Detecting impurities in drugs by Orbitrap MS

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  • Published: May 16, 2016
  • Author: Ryan De Vooght-Johnson
  • Channels: Gas Chromatography
thumbnail image: Detecting impurities in drugs by Orbitrap MS

An impure product

At many stages during the production of a drug, impurities can creep in. These impurities, defined as a “component of the drug product that is not the chemical entity defined as the drug substance or an excipient in the drug product” include heavy metals, catalysts, reagents, degraded end products and even charcoal.

At many stages during the production of a drug, impurities can creep in. These impurities, defined as a “component of the drug product that is not the chemical entity defined as the drug substance or an excipient in the drug product” include heavy metals, catalysts, reagents, degraded end products and even charcoal.

Apart from reducing the effectiveness of the end product, these impurities can potentially make it unsafe. As a result, regulatory authorities the world over have begun to close down on them, by settings limits on allowable levels of impurities in active pharmaceutical ingredients.

It is extremely difficult to characterise the impurities in the huge number of compounds being developed as drugs. There are however various possibilities. Gas chromatography/mass spectrometry (GC-MS), for example, is an established analytical technique that can be used to identify unknown elements, determine peak purity and quantify potentially toxic impurities. Traditionally, this has been done using electron or chemical ionisation (EI and CI, respectively) and just one quadrupole.

More recent advances, such as time-of-flight technology (in which the mass-to-charge ratio of an ion is determined based on how long it takes to reach a detector), have allowed more accurate mass measurements using the technique. “Impurity detection is important within the pharmaceutical industry, and high mass accuracy is an enormous advantage when it comes to looking at unknown sample impurities, often at low concentrations,” explains Dr Kyle D’Silva, Pharma & Biopharma Manager at Thermo Fisher Scientific.

Another tool to improve mass accuracy is the Orbitrap – a mass analyser that traps ions in an orbital motion and converts the image current into a mass spectrum. It was first launched in 2005 and has been used alongside liquid chromatography-mass spectrometry (LC-MS) for a decade. However, it wasn't until 2015 that an Orbitrap analyser was first commercialized for gas chromatography.

Despite its comparatively late development, this combination of technologies has huge potential. It offers high mass accuracy and high resolution at scan speeds that enable the identification of impurities, even in co-eluting peaks.

Orbitrap GC-MS/MS: taking it for a test drive

GC-MS is already a critical tool for identifying impurities during the development of pharmaceuticals. The addition of Orbitrap analysis advances it further and offers significant improvements to resolving power, mass accuracy, sensitivity and linear range, prompting Thermo Fisher Scientific to develop a combined system, called the Thermo Scientific™ Q Exactive™ GC Orbitrap™ GC-MS/MS system.

In a paper recently published in Rapid Communications in Mass Spectrometry, AstraZeneca researchers tested how well the system could identify and quantify impurities in real drugs. They tested a range of typical drug starting materials, analysing mass accuracy in both EI and CI mode and linearity over a wide dynamic range (required for quantitative analysis).

The number of scans obtained across chromatographic peaks was assessed at various resolutions. For reliable qualitative analysis, at least 10 scans are needed across a peak, and mass accuracy should be maintained across a wide linear range to ensure selectivity.

At the highest resolution, the scan speed produced 11 scans across the peaks and mass accuracy for all scans was within 1 part per million of textbook mass-to-charge ratio, a value good enough for impurity investigations and quantitative analysis and significantly more accurate than data reported previously from time-of-flight technology. This is big news for the pharmaceutical industry. “Accurate mass measurement across a very wide dynamic range, linearity and the ability to identify impurities in both EI & CI are incredibly powerful tools – All delivered in a system that is extremely easy to use,” says D’Silva.

The future of impurity identification

This study shows Orbitrap GC-MS to be a powerful tool for pharmaceutical research and development. The high resolving power of the technology provided consistent sub-ppm mass accuracy, enabling clear molecular identification even for peaks not fully resolved from the main peak. “The speed and efficiency of the Q Exactive GC gives confidence in pharmaceutical impurity identification with only one elemental formula being identified, allowing for rapid and unambiguous results,” D’Silva concludes.

Related Links

Rapid Commun Mass Spectrom., 2016, 30, 873-80. Baldwin et al.. Applicability of gas chromatography/quadrupole-Orbitrap mass spectrometry in support of pharmaceutical research and development.

Recent trends in the impurity profile of pharmaceuticals

Article by Ryan De Vooght-Johnson

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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