Our GMP agent-in-place brought up these issues, along with a proposed solution: reformulate. The required resources were not allocated, and production continued.When the product had to be transferred to another manufacturing facility, the FDA reviewing division checked on the homogeneity of production at the new site (evidently based on complaints that they had received for this product). Based on the FDA's request, a homogeneity test was added for the first three production batches, without a specification. Because the homogeneity test was just an assay repeated 10 times, the assay result was calculated as the average of the homogeneity. And because there were no set specifications for homogeneity, it always passed, even if one or more of the individual assays were out of specification.
Well, FDA got a hold of these data, ultimately issued a Warning Letter, and requested the recall of one product lot. "Of course," sighs our long-suffering GMP agent, "only after all of this happened were the resources allocated for the reformulation, and a real content uniformity specification was set for the homogeneity test."
Hot water problem gets the cold shoulder
At a particular manufacturing site, the cold water-for-injection [WFI] system was designed to provide up to 500 gallons per hour. "As production volumes went up, the usage requirements went up as well," explains our GMP Agent-in-Place. "The primary control for the system was to maintain pressure. The other controls were secondary. The system would turn on the cooling if the temperature rose, but not stop usage. To maintain the pressure, it would feed in hot WFI as the pressure source."
At times of peak usage, the heat exchanger used to cool the hot WFI into cold WFI was overtaxed, and the hot WFI would then flow directly into the cold WFI loop. The temperature charts showed this temperature fluctuation at times of peak usage.
"I saw this but couldn't get the attention of manufacturing or engineering," moaned our GMP Agent. "Nothing was done until an FDA inspector found it. The end result, due to this and other more serious problems, was a consent decree of permanent injunction for the site."
Just for kicks
"The vice-president of corporate regulatory came to visit our manufacturing site and the manager of incoming product release and I were hosting him," recalls our GMP Agent-in-Place. "The VP was concerned about the fit of stoppers into vials, and wanted us to control chart a lot of data."
But this site made tens of millions of vials per year. The added workload for the exact measurement using micrometers plus this control charting work would require about five more people, which we couldn't afford. "I tried to argue with the VP along these lines (bang for the buck)," says our practical GMP agent, "but the manager kicked me under the table, and we both agreed with him. The VP left happy." Of course the manager couldn't do the testing without the staff and didn't. "After that meeting, whenever my manager agrees to do something, I always ask with a grin, 'Are you really going to do this?'"
Pharmaceutical Technology's monthly "Agent-in-Place" column distills true-life cautionary tales from the secret files of Control, a senior compliance officer. If you have a story of clueless operators, oblivious management, inopportune lapses of judgment, or Murphy's Law in action, please send it to Control at [email protected]