Eventful Adversities

The road to compliance is sometimes littered with lost letters, hot lots, and unmixed mix-ups.
Jan 02, 2007

Dead-letter file

"You know how it is in the pharmaceutical industry," our GMP Agent-In-Place confides. "Companies are bought, products are spun off or sold. We had made a clot-busting product in the same facility for years, under three or four or five (I forget) different company names. Its distribution company in the United States had the same problem. Company A merged with Company B to form Company A–B, and the new company headquarters moved.




"They didn't tell us about the changes, so we continued to send the international adverse event (AE) reports to the old e-mail address for reporting to FDA as usual. It had been a dead-letter box for more than two years! The mergers on both sides of the ocean had created 'communications difficulties' (read: disasters). When FDA inspected the manufacturing site managed by a subsidiary of company number 4 (or was it 5?), it discovered that the AE's weren't being properly reported.

"What a SNAFU! In the end, both Company A–B and the parent company (of 4?) sent letters to FDA 'admitting' faults and committing to fix them."

Get your Red-Hots here!

"We had three AEs within days of the first distribution of one lot," reports our GMP Agent-In-Place. "We started an investigation, but when we received two more AEs the next day, it was Recall City. They were all 'shake-and-bake' (chills and tremors) AEs, typical of pyrogenic (hot) products.

"This lot had an unofficial (not in the FDA application) endotoxin test result of 32! But the official rabbit pyrogen test passed without additional bunnies, so the endotoxin test was considered an anomaly, and the lot unfortunately was released. Because the endotoxin result was unofficial and there was no limit assigned, no investigation resulted.

"The good news was that we only had distributed a portion of the lot. The bad news was that it was recalled days after distribution started."

Mixicology 101

"It was a fabulous product: a coated-bead, extended-dissolution, once-a-day product," observes our GMP Agent-In-Place. "Coating pans of beads were manufactured and then a blend was chosen to create the right dissolution profile in the final blend using a Patterson-Kelly blender. The individual pans of beads were tested for dissolution before blending by sampling, carrying the sample to the laboratory, and then scooping up beads from the sample bottle into capsules, and testing the capsules for dissolution. Frequently, the bead mixture tested was substantially different than was predicted by the mathematical combination of the pan test results, resulting in a rework of some mixtures.

"What a mess! The production staff was sure the lab couldn't test their way out of a paper bag, and the lab was sure the production staff didn't know a coating pan from a cake pan. An investigation revealed that during transport to the lab, the beads 'unmixed' in the sample bottle. This bottle was carried in the analyst's pocket from the blender up several flights of stairs. When the capsule shells were filled in the lab, they were scooped from the top of the sample, which tended to be larger beads. The beads produced slower profiles and would not be representative of the batch, resulting in a misblend and a failure to meet final specifications.

"The solution was easy: Remix the sample bottle and ensure the beads encapsulated manually for the dissolution test were scooped top-to-bottom of the sample bottle, not just from the top!"

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
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.