The Value of FDA 483s and Warning Letters

Q. We are a US-based start-up company, and we are about to put our quality management system in place. One of our consultants advised us to review Form 483 and warning letters issued by FDA. We looked at some of them but are unsure what we are expected to find or what to do with the information in these documents. Do you have any advice?

A. At the end of an FDA inspection, the inspectors will document observations of deviations from the codified regulations on Form FDA 483 (1). This document contains only the inspector’s most significant observations. Other observations may be communicated to the company verbally during the inspection. Importantly, FDA does not classify its inspection findings (e.g., as critical, major, or minor).

The inspector(s) submits his or her report to a district office. The district office classifies an inspection in one of three ways:

• Official action indicated (OAI), which means that the inspection was unsatisfactory, and the district advises enforcement actions.
• Voluntary action indicated (VAI), which means that deficiencies were identified, but these can be resolved by the company without the need for enforcement action.
• No action indicated (NAI), which means that no problems (or only very minor ones) were identified.

The district office will either issue an establishment inspection report (EIR) or, if advised, will take further action, such as issuing a warning letter. Warning letters are just one tool at FDA’s disposal to alert a firm to the fact its products are considered a risk to human health; therefore, authorities may take drastic action to safeguard patients (2). All warning letters are posted on FDA’s website and are visible to anyone interested, particularly the competition and customers. Making inspection reports easily accessible to the public is a peculiarity of FDA.

Redacted Form FDA 483s are available from FDA under Freedom of Information Act (FOIA) requests. Some commercial providers specialize in providing these at a fee.

What is the benefit of reviewing these documents, and what can you do with the information found? The rules and regulations (e.g., 21 Code of Federal Regulations Parts 210 and 211) describe the requirements a company must comply with. There are, however, many aspects that are not described in much detail, such as how to perform complaints investigations, how to respond to inspection observations in an acceptable manner, and much more. What you can glean from Form 483s and warning letters is basically an interpretation of the regulations (i.e., the agency’s thinking and expectations).

Of course, you need to filter the information and only review what may be relevant to your line of business. Still, there will be plenty of information that can help you avoid making costly mistakes. Bear in mind that the reported observation only tells part of the whole story, and there is much information, such as the actual product involved, that is confidential and thus not reported (i.e., redacted). As the observations on Form 483 are not classified, companies should take them all seriously. Not doing so could result in a warning letter, and that definitely would mean that the company is in trouble.

Making mistakes is human, repeating mistakes others made, and which have been reported in 483s or warning letters, is just plain careless and bad management. Unlike other regulatory agencies, FDA provides these valuable resources to anyone who cares to read them. It is a great opportunity for you to make good use of them.

References

1. FDA, “Form 483 Frequently Asked Questions,” www.fda.gov, accessed June 9, 2021.
2. FDA, “Warning Letters,” www.fda.gov, accessed June 9, 2021.

Article Details

BioPharm International
Vol. 34, No. 7
July 2021
Page: 33

Citation

When referring to this article, please cite it as S. Schmitt, “The Value of FDA 483s and Warning Letters” BioPharm International, 34(7) 2021.