Agent-In-Place

But They're Not Touching the Floor...

Pharmaceutical Technology's new monthly "Agent-in-Place" column distills true-life cautionary tales from the secret files of Control, a senior compliance officer

Untimely released beads Our GMP Agent-in-Place at a top-10 pharmaceutical manufacturing firm reports on a spill during the manufacture of a time-release capsule filled with coated beads. Because the coating process is variable, some coating pans produce beads with thicker coats, which are therefore slower to release their active ingredient, and some coating pans produce beads with thinner coats and faster API release. The product NDA specifies a blending process that mixes thick-coat beads with thin-coat beads to assure that capsules have the correct time-release profile. The beads are blended in a very large V-blender, with two feed ports at the top and a discharge port at the bottom of the V. "On this occasion," our Agent reports, "someone had left the bottom discharge port open while beads were loaded into the two top-side feed ports. The beads, naturally enough, fell straight through the V and spilled out onto the floor. This mistake was noticed part way through the loading process, and the process was stopped." The normally competent manufacturing manager proposed to our Agent-in-Place that the beads "not touching the floor" be scooped up and used in another batch of product. The beads touching the floor would "of course" be rejected and sent for active ingredient recovery. Injectable biological product...with a kick During the manufacture of a biological product, our GMP Agent-in-Place reports, "An operator cracked a valve on a clean and supposedly empty mixing vessel. A clear liquid trickled out of the 'empty' vessel. Touch and smell quickly showed that the fluid was alcohol"—an ethanol-methanol mixture leaking from coolant pipes running through baffles inside the mixer. "Because the production process used alcohol as a solvent and precipitation control ingredient, finding some alcohol in the mixing vessel might not have raised concerns, even though the solvent should have been extracted before the mixing step. The process solvent was, moreover, a specially denatured grade, with much lower methanol levels than the coolant. The process managers quickly realized that the leak could have contaminated earlier batches of this biological product processed in this particular vessel." Our Agent reports that the firm appropriately recalled all in-date product as a result of this finding. Steel-reinforced tablets Start-up tests of a new tablet product line discovered metal particles in the finished dosages. The ensuing investigation tracked the contamination to one particular ingredient. A visit to the ingredient supplier made it clear that it would be impossible in the short term to guarantee metal-free production of the product: The raw material was made in, and transported through, miles of steel piping; internal erosion produced the metallic impurities, and only a wholesale rebuilding of the plant could eliminate them. "Because the contaminants were ferromagnetic," reports our GMP Agent-in-Place, "the supplier introduced a magnet-based metal-removal step in its packing process...at the customer's insistence. And the tablet manufacturer itself installed a grid of very powerful, rare-earth magnets at the input port of the tablet granulation blender, effectively removing any residual metal particles, which were cleaned from the grid at the end of each run." PT