This is Part 3 of our series on virtual agency inspections. In this part, former FDA investigator Ricki Chase provides her insight into the best way to prepare for virtual inspections, including how to always be ready, how to go about reviewing documents, and which documents FDA is likely to request for review. Next time, in Part 4, Chase will provide advice on how to host a virtual inspection.

If you are just joining us, you’ll want to check out Parts 1 and 2. In Part 1, former FDA executive Howard Sklamberg reviewed the current inspection landscape and what may trigger an inspection these days. In Part 2 we reviewed a state-of-the-art virtual inspection platform using mixed reality technology developed by Thermo Fisher Scientific that was presented at the ISPE Biopharmaceutical Manufacturing Conference held virtually in early June.

Sklamberg and Chase were both speakers at a mid-June webinar sponsored by the law firm Arnold & Porter, titled “FDA Inspection Alternatives During the COVID-19 Pandemic: Requesting, Preparing for and Responding to FDA Virtual Inspections.”

Chase began her remarks by acknowledging that many firms are concerned about the impact of delayed FDA inspections, particularly on approvals or when it has to do with a firm’s compliance status—for example, if the company is under a warning letter and is looking to get that cleared. “There has been a lot of discussion about how FDA is going to manage remote inspections and how to request one if you think that you should be eligible for one, to move your product or your process along,” she said.

Chase discussed the elements that should be in place to increase a company’s chances of having a successful remote inspection, how to prepare for one, and requesting one. “Regardless of whether you make the request or FDA imposes this upon you, it is important that you make sure that you are prepared and that these elements are in place,” she emphasized.

[RELATED: A great way to prepare for an upcoming inspection is to know what is being cited in your CFR area. Get your free CFR report.]

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Always Be Prepared

Keep in mind that FDA can inspect your facility at any time, she pointed out. “We all know that FDA’s motto is, ‘if you are open for business, then we can come and inspect you.’ A virtual inspection can be the same way. It could be preannounced or it may not be. In at least one instance that we know of FDA called the very day of the start of the inspection.”

“Imagine you are sitting at your desk and you are thinking everything is fine. Suddenly your phone rings and someone says, ‘Hi. I am investigator Chase with the U.S. Food Drug Administration. I am here to conduct an inspection.’ You may not know exactly how to react. It is important that you practice and that you get prepared for any scenario that FDA could throw at you,” Chase emphasized.

Imagine you are sitting at your desk and you are thinking everything is fine. Suddenly your phone rings and someone says, ‘Hi. I am investigator Chase with the U.S. Food Drug Administration. I am here to conduct an inspection.’

An exception to unannounced inspections is for medical devices if it is purely a medical device and not a combination product. It is FDA policy that device inspections are preannounced three to five days in advance.

There are some exceptions—for example, if the company is currently under a warning letter or has an official action indicated (OAI) status, or if it is for cause, then FDA does not need to preannounce. “I have not heard anything and I am not aware of whether they are holding to their three to five-day preannouncement policy in the case of a virtual inspection,” Chase said.

It is also possible that FDA may send your company an email. And in that email, they may request documents and they may request those to be provided to them by a certain deadline. There are a lot of ways that FDA can engage with companies for a virtual inspection.

Remember that for FDA to have the legal authority to conduct a true inspection and collect records for that purpose they need to issue the 482 notice of inspection to the company.

Types of FDA Inspections Reviewed

There are several types of inspections that FDA can conduct.

There is the routine surveillance inspection. “One of the things I would like to point out particularly given this weird time where we have MDUFA (Medical Device User Fee Amendment) and PDUFA (Prescription Drug User Fee Amendment) deadlines, is that FDA also has a two-year statutory requirement for medical devices. They are technically supposed to conduct an inspection of their entire medical device inventory at least every two years. We know that sometimes they have been hit or miss on that, but this would be particularly challenging at a time where they cannot necessarily get out there to do the inspections.”

There is also a directed inspection, in which the agency is looking for specific information, and for-cause inspections. There are triggers for those, such as a company filing MDRs (Medical Device Reports) or recalls or field alerts.

In the pharma industry REMS (Risk Evaluation and Mitigation Strategies) inspections and pharmacovigilance inspections are smaller in scope. So rather than being a general surveillance inspection, it might be easier to conduct these types of inspections virtually or with a records review, particularly with pharmacovigilance, because they are focused on a very particular subject matter.

Questions to Ask FDA

Chase explained that FDA may or may not engage in dialogue with you. They may or may not be open to discussion at the onset of the inspection. It is important, though, if they are that you ask certain questions so that you can make sure that you understand exactly how they plan to conduct the inspection.

Here are some examples she provided of questions a company might want to ask FDA:

  • How we are supposed to provide our responses?
  • If we are sending documentation, can we expect to have it returned?
  • Will we have live interaction meetings before, during, or after document review?
  • Will this be a live inspection using real-time document submission and interaction over video conference? If not, what is the format?
  • How should we communicate—for example, e-mail, document rooms, or through the U.S. Postal Service?

It is particularly important that you understand the expectations so that you know how to respond appropriately.

“Two of the most important concepts for virtual inspection include ensuring you having the opportunity to provide context to the documents they request and understanding how you will have a chance for dialogue if a 483 is issued,” Chase said.

She pointed to the situation in a live in-person inspection when the investigator requests a document and a review of that document in the back room prior to giving it to the investigator indicates that there will likely be questions. “Think about doing this virtually, particularly if you are communicating through sending documents and you are not having, say, a WebEx live inspection, how do you get to explain or give context to the things that they may see and want to know more about?”

She emphasized the importance of thinking through this type of situation and how the context can be provided when a response is submitted in writing. She recommended asking the agency how you will have that opportunity.

Review Your Documents

With a virtual inspection, just as with any other inspection, you want to make sure that you are reviewing your documents in advance. You want to think about how FDA is going to be able to determine your state of compliance and control. They are not on site. They cannot watch you. Unless you are going to take a video camera around for them, which I think would be unusual, they are not going to be able to see your facility or your equipment or your operations. (See Part 2 of this series, A State-of-the-Art Virtual Inspection Methodology Using Mixed Reality Technology Gets High Marks from European Medicines Agency Inspector).

As Howard Sklamberg said in Part 1 of this series, spontaneous interviews are important to them. Without the ability to do that, without those tools in their tool kit, how are you going to be able to demonstrate that you are compliant?

You need to make sure that you are maintaining your state of readiness through making sure that you are reviewing your SOPs to see they are current. Do not keep old ones around. If you are doing an inspection virtually make sure that you review them ahead of time.

You need to make sure that you are maintaining your state of readiness through making sure that you are reviewing your SOPs to see they are current. Do not keep old ones around. If you are doing an inspection virtually make sure that you review them ahead of time.

Make sure your quality metrics are current and not only current but have been evaluated them and you know what they are indicating. Trends in your quality metrics will be reviewed. Know what those are and how you can show that you are addressing quality signals and that you have taken appropriate actions where necessary.

Always make sure that your complaints, deviations, nonconformances, and CAPAs are reviewed. “We know that those are top 483 observations. You want to make sure that not only are those reviewed and they are complete, but you have all the documentation to support any actions that you may have taken,” Chase advised.

Review out-of-specification (OOS) investigations, ensuring that you have complete investigations and supporting data. Also review evidence of supplier quality agreements, your company’s current approved supplier list, and evidence of internal audits including the audit schedule and documentation of completion.

If you manufacture combination products with, for example, the pharma product being the lead, it is important to make sure that you are meeting the requirements of the other regulatory provisions, such as 21 CFR 820, the quality system regulation.

“You cannot assume that because they are doing a pharma-lead, a CDER-led inspection, that they are not going to ask questions about how you are filling the gaps on the device side if you have a drug/device combination product. You need to make sure that you have things such as evidence of management review and established quality objectives, because it is highly likely that they would ask for those things.”

For medical devices or combination products, the design history files (DHF) are often extremely large, and it would be unlikely to have an entire DHF requested for a remote review.  Ensure your DHFs for your most high-risk and/or new products are organized and complete. Common requests would be for the design development plan (DDP), risk analysis, input/output matrix, and Design and Use Failure Mode Effects Analysis (DFMEA/UFMEA) documents.

Changes are always a point of interest. If you have put in a new piece of major equipment, started any new processes, or made any major changes to your facility or your products, those are usually areas that become a point of focus.

Changes are always a point of interest. If you have put in a new piece of major equipment, started any new processes, or made any major changes to your facility or your products, those are usually areas that become a point of focus.

For example, if new, major production equipment has been installed, be prepared with a diagram or schematics to help the investigator visualize the change. Ensure that IQ/OQ/PQ (Installation Qualification, Operational Qualification, and Performance Qualification) documents are complete. Many times, these are large files. Ensure that the sections are clearly identified. Usually, the Protocol and Report sections are the primary ones to be reviewed.

Where new or changed processes have been implemented, or where there is a high-risk process, ensure the current process validation documentation is complete and approved, and that any deviations of non-conformances are clearly explained and justified.

For facilities, particularly aseptic facilities, environmental and microbiological controls are key. Ensure you have trending data on your environmental monitoring and that any necessary actions were discovered, completed, documented, and corrected or prevented. Corrections to excursions should be a point of focus.

Submit High-Quality Documents and Remember Inspections Focus on Risk

It is particularly important when you are providing documents to FDA that you ensure your documents are clear and legible and free from extraneous comments and sticky notes, etc. with no pages missing. 

“We have all been in a situation where we have opened a batch record and we see that somebody has written a note on it on a sticky and they stuck it in the file. You want to make sure that you do not have any of those extraneous documents stuck in a file that should not be there.”

You need to have all the pages accounted for. You will not be sending original documentation. You are either going to be doing a scan or a photocopy. You want to make sure that the material is going to copy well and it is going to be able to be read by the investigators. What you do not want them to do is to have them come back and continue to ask for different copies because they cannot read what you sent them.

It is also important when you are sending something like a log or a notebook that you are only sending the data which has been requested. “We know that sometimes in our notebooks maybe a page is shared with the beginning of another test. You want to make sure that you are only providing the information relevant the question and you are not allowing that extra information to be shared unless it is specifically requested from the investigator,” Chase said.

She pointed out that it is important to keep in mind when preparing for any inspection that investigators are specifically targeting higher-risk products and processes.

‘Inspections generally are supposed to focus on risk,’ Chase pointed out. ‘FDA has a limited amount of time. An audit is just an audit. They are asked to look at those areas which are higher risk and to focus on those areas as a measuring stick for the rest of your quality system.’

“Inspections generally are supposed to focus on risk,” Chase pointed out. “FDA has a limited amount of time. An audit is just an audit. They are asked to look at those areas which are higher risk and to focus on those areas as a measuring stick for the rest of your quality system.”

“If there are gaps in your high-risk areas, it really becomes easy for them now to say, ‘you have some gaps in a critical area, so we want to look at what might be underlying those gaps.’ That is when they start asking questions about whether you have enough resources available, or have done the proper training, and if your documents support your current process.”

“They are probably going to start with high-risk areas. But as they find deficiencies in those, they will start looking at areas that you might think are of less importance to substantiate their claims on the higher risk areas. The message is that in those areas which you think would by necessity be lower risk, doing the training and having the proper document control becomes important.”

[RELATED: A great way to prepare for an upcoming inspection is to know what is being cited in your CFR area. Get your free CFR report.]

Get your CFR Trend Report from Redica

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