by Barbara Unger, GMP Quality Expert, and GMP Regulatory Intelligence Editor-in-Chief
A form-483 is the document that the FDA issues at the close of an inspection where they identify observations made during the inspection. If no observations are made, no 483 is issued. Based on the response submitted by the firm, the FDA classifies the inspection as: No Action Indicated (NAI) when no 483 is issued, Voluntary Action Indicated (VAI), or Official Action Indicated (OAI). In general, where the FDA issues a 483 with observations and the firm’s response is satisfactory, the inspection is classified VAI.
The agency will confirm implementation of corrective and preventive actions at the next inspection. In the absence of acceptable responses, the FDA can determine that these observations represent a failure to comply with GMP regulations, classify the inspection as OAI, issue a warning letter, and/or take additional enforcement action (i.e., an import alert or product seizure).
Among the challenges with interpreting 483s are that they don’t provide the context for what occurred during the inspection and how the issues were identified.
To evaluate the seriousness of a 483 and the potential for additional enforcement action, I ask the following questions:
- Is the 483 longer than 8-10 pages? Longer is not better. That doesn’t mean that a short 483 may not lead to serious enforcement actions, but a long 483 suggests problems may exist in many quality systems. The FDA also concludes that if one quality system is out of control, they are all out of control.
- Do any of the observations have an extensive description of examples? At the end of 2015, a 483 issued to a firm in China identified 6 ½ pages of examples of how the firm manipulated electronic records. Again, this is a situation where the FDA may be attempting to drive home a point to the firm and to others who read the 483. Any observation supported by more than three examples is one where the agency is trying to send a message about the breadth of the problem within the organization and may be an indication that additional enforcement actions are in store.
- Do any of the observations state that they are repeat observations from previous inspections? This observation indicates that while the firm’s response to the previous inspection may have been acceptable, they didn’t implement effective/corrective/preventive actions to ensure a permanent ‘fix’ for the problem. This type of observation suggests that additional enforcement actions may be forthcoming.
- Is the 483 issued to an executive, for example the VP of Quality, other than the head of the site at which the inspection was conducted? If so, it is yet another suggestion that the FDA is sending a message to the corporation regarding the seriousness of the inspection observations.
- Do the areas addressed include lack of data integrity and poor aseptic practices with potential for contamination or cross-contamination? This combination of problems, particularly in the past few years, has frequently resulted in a warning letter or additional enforcement action.
While not listed in the five items above, I also look to see how many investigators performed the inspection and who they were. If any are national experts, that is important because observations in their areas of recognized expertise often reflect an agency wide focus.
Unlike EIRs, 483s do not provide context. So trying to interpret these is like reading tea leaves or gazing at a mostly cloudy crystal ball. Nevertheless, with careful review of relevant 483s and these questions, a firm can make some evidence-based predictions. Access our 483 database here.
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