Innovations in measurement, analysis and testing


Accurate, timely and efficient measurement techniques are key to optimising production processes and providing regulators with assurance on product quality

Richard Moseley, Chief Technologist at Microsaic Systems, looks at innovations in analytical techniques, particularly the capabilities of chip-based mass spectrometry to improve production processes.

Specialist analytical chemists typically measure off-line manufacturing samples, often in a centralised lab. This takes time to complete, particularly if the lab is located remotely from the production facility; plus, traditional analytical methods, such as optical or UV detection, only give a limited snapshot of information to the user.

Commercial laboratories are increasingly under pressure to get new drugs to market faster … and an increasing trend has been to bring sample and reaction analysis closer to the user. This is a challenge for traditional mass spectrometry, often used as a gold standard in chemical and biological analysis, owing to its size and capital-intensive infrastructure needs.

By miniaturising the mass spectrometer so that it can be used on the laboratory bench, at the bioreactor or in the fume cupboard, synthetic and biological chemists can see reactions in real-time.

This creates certainty for the chemist regarding product intermediaries, by-products and impurities, enabling better decision making and, ultimately, greater productivity as manufacturing processes can be adjusted or stopped by quality assurance and control labs as needed and in real-time.

Two core uses of miniaturised mass spectrometry in pharma are end-product confirmation and automated online reaction monitoring. For the latter, small samples are withdrawn periodically as the reaction progresses — but, importantly — with no need for chromatographic separation.

This avoids sample decomposition, which can occur when dealing with unstable compounds. With faster answers available in real-time, reaction conditions and critical quality attributes (CQAs) can be more closely monitored and optimised accordingly. The inherent sensitivity involved in biopharmaceutical production means that process analytical technology (PAT) for continuous manufacturing is fast becoming essential.


It’s thanks to micro-electro-mechanical systems technology or MEMS that the key subcomponents of mass spectrometers can be miniaturised, including ion sources, mass filters, ion detectors, vacuum gauges and pumps.

First developed in the early 1970s for applications such as residual gas analysis (RGA) for process control and contamination in vacuums, and for space exploration, miniaturised mass spectrometers were precision engineered to meet the critical weight and size requirements for these challenging environmental conditions.1

In MEMS-based mass spectrometry, the physics remains the same as that of traditional MS instruments; ions are created using known methods and are filtered using electric fields. However, by utilising microengineering manufacturing processes that are typically used to make silicon chips in a desktop computer, the size of a conventional quadrupole mass spectrometer can be significantly reduced.

This enables complex parts to be made in large volumes with very high precision and reproducibility … and at reasonable cost. The result is a portable and fully self-contained MS system, including PC and pumps in a unit the size of a conventional UV detector.

Looking at the key components in a little more detail — all mass spectrometers require an ion source, a mass filter, an ion detector plus a vacuum chamber, a method of sample introduction, vacuum pumps, a pressure gauge, control electronics and data acquisition, display and storage.

Figure 1: Miniaturised mass spectrometry components: spraychip, vac-chip and ionchip

Figure 1: Miniaturised mass spectrometry components: spraychip, vac-chip and ionchip

Mass filters separate the ions based on their mass-to-charge ratio using time varying electric fields applied in a vacuum. Examples of these miniaturised components (Figure 1) include

  • the spraychip, an electrospray ionisation source
  • a vacuum interface, vac-chip, which carries ions from the ambient source to the vacuum chamber
  • a quadrupole mass filter, ionchip, contained inside the vacuum chamber.


When considering mass spectrometry for use in pharma and biopharma production, key performance indicators are sensitivity, mass range, mass resolution and the ability of the system to distinguish different ions. For example, a mass range of 1400 m/z is suitable for the analysis of small molecule drugs in pharma, but biopharma analytics requires a higher mass range (approximately 3200 m/z) to identify protein-based therapeutic drugs.

When it comes to sample preparation, complex mixtures are sometimes separated into their components prior to analysis in a mass spectrometer — and miniaturised MS is no different. Owing to the nature of pharmaceutical samples, liquid chromatography (LC) is usually the preferred separation method.

Such hyphenated LC-MS systems, when chip-scale LC is combined with MEMS miniaturised mass spectrometry, allow small samples to be processed without excessive dilution, giving high detection sensitivities.2 As a case study, the mass spectra (Figure 2) of the alkaloid drug Reserpine obtained from a conventional MS and a miniaturised MS show no differences in sensitivities between instruments.

Figure 2: Mass spectra comparing miniaturised MS performance with traditional MS

Figure 2: Mass spectra comparing miniaturised MS performance with traditional MS


For the production of larger, biologically derived drugs, key challenges include molecule characterisation, stability and continuous manufacturing. As biologics are much more complex and heterogenous than small molecule drug compounds, there is a need to monitor and control every bioprocessing step.

Seemingly minor chemical changes in a biologic can have severe consequences to the end patient. Miniaturised MS can seamlessly fit into online or at-line bioprocessing and monitor both the CQAs of the biologic and the metabolites, nutrients, protein contaminants and other chemicals present during processing.

By helping to monitor and control bioprocessing, MS ultimately improves throughput and reduces waste. And with a need to move away from batch production to a more sustainable and commercially viable model of continuous production, miniaturised MS presents a practical analytical solution.

Advanced process controls

Regulators require assurance on biopharmaceutical product quality, such as safety, purity and potency. In terms of producing a final drug with consistent quality, the control strategy for manufacturing biologics is critical. Applying Quality by Design (QbD) approaches to develop this strategy moves testing and monitoring earlier into the process, enabling CQAs of the outputs such as the nature and potency of the biologic, as well as product and process-related impurities, to be monitored in real-time.

Here, miniaturised mass spectrometry offers enhanced analytics to better understand both the biological product and the process, resulting in better product and process data to consistently control output quality.

With further technology advancement, miniaturised mass spectrometry is increasingly being used to rapidly characterise biologics during production, such as at-line intact antibody analysis to assess the impact of downstream processing on its molecular structure, as well as the impact of reaction conditions and harvest timings on output.3

Accurate data from miniaturised mass spectrometry on process intermediates enables users to more closely analyse and therefore link process parameters with specific CQAs, thereby achieving a more efficient, robust and consistent manufacturing process in a much shorter time frame than was previously possible.

The future

Delivering broader data than previous analytical tools, miniaturised mass spectrometry offers real-time control to production scientists in pharma and biopharma alike. The ongoing development and validation of chip-based mass spectrometry technology is already leading to more advanced process control at the point-of-need, further improving overall productivity.


  1. R.R.A. Syms and S. Wright, “MEMS Mass Spectrometers: The Next Wave of Miniaturization,” J. Micromech. Microeng. 26(2): 023001 (2016).
  2. A. Malcolm, et al., “A Miniature Mass Spectrometer for Liquid Chromatography Applications,” Rapid Communications in Mass Spectrometry 25(21), 3281–3288 (2011).
  3. R.W. Moseley and A.I. McIntosh, “Monitor and Control Upstream Bioprocessing Using a Point-of-Need Mass Spectrometer,” Biophysical Journal 114(3), 411A (2018).