You may read in the news or a company press release that a manufacturing site has received a ‘483. This is usually considered bad news. Indeed, failure to remedy observations in a ‘483 can lead to withheld product approvals or even plant closure.
When the FDA makes a visit to inspect a facility (manufacturer, lab, supplier, etc.) the inspector is looking for compliance with cGMP. Significant observations are recorded on FDA Form 483 (often shortened to 483 or ‘483). An overall summary of the inspection is recorded in an Establishment Inspection Report, EIR for short. Thus, an EIR is always given and a ‘483 may or may not be given, depending on what is found.
The facility’s management has to respond to a ‘483 – what it is going to do to fix the problem(s) and when they will be fixed. The FDA will decide if the plan is acceptable. Significant deviations may prompt FDA to come back at a later date to see if the planned fixes were implemented.
Where does the ‘483 come into play for product approval? During the review of an NDA or ANDA, the CMC reviewer requests input from FDA field operations to see if the manufacturing site, labs, suppliers, etc. have had acceptable inspections. This is know as Pre-Approval Inspection, or PAI for short. Once the field gives the okay and any CMC review issues are closed successfully, then the CMC review may finish and then the approval decision can be made.
The field operations may decide that it needs to inspect. The field is under no hurry to get their work done, they are not subject to PDUFA. If ‘483 observations are made, the company has to propose a remedy plan. The field may or may not agree to the proposed fixes or the timeline or both. Then the company has to wait for the field to get back to them and then respond appropriately, if it can. From my discussion, the reader should understand that the time for the field clearance is unpredictable by either the company or the review division.
To avoid ‘483’s delaying your product approval, your site(s) should undergo training and a mock PAI. This work should be outsourced to a third party to minimize bias.
For more information see: Inspection Overview