Leachable and extractable studies on single-use system technologies in commercial scale drug filling lines [thesis]

Nicole Marion Doris Scherer
Stir-bar sorptive extraction (SBSE) in combination with thermal desorption and gas chromatography-mass spectrometry (TD-GC-MS) is widely accepted as the gold–standard analysis method for trace amounts of organic substances, including leachables in aqueous matrices. Meanwhile, as far as pharmaceutical quality control in protein-based parenteral drugs is concerned, the use of SBSE analysis remains unexplored. Previous studies reported a strong influence of the matrix on the method's recovery. The
more » ... scope of the present work was to fill in the unexplored territory in a fourfold manner 1) by quantifying the effects that various matrices commonly found in pharmaceutical processing have on the recovery, 2) by comparing between different coating materials for stir bar (namely between polydimethylsiloxane (PDMS) material and ethylene-glycol (EG)-PDMS), 3) by determining the concentration behavior of SBSE in alcoholic solutions compared to the direct injection and 4) by proposing among possible optimizations a preparation step for stir-bar to mitigate inhibitory effects. The current study shows no inhibition of SBSE by protein matrices (p > 0.15). Further the influence of various drug matrices on the recovery of leachables with a log K O/W ≥ 3.6 is negligible (-3.9 to 3.8%). In contrast, the inhibition effect caused by an alkaline media led to a recovery decrease of -42.9%. For leachables with a log K O/W < 3.6, the relative recovery in the presence of various proteins ranged from -72.8% to 15.6%, depending on the excipients of the drug product and not on the protein itself. The highest loss in sensitivity was observed when the excipient benzyl alcohol was present in the drug. Nonetheless, the limit of detection for the tested leachables in the inhibitory matrices was still below 3 μg/L (ppb), due to the concentration behavior of SBSE. Additionally, SBSE was observed to be quantitatively reliable in all tested drug matrices for concentrations from 0.005 to 0.1 mg/mL (r^2 > 0.992). On average, the conventional PDMS [...]
doi:10.5282/edoc.24707 fatcat:zun3cq7frbagnbzyz75flnjn2a