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

Scherer, Nicole Marion Doris (2019): Leachable and extractable studies on single-use system technologies in commercial scale drug filling lines. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

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 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 coating resulted in a 28-fold higher signal-to-noise ratio compared to EG-PDMS. Moreover, the PDMS coated stir-bar reached better reconcentrate in inhibitory alcoholic solutions. Furthermore, a broader range of leachables was detectable with the PDSM coating. Preceding stir-bar preparation consisting of a simple soaking step improved the enrichment by 14%, effectively lowering the limit of detection. The increasing application of Single-Use Systems (SUSs) in pharmaceutical manufacturing lines poses a potential risk of polymer-related impurities leaching into the process stream and persisting through the manufacturing process. To minimize any potential toxicity and impairment to the product’s quality, safety thresholds are strictly regulated and enforced in particular for parenteral solutions. At present, impurities are estimated from extractable profiles, which are generated for each SUS with thermal or static extraction. In this study we employed target leachable-testing by taking samples directly from an industrial filling line probed during real-life processing of three parenteral drugs (n=2) under actual process-conditions, to estimate the concentration of leachables throughout drug-manufacturing. At five different points, samples were drawn to study the individual impact of SUSs on the leachable accumulation within the drug-filling process. The drug products were examined for leachables using stir-bar-sorptive-extraction (SBSE) with poly-dimethylsiloxane (PDMS) and ethylene glycol (EG)-PDMS coated stir-bars. Subsequent extraction from the stir-bars and analysis of the substances was performed with TD-GC-MS and solvent-back-extraction (SBE)-UPLC/QTOF-MS/MS analytics. Our study revealed the following main results: 1) Leachables were found in extremely low concentrations, all below toxicological thresholds (highest leachable concentration in the final drug product 1 (DP1): 0.274 ppm < drug specific threshold: 6.0 ppm; DP2: 0.010 ppm < 0.2 ppm; DP3: 0.011 ppm < 0.5 ppm). All compounds identified in the leachables study were found to be non-genotoxic. 2) Most of the leachables (68%) that were found were already observed at the beginning of the filling process, delivered by the API either a common source of leaching could be identified within the filling-line nor a specific product influence on quality or quantity of leachables. 3) No leachable increase could be observed over the filling process. On the contrary leachable concentrations declined with 83%, which was partly due to dilution by buffer-feed and to a proven absorption of leachables by filters and silicon tubing. 4) No active ingredient influence on the leachable-outcome was observed by placebo to drug product comparison. In contrast, the pH-setting of the drug product influenced the leaching-behavior to the greatest possible extent.

Abstract

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Leachable, Extractable, Filling Line, Drug Product, SBSE, TD-GC-MS, UPLC/QTOF-MS/MS
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 30. April 2019
• 1. Bericht­erstatter:in: Winter, Gerhard