What Leads to a 483?
A 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)
- Official Action Indicated (OAI)
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In general, when the FDA issues a 483 with observations and the firm’s response is satisfactory, the inspection is classified VAI. FDA is now informing drug/API manufacturing facilities of their inspection status within 90 days after the end of the inspection. This change came with FDA’s commitments as part of GDUFA II and applies to all firms, not just the generic drug industry.
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)
How to Interpret a 483?
A challenge with interpreting 483s that are issued to firms other than your own is that 483s 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. I think any observation supported by more than 3 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 statement 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 statement suggests that additional enforcement actions may be forthcoming.
- Is the 483 issued to an executive? For example, the CEO of the Company rather 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.
- How many investigators performed the inspection and who were they? If any are national experts, that is important because observations in their areas of recognized expertise often reflect an agency wide focus and interpretation of requirements.
With careful review of relevant 483s and these 6 questions, a firm can make some evidence-based predictions. Access 27,500+ Form FDA 483s in our database that are keyword tagged, searchable, cross-referenced for easy comparison, and easy to copy/paste/print.
Want to learn more about FDA 483s? Check out the other articles in our FDA 483s Crash Course:
- How to Respond to FDA 483s
- How the FDA and the 483 Have Changed
- What’s the Big Deal with Form FDA 483s?
- A Bad 483 Could Cost a Company Millions
- The New FDA GMP Inspection Model
- Who Can See Form FDA 483s, and Where Do I Get Them?
Learn more about how FDAzilla can help you achieve your quality and inspection preparation goals: get 483s, InspectorProfiles, Enforcement Analytics, and GMP Regulatory Intelligence. Contact us if you ever have questions at [email protected].
*Updated in 2018 | Originally posted in 2016.
About the Author
Barbara W. Unger is Govzilla’s Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence. She formed Unger Consulting, Inc. in December 2014 to provide GMP Quality consulting services to the pharmaceutical and biopharmaceutical industry. At Amgen, she led the segment of the Corporate GMP Audit group at Amgen focused on API manufacturers, Quality Systems and Computers. She developed, implemented and maintained the GMP Regulatory Intelligence program for 8 years at Amgen Inc. This included surveillance, analysis and communication of GMP related legislation, regulations, guidance and industry compliance enforcement trends. This was an essential service and tool within the Corporate Audit function.
Unger Consulting Inc. | www.ungerconsulting.net | 805.217.9360