Ask for anything but time
"The problem with microbiological problems is that of time," grumped our GMP Agent-In-Place. "By the time something shows growth on the plate or in the tube, the equipment used has been cleaned and reused, sometimes multiple times. For example, for one product, the sequence is to make the nonsterile bulk and take a bioburden sample. While the bioburden sample is being tested (three days), we sterile-filter the lot and fill the lot into vials. The filtration-and-filling process usually takes 1 to 2 days. So by the time the test is done, the product is in vials.
"In this case, the investigation included sampling equipment for germs and reviewing cleaning records and validation data. Because the sampling for germs takes three days to grow out, more product is processed in the meantime. We found the cause of the contamination, which was a defective bottom valve on the bulk vessel. But by that time we had four more lots processed through that vessel and we had four more bioburden failures. The bioburden results were so high that we couldn't justify the sterility after filtration and the lots were rejected."It wasn't all it was cracked up to be
"I hate complaints," complained our GMP Agent-In-Place. "We have a product that is sold with a diluent and cracks were found in the diluent vials. (The product was fine.) When we inspected the returned vials, cracks were found to be caused by seam overlap from the glass-molding process, and were not related to the general suitability of the vial. We were relieved, but more complaints rolled in. Additional complaints were for cracks caused by our manufacturing and packaging process. The diluent, unlike the product, is steam sterilized in an autoclave. Because of the numerous manufacturing-related complaints that came in, we ultimately recalled the lot of diluent that was used in several product shipments. Ouch."
Running the gauntlet
"Of all the rotten lousy things to happen during an FDA inspection," our GMP Agent-In-Place groused, "it was sticky beads. We were manufacturing time-release beads, which need to be coated to slow their dissolution rate. The coating process hadn't gone smoothly, and some beads were sticking together and forming clumps. Our operator moved them out of the coating pan and through a screen to remove the clumps. He had a face mask on and was using gloved hands and gauntlets to push the beads through the screen before they hardened.
"The FDA inspector noted that little bits of Teflon from the gauntlets seemed to be flaking off into the beads and through the screen. The supervisor immediately asked the operator to replace the gauntlets and not to rub them on the screen, but the damage was done," sighed our agent. "The product was contaminated and there was no good way to rework it. We rejected the batch."
Seeing through the haze
"New staff in our tablet-granulation area were given safety briefings and the batch- manufacturing records were updated to list the required safety equipment," our GMP Agent-In-Place began. "But new employees hated dust masks because they got soggy, and with little dust involved in this particular product process, they elected not to wear them. Supervisors and experienced employees let this go as a way to haze the new staff. The next day, the new employees complained about flushing and heart palpitations, which tend to be side effects of a high dose of this product.
"The product was sold to another company 15 years ago. Do they haze their new employees the same way?" wondered our agent.
Pharmaceutical Technology's monthly "Agent-in-Place" column distills true-life cautionary tales from the files of Control, a senior compliance officer. If you have a story to share, please email it to Control at AgentinPlace@advanstar.com