA’s “virtual” audits will likely be informed by its experience in performing medical device inspections from offsite, which it has been doing for some time.

At the FDLI Enforcement, Litigation, and Compliance Conference held virtually in December 2020, Medtronic Senior Principal Legal Counsel Anne Miller discussed the criteria FDA is using to evaluate whether it can perform an onsite drug inspection.  She also discussed her company’s experience with remote medical device inspections involving FDA that could be used to inform the agency’s remote pharma inspection efforts.

[Related: Are you looking for in-depth information about virtual inspections?  Download a special report by the author that looks at virtual inspections, including new technologies to facilitate virtual inspections.]


Criteria for Onsite FDA Inspections

Regarding onsite inspections, note that FDA looks not only at the COVID-19 infection rates in the county where the inspection is to occur, but also takes into consideration the rates in the county where the investigators live.  Rates can vary from county to county.  If an investigator is traveling, even by car across county lines, that will also be taken into consideration.

The rating system is based on three metrics. It looks at:

  • The pandemic phase of the state—which is defined by White House guidelines
  • County-level statistics evaluating the rate of infection
  • County-level statistics evaluating the intensity of the infection

FDA will look at the days of downward trend in a county.  A benchmark for FDA to consider an inspection is generally 14 or more days downward trend.  With respect to intensity, FDA will look at a two-week timeframe, looking at new cases per 100,000.  The benchmark for FDA is to have 10 or fewer per 100,000 in the county where it would like to inspect.

Considering those metrics together, a risk level is assigned for the county. It will be either red, yellow, or green.  For most FDA inspections, it will need to be yellow or green before the agency will consider going in to inspect onsite.

FDA also prioritizes mission-critical inspections, which it has not specifically defined.  “However, we have learned that pre-approval inspections are mission-critical.  Those are also generally quite focused, very narrowly tailored inspections where the inspectors can generally get in and get out more quickly than perhaps with a GMP inspection,” Miller explained.

“I also think that if FDA were to have a for-cause inspection or a need or a product or a patient risk that it deemed was significant enough, it would go in and inspect. Independent of the color code of a zone a facility is in, if FDA thinks that the public health concern is high enough, it will figure out a way to assess the criticality and inspect,” she commented.

Preparing for an Onsite FDA Inspection

The COVID-19 pandemic and the resulting travel and visitation restrictions will be in effect well into 2021.  However, onsite FDA inspections for mission-critical situations may still take place and it will be prudent for companies to be prepared.

Since all inspections are pre-announced, that affords an opportunity to review onsite protocols and screening processes before FDA comes onsite.  For example:

  • Are people’s temperatures taken prior to entering a facility as a screening tool?
  • What are the mask requirements?
  • Approvals may be needed from somebody within the company to let FDA onsite; this should be attended to in advance, if possible.

There may also be an FDA site assessment to complete.  This will include what the practices are—for example, if the company becomes aware of a positive COVID instance when the agency is onsite.  It is also likely that FDA is going to want to do its work in as short a time as possible.

There will probably be a record request from the agency in advance of the inspection.  Some of the records will need to be supplied before FDA investigators arrive, others after they arrive.

In preparation for an onsite visit, the firm will need to consider how to bring staff back to the plant.  Since most staff are working off site, the company will need to decide who is needed onsite for an inspection, whether they can come back, and who may need to participate from offsite via teleconference.

Hosting an Onsite FDA Inspection

The front room where FDA is being hosted needs to be set up with physical distancing.  Everyone will need to wear masks and maintain a six-foot distance with other people.  That will require some thought in advance—how to have the people in the room who should be and how to space them apart.

It may involve setting up TV monitors in the room for record review—for example, using Zoom or WebEx. “In our experience, we are not exchanging paper documents the way we used to.  So, it is not like the past, where copies are being made and people are running back and forth into the front room.  Some of this will need to be done virtually, even though FDA is onsite,” Miller commented.

If FDA thinks that the public health concern is high enough, it will figure out a way to assess the criticality and inspect

She recommends practicing hosting an inspection under the new circumstances—for example, thinking about the best way to transfer the records from the back room.  “You get a record request.  The back room will get it and do whatever review of that record needs done before it goes into the front room,” the Medtronic attorney explained.  “Then practice how you are going to transfer records to the front room electronically—for example, using an electronic file transfer system like Box.”

Also remember that FDA has electronic size limitations.  So, do not assume for instance, that FDA will be able to download a file from Box or Dropbox.  Documents may need to be put on a USB stick and physically provided later.  Be sure to have a way of tracking the records that are provided to FDA since it will probably not be a paper exchange as in the past.

Miller stressed that it is critical to have dedicated IT support during the entire inspection.  That applies not only for FDA onsite, but also for company personnel dialing in remotely.  Make sure they have the support they need to ensure the interactions are smooth.

[Editor’s Note: More expert advice on hosting a remote regulatory agency inspection is available here.]

A Pilot for Remote FDA Inspections?

We know that FDA is considering a pilot on remote or virtual inspections. Some questions that come to mind are: 

  • What will the pilots look like?
  • Are they going to be factory inspections, assessments, or appraisals?
  • Are they going to be something other than what we consider to be true inspections?
  • Who can participate?
  • Can only those who were part of the pilot participate?
  • Will only certain companies that fit certain threshold criteria be allowed to participate?

“I think FDA might be wrestling with some of those basic questions before we even get to the practical considerations of how the remote inspections will work,” Miller commented.

FDA Medical Device Inspection Experience

In the European Union, organizations known as “Notified Bodies” are designated by member states to perform inspections to assess the conformity of products as outlined in EU directives that are needed to place products on the EU market, including medical devices.

The European Commission (EC) gave approval to Notified Bodies to perform remote inspections to help ensure completion of the assessments prior to the EU Medical Device Regulation (MDR) coming into effect in May 2021, and the In Vitro Device Regulation (IVDR) in May 2022.  The EC reportedly made the decision by examining evidence that remote or “distance” audits—as they are often called in the European Union—work, and in response to concerns that if the assessments are not completed that market shortages could happen.

It is also likely that FDA is going to want to do its work in as short a time as possible

However, the EC does require some justification for performing the remote audits and recommends that an onsite inspection be conducted as soon afterward as is feasible.

As of July 2020, there were 15 Notified Bodies (NBs) designated to MDR and four (4) designated to IVDR, with at least nine (9) additional NBs pending designation.

Medical Device Remote Audits

In her talk, Miller referred to her company’s experience with MDSAP audits.  MDSAP—the Medical Device Single Audit Program—was envisioned by the International Medical Device Regulators Forum in 2012.  It allows an MDSAP-recognized auditing organization like FDA to conduct a single audit of a medical device manufacturer that will be recognized by all other member organizations.

“At Medtronic, on the device side, we do have quite a bit of experience through our Notified Body audits,” she pointed out.  “Notified Bodies in Europe have been conducting remote inspections throughout the duration of the pandemic.  They started off a little bit clunky but have gotten better over time in terms of how to use the technology, how to transfer records, etc.”

FDA’s MDSAP audits, Miller said, have been taking place remotely.  “So, FDA does have some experience with remote audits and how they might work in practice.  Hopefully, the agency can borrow from and take some lessons from that experience for remote drug inspections.”

Are Remote FDA Inspections Effective?

Commenting on FDA conducting remote pharma inspections, Miller said, “I think they can be a really good alternative for FDA, even potentially after we are on the other side of this pandemic, especially for inspections that are heavy on records.  If it is a record review and not a factory tour, I think you can do remote inspections as effectively as in-person inspections.”

However, remote inspections do require some preparation. [Editor’s Note: More expert advice on preparing for a remote regulatory agency inspection is available here.]

For example, in a remote inspection there are fewer restrictions in terms of who participates.  There may be multiple auditors.  “That has been our experience with some of the Notified Body inspections. I think four is the max we have done.”

Multiple auditors each create a separate workstream that requires its own staffing.  Front and backrooms will need to be set up for each, created virtually. Also, keep in mind that multiple time zones may need to be managed.

 It is critical to have dedicated IT support during the entire inspection

The typical back room review of documents and presenting them to the auditor in the front room must be designed and managed virtually.

“From our experience, some like to stay on Zoom the entire time they are reviewing a record,” Miller reported.  “For those individuals, company personnel must be prepared for long periods of silence while the documents are reviewed.  Others may permit you to mute your connection and do other things while documents are reviewed and then be ready for questions when they come up.”

When communicating online with other company personnel, it is important to ensure the chat is private and not visible to the auditor.

Regarding factory tours, it is possible to do a remote factory tour.  Video can be used effectively, “but I would be hesitant to allow it to be recorded,” the Medtronic executive emphasized.  “It’s one thing to be on a live video, walking through your plant, but you would have to be really careful and thoughtful about allowing a recording of the video of the factory tour that then can be passed around and shared.  That would be my primary concern in terms of remote inspections.” [Editor’s Note: A review of current state-of-the-art remote inspection technology is available here.]

[Related: Are you looking for in-depth information about virtual inspections?  Download a special report by the author that looks at virtual inspections, including new technologies to facilitate virtual inspections.]


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