This article was originally published on August 27, 2020. It has been updated with new information.

Part I of this series summarizing the May 28 webinar,  “Guess Who’s Knocking at Your Door: Assuring Inspection Success!”, covered Steven Niedelman’s remarks on the legal and regulatory framework for FDA inspections.

The following looks at the types of inspections FDA conducts plus what the agency can inspect and what it cannot inspect. 

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Types of FDA Inspections

FDA conducts three main types of inspections. Preapproval inspections generally support New Drug Applications (NDAs), Premarket Approvals (PMAs), and licensing agreements. For-cause inspections are conducted in response to information the agency considers a potential public health risk. These include:

  • Increased adverse events
  • Significant adverse event
  • Possible catastrophic Medical Device Report (MDR) 
  • Escalating numbers of reports
  • Circulating issues that give cause for concern
  • Increases in recalls or Class 1 recalls
  • Significant increase in customer complaints
  • Whistleblower reports

“The agency also conducts bioresearch monitoring inspections of clinical studies to assure that protocols are being followed,” Niedelman said. “These are conducted at the investigative sites as well as the sponsor sites. It also makes sure that documents are being maintained contemporaneously and that there is no product diversion.”

[Editor’s Note: For more on the different types of inspections, check out the webinar clip below.]

Factors That Increase Inspection Chances

Several factors can increase the likelihood of an FDA inspection. U.S. Congressional legislation now mandates FDA use risk-based factors when choosing to inspect a site. This replaces the previous two-year inspection requirement. 

Niedelman listed a number of factors FDA looks at when determining to conduct an inspection (Figure 1).

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Figure 1 Risk Factors for Inspection

“Prior inspectional history is important,” he said. “If you have had poor inspections in the past, that is going to be a continuing, annoying concern at FDA that requires them to come and do follow-up inspections. That would include follow-ups to warning letters, untitled letters, etc.”

Further, FDA is more likely to inspect a site which has a history of not correcting issues cited by the agency.

Additionally, “if you have significantly challenging products to manufacture or very high risk products or new and novel technologies, FDA is going to want to come in and inspect more frequently at your firm than at one that makes a more sedentary product, one that is not as challenging to manufacture or might not be as clinically significant as one of your competitors,” Niedelman said. “For example, if you are manufacturing a sterile product versus a non-sterile product. Even within sterile products, aseptic processing is a more challenging process than some other types of sterilization.”

If you have had poor inspections in the past, that is going to be a continuing, annoying concern at FDA

So, What Can FDA Inspect?

Niedelman outlined a number of areas/items FDA can inspect (Figure 2).

Figure 2 What Can FDA Inspect

Figure 2 What FDA Can Inspect

“FDA can inspect vehicles used to hold or transport pharmaceuticals or medical devices,” he said. “FDA has seized trailers full of products. There are firms where FDA would come in the front door and the violative product would go out the back door or be stored in tractor trailers and then sealed. FDA would become aware of it. And FDA would freeze that trailer on site. There are many times that the FDA has seized trailers in transport. They do have access to all your transport vehicles, including rental ones.”

FDA investigators can also look at raw materials and their components. With manufacturing equipment, they can look at any piece to ensure it has been installed properly as part of the validation process.

Any finished or unfinished pharmaceuticals are fair game,” Niedelman said. “The same goes for medical devices, along with any containers used to manufacture, store, or distribute pharmaceuticals.”

Source containers for medical devices and labeling can also be inspected, although investigators generally do not comment on labeling. 

There are many times that FDA has seized trailers in transport

Records that can be inspected include details on the movement of products in the supply chain, all records pertaining to adverse events, recalls, MDRs, etc., and all records required by CGMP or the quality system, including drug master files, device master records, batch records, device history records, product reviews, complaint files. 

He stressed that it is important to document what inspectors looked at to ensure adequate follow-up in case questions arise after the inspection.

What Is FDA Prohibited from Inspecting?

While FDA investigators can inspect many things at a site, there are a number of things they cannot ask to review (Figure 3).

“FDA investigators are trained to ask for the sky, the moon, and the stars,” Niedelman said. “It is up to you to be able to know what they are and are not entitled to during an inspection.” 

Figure 3 What FDA Cannot Inspect

 Figure 3 What FDA Cannot Inspect

For example, the FDA is not entitled to review a firm’s financial data, such as profit margins. 

“FDA really does not care about dollars,” Niedelman said. “That is not an argument that holds water. Even when a recall is taking place, you will not necessarily get the ear of FDA if you say, ‘well, these products cost a lot of money, it is going to put us out of business.’ For FDA, it is all about the public health.”

Most importantly, investigators are not entitled to records or reports resulting from internal audits, management reviews, or supplier audits as these are outside their scope. FDA wants companies to feel they have the freedom to identify and correct problems on their own. But investigators can examine written procedures established for internal audits, management reviews, and supplier audits, even requesting written certification that these activities have been performed and documented. Any CAPAs opened as a result of these activities are also fair game. 

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