Today I want to talk about a 483 given to a gene therapy drug substance manufacturer. The actual 483 can be found on the fda.gov website for those interested, but I am not going to talk about the company or location.
The first observation noted that the company “failed to ensure the integrity and effectiveness of the Quality Management System,” which is rather broad, so we’ll have to dig a bit to find out what is going on. Although the 483 is redacted, we can figure out that a change control was not approved by the quality unit prior to lot release, the change control was not scientifically justified, and did not include an analysis of the impact of the change (a risk assessment), as required by SOP. At a high level, this is not following an SOP. When we dig a bit, we find that the change control must be scientifically justified, and to do that, we need some type of risk assessment that analyzes the change and the impact of the change, which was not performed. Of course, every change control associated with a lot must also be approved by quality prior to the lot being released. This demonstrates that the change control system must be used in the proper way (effective) and the change must be analyzed with good science (risk assessment). In other words, change control is not just paperwork.
The second observation states that “the Quality Unit failed to address issues that have the potential to impact the quality of the product.” Again, this is rather broad, so we’ll have to dig into the specifics and try to read between the redacted lines. We find that the quality unit did not follow their Deviations SOP. The Deviations SOP required something that was missing. That something is performed by quality and subject matter experts. At a high level, this is not following an SOP, which of course is super important when it comes to deviations. Quality typically creates and signs off on this type of SOP, so of course they need to follow it. Every deviation must have a sufficient investigation and resolution/justification for the lot to be released. This particular deviation was approved without the required step. We don’t know what that step was, but it could be a good investigation and justification as to why the lot has sufficient quality to release it. Deviation investigations should be sufficient (in comparison to the seriousness of the deviation), be scientifically investigated/justified and of course follow the deviations SOP.
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