Blog Post 3 – From fill line to fault line: tracing impurities in drug manufacturing
2 min reading time
Among the numerous potential sources of impurities, changes in the manufacturing of pharmaceutical products are easily overlooked. Replacement of materials in the filling lines, for example, may unsuspectingly cause leaching of unwanted chemicals into the drug product. In this blog post, we present a case study based on an urgent request to identify an unknown impurity found during QC stability testing of a drug product which had been on the market for years.
The customer’s method was transferred to a Liquid Chromatography with Ultraviolet and Mass Spectrometer detection (LC/UV/MS) method to reproduce the detection of the impurity in our lab and at the same time provide the necessary data for MS-based identification. The transfer was successful: the impurity could also be detected based on UV signals and the same relative retention time.
Figure 1: Analytical method for impurity identification
The next step in the investigation involved interpreting the mass spectrometric (MS) data. Initially, we stumbled on 2 setbacks: the positively charged signals didn’t seem to align well with the UV peak of the impurity and no signals were detected in the negative ion mode. These issues stemmed primarily from the transferred method being not fully compatible with MS detection. To address this, we tweaked the method parameters by replacing the ion-pairing reagent in the mobile phase. This modification resulted in a much better MS sensitivity in negative mode and enabled to establish a clear correlation between the MS and UV signals of the impurity.
With a reliable MS fingerprint of the impurity in hand, the identification process could continue. Using accurate mass of the molecular ion, we determined the elemental composition. This formula was then searched in our Nelson Labs’ proprietary screener database, which yielded one plausible candidate structure. Conveniently, an authentic reference standard of that molecule was available in-house. Analysis of this standard using the transferred method confirmed the identity of the impurity.
The confirmation of the impurity’s identity was crucial to understand how the impurity ended up in the drug product. It was unrelated to the Active Pharmaceutical Ingredient (API) or to any substances used in the synthesis pathway. Rather, this molecule is a well-known leachable compound, commonly associated with peroxide-cured silicone tubing. This insight eventually led the manufacturer to discover that the filling line tubing had been switched – from platinum-cured to peroxide-cured silicone – accounting for the impurity’s unexpected presence.
If you have additional questions about Impurities Identification test services or would like to consult with the experts at Nelson Labs, just send an e-mail to [email protected].
