Issued by the US Food and Drug Administration (FDA), Form 483 documents notify companies of the observations, conditions or practices that could potentially be violating FDA regulations following an inspection carried out at their facilities.
The FDA Form 483 is not an extensive list of all potential problems, but only those that inspectors can clearly identify as potential violations to FDA regulations. A detailed establishment inspection report (EIR) is written by the FDA inspector/inspection team that further outlines details of the company, its facilities, processes, quality systems, products, refusals, inspectional observations and discussion with management.
The company should address these inspectional observations in a written response to the FDA following the inspection. The written response to the FDA 483 should outline the holistic improvements and corrective actions to be taken to remedy the observation and the timeline that it will take to complete them.
Pharmaceutical Technology spoke to Maxine Fritz, Executive Vice President at NSF International’s pharmaceutical arm, about addressing issues raised in a Form 483 and how third-party consultancy services can help.
What is the difference between the Form 483 and a warning letter?
Maxine Fritz: There is a big difference. The Form 483 is used purely for inspection observations that are found by the investigator. Once that Form 483 is issued to the site or to the company, the FDA investigator then goes back and writes a report called the establishment inspection report (EIR).
That report, along with the Form 483, is further evaluated by a compliance officer who will determine whether the regulatory status is a voluntary action indicated (VAI) or an official action indicated (OAI). Typically, an OAI determination will enact a warning letter from the FDA. If, in fact, it is determined that the observations are egregious enough, there may be further action taken, and that could be in the form of a seizure, recall, import detention or other.
What are some of limitations of Form 483?
MF: It’s a simple form that outlines the observations and findings observed by the investigator at the inspection. If you receive a 483 at the conclusion of the inspection, it simply means that you have some issues or some items that need to be addressed based upon the investigator’s findings. That doesn’t mean that it’s all the issues; it’s just what that investigator has observed.
What happens if the issues raised in Form 483 aren’t rectified?
MF: Once a Form 483 is issued to a company, it has 15 days to respond and provide the appropriate corrective action or a response to the findings and how they will be corrected. If the company does not correct the findings on re-inspection, there may be further action taken by the FDA.
How can NSF help clients with Form 483 issues?
MF: Part of our core competency is to provide consultancy services and strategic advice on how to correct items on the 483 so that at the next inspection, or even before the next inspection, the FDA has confidence that the issues will have been corrected. NSF can also go in to a site and help companies to correct problems, providing remediation services so that there is a high degree of confidence that the issues will not reoccur on the next inspection.
We have worked with a number of clients who have been in trouble with the FDA. They may be foreign companies who are having difficulties importing their products into the US, and we have gone in and provided resources to work with them side by side. We work to correct problems, to help manufacturers develop procedures that will improve their quality, and coach and mentor staff so that they understand compliance, while encouraging a quality mindset. We firmly believe that if you have a quality mindset, you will be in compliance.
The outcomes have been quite successful with the FDA coming back in and having no further concerns about the previous issues.
What advice would you give companies dealing with Form 483 issues?
MF: My advice to companies is understand the observations and concerns of the investigator/inspector and seek third-party help with developing the appropriate corrective actions and writing the response to the 483. The implementation of the corrective actions and determining their effectiveness are paramount to a successful outcome.
Read our article, Pharma compliance: Build it in from the start with a quality mindset, and watch our video on how to get your company into the quality mindset.