Too Little and Too Much

Gone with the wind

A new oral dosage product was designed as "encapsulated tablets." In production, the drug product was pressed into tablets, which were then fed into a revolving capsule-filling table. The encapsulation machine selected the gel-capsule shells, oriented them with the cover on top, pulled the capsule halves apart, slid the open capsule base under a filling jig with holes in the top, fed in the correct number of tablets one at a time through the tabletop, moved the filled tablets to the edge of the revolving table, checked for proper filling, reassembled the capsule, and dropped the completed product into the bottle.

Control

In theory.

In practice, says our puzzled GMP Agent-in-Place, the production start-up team noticed that a very few capsules were reassembled with a tablet or two missing.

"Now, the encapsulation machine had pin-probes that lowered into the bottom capsule shell to make sure it was full. If the pins didn't 'feel' the right number of tablets in the capsule, the line should have rejected it.

"This wasn't happening. We couldn't imagine what was going wrong, and we were worried. If badly filled capsules had gotten into the market, we would have faced recalls and losses."

Our eagle-eyed Agent-In-Place camped out on the line, watching every move of every operation.

"Its process was really dusty: product and capsule-shell dust would build up particularly fast in the center of the table. Management had told the operators to keep the machine clean...but run it efficiently. So they were, logically, cleaning the table while it was running. With a vacuum. An operator would open up the side-shield doors and stick the snout of the vacuum over the filling table.

"That's where I spotted the problem. As he moved the nozzle through the doors to the middle of the table, he needed to maneuver it between the fill-checking pin station and recapping station. So the vacuum passed, for just an instant, over open capsules that had already registered as correctly filled. The vacuum could, and occasionally did, suck a tablet or two up out of the capsule base.

"Fortunately, this problem was easy to fix once we realized what the problem was—change the cleaning access point. Until then, though, we were tense, I'll tell you."

Too much of a B12 thing

"During a routine stability study of a vitamin product, the B12 (cyanocobalamin) test result was too high by a factor of ten," reports our GMP Agent-In-Place. "Several people looked at the calculations. They figured that someone had made a mistake in the dilution factor, or something similar, but nobody could find the error.

"We retested the batch, with the same out-of-specification (OOS) result. As part of the stability investigation, I looked back at the initial release test results to confirm the B12 value. And, lo, there in the paperwork was a retest for a ten-times-too-high reading.

"Now, that initial release test had been performed by a new analyst, and the quality control folks had assumed that she'd moved a decimal point in one of her calculations. An 'experienced' analyst repeated the release test. Looking at the documentation and the crossed-out calculations, I realized that this test, too, had actually yielded a 10× the OOS result...but that the experienced analyst had treated it as his own calculation error, and made it go away by dividing by his own fudge factor. That result stood, and the batch was released.

"On the evidence, then, the stability test showed ten times too much B12 because the batch had ten times too much B12. We dug back further through the records.

"According to the batch record, the operators had added the correct amount of B12. There was even a second weight check in the manufacturing area, and it reported in-specification results.

"But when we finally got to the dispensing records, they told another story—somebody had put ten times more cyanocobalamin into the recipe than they were supposed to. Sure, a ten-fold error sounds like a lot, but B12 is added in such small quantities that nobody could catch it visually."

Pharmaceutical Technology's monthly "Agent-in-Place" columndistills true-life cautionary tales from the secret files of Control, a senior compliance officer. If you have a story of cluelessoperators, oblivious management, inopportune lapses of judgment, or Murphy's Law in action, please send it to Control atAgentInPlace@advanstar.com We won't use any names, but if we do use your tale of disaster,courage, or just plain weirdness, Control will send you a coveted Pharmaceutical Technology t-shirt.