What are the best practices for dealing with FDA inspections?

Robert Dormer

Q
Question: What are the best practices for dealing with FDA inspections?
A
Answer:

Many life sciences companies may regard the prospect of an FDA inspection with dread, in part because they view the process and result as somewhat unpredictable. However, the Agency’s goals in conducting inspections and the processes and materials that will be the focus of its inspections are easy to ascertain. Once what can be expected is known, preparation should be easier. 

Types of FDA Inspections

There are several categories of FDA inspections: routine inspections; “for cause” or “directed” inspections; follow-up inspections; specific product or process inspections; and pre-approval/pre-clearance inspections. Though conducted for varying purposes, the FDA’s primary focus in each of the different inspections is the same, and as such the same practices and preparation should yield the same positive results for kind of inspection.

Routine 

Routine inspections are generally the most benign, and are a periodic (by statute every 2 years) check of a firm’s overall regulatory compliance. Of course, because of limited resources, FDA will not inspect every company every two years. If a company had a positive prior inspection and no regulatory problems, it may not see the Agency for three or four years. In contrast, if a company has a history of poor regulatory compliance, it may expect to see the FDA more frequently than every two years.

For Cause 

A “for cause” or “directed” inspection, by contrast, occurs after the FDA has become aware of a problem, and can be a focused civil or criminal investigation targeting a major problem area, e.g. product safety, data integrity, or c​ommercial fraud. These are often triggered by complaints, which may come from someone internal (i.e. “whistleblower”), or even a competing manufacturer.

Follow-Up

A follow-up inspection is intended to verify that appropriate corrective actions​ have been taken. A common scenario under which a follow-up inspection is conducted is after a recall has been undertaken by a regulated entity.

Specific Product or Process

Specific product or process inspections are generally undertaken in response to an outside complaint to the FDA. For example, the Agency might initiate a specific product or process inspection after receiving one or more user complaints alleging injury as a result of product use. In such a case, the FDA may visit the company to ascertain whether such complaints can be substantiated and identify inadequacies in product or processes that may be causing the complained-of adverse events.

Pre-Approval/Pre-Clearance

Finally, pre-approval or pre-clearance inspection may take place as part of the drug or device approval process. For most drug products, there will be a pre-approval insp​ection before approval of an NDA or ANDA. These are perhaps the (only) inspections welcomed by life sciences companies, eager for the FDA’s approval of their product. Pre-Market Approval (PMA) devices almost certainly require facility inspections as a contingency of approval, while inspections of manufacturers of 510(k) devices are done more selectively and at the discretion of the Agency, largely depending on the class of device. For example, the manufacturer of a Class III implant, would be a more likely candidate for a pre-approval inspection than that of a blood pressure cuff, a Class I device.

FDA's Inspectional Authority & Limits Thereon

Reasonableness

FDA’s inspectional authority is to be reasonable—Section 704(a) of the Food, Drug and Cosmetic Act (the Act) authorizes the agency “…to inspect, at reasonable times and within reasonable limits and in a reasonable manner.” Though it is difficult to say with certainty when an inspection becomes unreasonable, such a determination is largely based on the circumstances of the company being inspected. Though disputes between companies and the FDA regarding the reasonableness of inspections are rare, there have been instances when the duration of an inspection has become unreasonable. For example, if the Agency is showing up repeatedly over a period of two or more months, there may be a case that the inspection, though reasonably begun, has become unreasonably burdensome on the inspected firm. 

It is also important to note that reasonableness has nothing to do with consent—permission or authorization to inspect is not required for the firm to be inspected. In fact, a refusal to permit “entry or inspection” is prohibited under the Act. Any type of refusal will be noted in the report the Agency inspector prepares at the conclusion of the inspection, and will be a "red flag" to the Agency and almost certainly to result in heightened regulatory scrutiny if not immediate enforcement action.

Collection of Samples 

The FDA may collect and analyze samples. Companies may request payment for samples, but it is unusual to do so except in the cases of expensive devices, for example. When samples are taken, it is wise for firms to take duplicate samples for their own retention, and label that sample with the date.

Limits on FDA's Inspectional Authority

Though the inspectional authority of the Agency is broad, there are items to which the FDA is not entitled without a court order. Among these are most company financial records, including sales data (other than what is publicly available, as in the case with publicly traded firms) and pricing data (i.e. how much it costs the manufacturer to produce the unit). Although the FDA is not entitled to that information, companies should be mindful that if they voluntarily provide that information to the Agency, it can certainly use it in its analysis.

The FDA also does not have a right to see personnel files, except for information pertinent to the qualifications and training related to regulatory compliance and product quality positions. (For example, the FDA may see the experience of QA/RA professionals to justify their placement in the position of quality control or the CV of a medical director who is running a clinical trial on your product).

Research and development plans and information are also off-limits to the FDA. That is, Agency inspectors may not have access to research on products that have not yet reached the level of testing on people, or for products that the company has abandoned.

The Act acknowledges that the FDA does have access to substantial amounts of other confidential information, and prohibits the use by the FDA of any proprietary information discovered during an inspection. Indeed, FDA employees who do share such information can be and have been criminally prosecuted.

What the FDA Looks at During an Inspection

For all of the aforementioned types of inspections, the principal goal of an FDA inspection is to ascertain a company’s regulatory compliance.

Specifically, the FDA will look for:

  • Compliance with Quality System Regulations (QSR) including Good Manufacturing Practices (GMPs) (for medical devices)
  • Compliance with Current Good Manufacturing Practices (cGMPs) in Manufacturing, Processing, Packing, or Holding of Drugs and cGMP for Finished Pharmaceuticals (for drugs)
  • Documentation demonstrating compliance with QSR requirements (such as SOPs and recordkeeping)
  • Compliance with medical device reporting (MDR) and adverse drug experience reporting regulations
  • Compliance with labeling requirements (including promotional statements)
  • Company’s corrective actions (if there was a previous inspection where deficiencies were observed)

General Aspects of FDA Inspections

  • There is no requirement that the FDA provides advanced notice of an inspection. Although, for medical-device companies that have a good history of inspections, the Agency has been providing one or two days of notice.
  • Compliance is the expectation—the inspection looks for non-compliance.
  • If something is not documented, the Agency takes the position it was not done.
  • There is often more than one investigator.
  • The majority of these inspections are directed by FDA's District Offices.
  • The Agency does have national experts for specific areas, e.g. for sophisticated software.
  • Investigators will review a company's prior regulatory history prior to coming to inspect.
  • FDA investigators can and do communicate with comparable state officials and can coordinate inspections with state government officials.
  • Inspections are a significant burden, can be intrusive, and can disrupt a company's business activities.

Form 483s: Issuance and Response

At the close of the inspection, the FDA inspector will hold an exit conference with company management during which the Form 483 (listing inspectional observations) is issued. It is important to take advantage of this conference and discuss the findings and corrective actions. This is also an opportunity to demonstrate that any of the observations are incorrect, or to note any observation for which the corrective action was made during the inspection. In these cases, the company can and should request annotation of the 483.

While providing a response to an FDA 483 is not required by law, it is certainly in a company’s best interest. If it is to be considered by the Agency in determining whether an enforcement action is warranted, the response must be submitted to the Agency within 15 working days from receipt of the 483. The response is the firm’s opportunity to demonstrate the importance with which it regards regulatory compliance and the priority it gives to remedying any observations the agent noted on the 483. A good response to a 483 may prevent a Warning Letter or another inspection. Be sure to provide documentation of all remedial actions.

In addition to the 483, the FDA also prepares an “Establishment Inspection Report” (EIR), which is a narrative of the inspection including what the investigator did and saw, the observations, and what documents and samples were obtained from the company. It is a good idea for companies to request a copy of the EIR about 30 days after the inspection.

Potential Consequences​ of a Bad Inspection

  • Warning Letter
  • Refusal to Approve Applications
  • Import Detentions
  • Seizure
  • Injunction (Consent Decree)
  • Civil Penalties
  • Criminal Prosecution

FDA Inspection Risk Management Tips

  • Document Everything. It is not enough to comport with Quality System Requirements without diligently documenting these activities. The FDA takes the position that if something was not documented, it was not done.
  • Politely Refuse Photography. There is no definitive case law about whether the FDA has authority to take pictures during an inspection. However, it is likely in the company’s best interest to refuse to permit photography.
  • Keep duplicate documents and sample. Any documents provided to the FDA should be duplicated and retained by the company. Furthermore, if a sample of product or labeling is provided to the FDA, the company should take a duplicate sample from the same batch at the same time and promptly label it as such with the date.
  • Label Documents as “Confidential.” All documents provided to the FDA should be stamped or labeled “confidential” to better protect against their disclosure.
  • Accompany the Inspector. It is wise to have at least two people from the company accompany the FDA investigator for the duration of the inspection. It is important to have at least one person taking notes on what the investigator is saying and looking at, and another person providing answers to any questions the investigator has, retrieving product samples, etc.
  • Do Not Lie. All questions should be answered truthfully, but it is perfectly acceptable to say, “I do not know the answer right now, let me find out and get back to you.”
  • Make use of the 482. The FDA Form 482 is the notice of inspection. Receiving this from the investigator is an opportunity to inquire about what the Agency is particularly interested in looking at, and to get a sense of the impetus for the inspection.
  • Make Realistic Promises. Although promising corrective actions is appropriate, ensure that the promised dates of completion are realistic. It is likely worse to fail to complete the actions upon a promised date than to propose a longer-term completion date.
  • Don’t Read or Sign an FDA Affidavit. FDA will prepare affidavits for company employees about what happened during the inspection. If signed, this constitutes an acknowledgment of the contents of the affidavit, which the company may want to dispute later.

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