The Column spoke with experts in the pharmaceutical industry about current and emerging trends in pharmaceutical analysis, including the use of LC–MS instead of LC–UV for routine assays, best practices for impurity profiling, and areas where commonly used methods are likely to improve. Participants in this technology forum include Ann Van Schepdael, a professor at the KU Leuven in Leuven, Belgium, Tom van Wijk, a senior scientist at Abbott Healthcare BV in Weesp, the Netherlands, and Harm Niederlander, who was a project leader at Synthon Biopharmaceuticals in Nijmegen, the Netherlands, until August 2013.
Q: Has there been any significant adoption of liquid chromatography coupled to mass spectrometry (LC–MS) for routine pharmaceutical analyses? Or is liquid chromatography–ultraviolet (LC–UV) still applied more often for routine assays and quantitative analysis?
Ann Van Schepdael:
Many monographs still use UV as a detection technique and LC–UV for assays and related substances. LC–UV equipment is affordable and robust, and the available column chemistries allow the analyst to play with the selectivity of the system. LC–MS may also be in use in the industry on a routine basis, but it appears less in pharmacopoeial texts. It seems that LC–MS is very important for the preparation of regulatory files for a new chemical entity (NCE): It is significant for the structural characterization of unknown impurities on the one hand, and for quantitation of the drug and its metabolites in biological samples on the other. This is because of its better sensitivity and very good selectivity. The study of a drug's pharmacokinetics (metabolite characterization, quantitation of excretion, kinetics of metabolism, and drug interactions) is quite well supported by LC–MS.
Tom van Wijk:
LC–MS plays a crucial role in pharmaceutical analysis, but in contrast to biopharmaceutical analysis, LC–MS is hardly used for routine analysis. Although it is technically feasible to quantitate known impurities with variations within current requirements, the use of LC–MS for routine testing in pharmaceutical analysis is generally avoided. Aside from the fact that more technical details need to be in place, in general a number of non-technical issues, such as cost of analysis, transferability, and obtaining and maintaining sufficient knowledge levels, put off running this type of method. Quantitative LC–UV–MS methods are used in early development in cases where specific and sensitive detection is required; for example, for the analysis of low level genotoxic impurities or impurities without a chromophore. For the latter, often an alternative method will be developed for quality control (QC) purposes. Routine testing of genotoxic impurities in the final product can often be avoided by controlling impurities in the intermediate steps of the process.
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To answer this, we need to consider what is routine. LC–MS is used in analytical method development in pharmaceutical analysis more and more. As method development is increasingly becoming an automated task (though still requiring case-by-case expert evaluation), LC–MS can be considered an important tool in "routine analysis". Furthermore, though less routine, the role of LC–MS in product characterization and structure elucidation of "unknowns" in both pharmaceutical and biopharmaceutical analysis is indispensable. If, however, you are talking about release and stability testing, LC–MS is largely avoided because its application is still not as straightforward as UV detection, for example.