FDA compliance officials are stressing that their judgment of the significance of an investigator’s 483 observation is case-specific, reflecting its implications for the quality of product(s) and the firm’s transparency with the agency about that potential impact.
At the Great Lakes cGMP Regulatory Science Forum cosponsored by the University of Illinois at Chicago College of Pharmacy, FDA and the North Central Association of Food and Drug Officials in mid-October, New Jersey District Office Compliance Branch Director Nancy Rolli explained that industry frequently questions compliance managers like herself regarding how the significance of a 483 finding is determined.
Rolli provided examples of 483 observations and discussed how their significance would be determined related to: ● manufacturing equipment ● packaging ● labeling control ● QC and micro labs ● validation ● sterile products ● complaint files ● annual product reviews, and ● stability.
The compliance official outlined how the thinking process regarding significance unfolds and its case-by-case nature by comparing a 483 observation to a speeding violation. If a vehicle is going over the speed limit, she explained, the significance of the violation will depend on the weather, road conditions and what else is happening in the vicinity.
“If you are going ten miles over the speed limit and it is a nice, clear day, you are still in violation. But it is not as bad as if it is an icy road, if it is nighttime and there is an accident…and there are a bunch of people standing on the side of the road. Those actions all add to the significance.” As with a 483 observation, the significance depends on “not just the actual violation, but what is going on around it.”