SORS and the Power of Light in Pharma

Spatially offset Raman spectroscopy (SORS) has expanded the boundaries of traditional Raman analysis. Developed from unexpected findings in ultrafast laser experiments at the Science and Technology Facilities Council (STFC) Central Laser Facility, SORS allows for detailed chemical analysis of opaque or layered materials, including powders, coated tablets, and even products within sealed containers – making it a valuable tool for raw material verification, detection of counterfeit medicines, among other uses.

Pavel Matousek, one of the key figures behind SORS, co-founded Cobalt Light Systems through STFC to commercialize this technology. Rob Stokes joined in 2013, and then the company was acquired by Agilent Technologies in 2017, which helped bring SORS to a wider customer base. 

Here, Matousek (STFC Senior Fellow at the Central Laser Facility) and Stokes (Director, Raman Spectroscopy at Agilent) share insights into how SORS has evolved and its applications in pharma.

Please describe the broad concept of Raman spectroscopy for the uninitiated…
 

Pavel Matousek: I like to present it as a method for chemical analysis using light. It’s actually a very straightforward technique, so much so that even physicists like me can do chemical analysis! You activate the system, observe the scattered light, and analyze how the color of certain light components changes. These color changes result from interactions with molecular vibrations – specific oscillations within molecules – that create a unique pattern that can be described as a molecular fingerprint. This fingerprint allows you to identify individual molecules, distinguish between isomers, or even detect subtle markers, distributions, or different crystalline forms. What’s especially appealing about Raman spectroscopy is that the analysis is immediate. No sample preparation is required, it’s non-destructive, fast, and highly specific, which makes it a very practical approach.

Rob Stokes: Raman spectroscopy provides highly detailed information, but it’s also a very simple technique. This simplicity opens up a wide range of applications, even for operators who aren’t trained scientists or laboratory technicians. And that’s why it has become so valuable outside of the traditional lab setting. It can be used in manufacturing facilities and even for field-based analyzes thanks to the development of handheld Raman devices.

PM: I’ll also add that this simplicity is tied to how the technique has recently evolved. About 15 years ago, Raman spectroscopy was primarily confined to scientific labs and research institutes. Advances in detectors, filters, and lasers, which are now smaller, more affordable, and more effective, have made it possible to apply the technique to real-world settings. Raman spectroscopy provides a level of chemical specificity similar to infrared spectroscopy, but has somewhat different practical application niches due to different underlying physical phenomena."

What is SORS? And how does it expand the clinical research applications of Raman spectroscopy?
 

PM: SORS addresses a limitation of conventional Raman spectroscopy. If you have a dense powder or opaque object, traditional Raman can only analyze the surface – not what’s deeper within. For instance, if you have a tablet with multiple layers, you might only be able to analyze the outer coating. Similarly, if the product is inside a container, then you will only be able to analyze the container.

SORS probes beyond the surface and can even analyze contents inside opaque containers. It was developed somewhat accidentally in the 2000s as part of a set of ultrafast laser experiments we were conducting at STFC’s Central Laser Facility. Initially, these unexpected results were a nuisance in our trials! But when we investigated further, we realized that the phenomenon could allow us to chemically analyze materials beneath surfaces, including deep powders and even in biological tissues to detect bone diseases or cancer lesion. By capturing Raman signals at different offsets from the laser illumination point, SORS can isolate information from various depths within a sample.

We formed Cobalt Light Systems to develop the technology into practical instruments that could be used in the real world – rather than just the dark world of laboratory research!

RS: The first product that Cobalt released didn’t actually use SORS; it used transmission Raman spectroscopy technology, which is very useful for content uniformity testing in pharmaceutical doses. The first impactful application of SORS in pharma was a mobile system called RapID, which was about the size of R2D2 from Star Wars. It had a handheld component that can be used to quickly verify the contents of containers; for example, allowing pharma companies to check incoming raw materials, without needing to open containers and/or packaging. These systems are still in use today!

From there, we expanded into other applications, including security and detection. This led to use cases in customs and border protection, which brings us back to pharmaceuticals in the form of counterfeit medicines.

What were the challenges of developing SORS for real-world use?
 

RS: We are confident about SORS’ potential to do good in the world, but a major challenge was the fact that users wouldn’t be trained analytical scientists. Take airport security, for instance. Officers have countless tasks and procedures to handle, all while ensuring passenger flow through checkpoints. We condensed the technology into a desktop device that could scan containers within seconds without opening them, and provide a definitive answer to help officers make critical decisions.

The same challenge exists in the pharmaceutical industry, where regulations are rigorous. We needed to ensure the technology was compliant with pharmaceutical regulations while still being user-friendly, and able to handle high throughput. Balancing usability with regulatory compliance was one of the biggest challenges early on.

We became the first company to sell a handheld Raman system specifically for raw material identification. Though other Raman-based systems existed, our products used the SORS technology developed by Pavel and his colleagues at Oxford. This technology allows us to analyze through more barriers with higher performance, making it applicable in ways that were previously out of reach. Some of that initial groundwork was done in a more basic form, but SORS truly advanced those capabilities.

The pharma industry can be conservative; were there any issues in getting companies to try the technology?
 

RS: Across almost any industry, established methods and technologies can be hard to replace. Traditional scientific methods differ greatly from Raman, often requiring you to take a sample and analyze it with large, complex lab instruments. They report different characteristics and involve a lengthier process. Raman, which provides rapid, straightforward analysis, can almost seem too good to be true. And there are always questions in pharma about whether a new technology will comply with industry standards.

Ultimately, what helped convince people was the clear return on investment. Raman is fast, simple, and can translate quickly into tangible efficiencies and cost savings for businesses.

PM: I’d also like to give credit to the large pharmaceutical companies that maintain specialist teams who were willing to engage with us, understand our message, and explore our technology. When we introduced SORS, we performed proof-of-concept studies to demonstrate that the technology could deliver quantification of pharmaceutical formulations, without the need for extensive sample preparation or destruction, and analyze raw materials within standard containers. Once we completed the concept stage, companies were prepared to adopt the technology in their own product development. As they became more familiar with the technology, they became keen to deploy it in other applications too.

How can SORS be used to detect counterfeit medicines?
 

RS: This is all in the research stage and it’s all about pushing the limits of SORS. It lends itself very well to liquid medicines. We were already thinking about looking into the analysis of counterfeits – and our work happened to be coincident with that of another group of academics.

PM: At the start of the COVID-19 pandemic, Prof. Paul Newton from the Medicine Quality Research Group at Oxford University contacted us and we ended up having a socially distanced meeting in a park in Oxford! He was wondering whether the technology we had developed could be harnessed and translated to probe unopened vaccine vials in the field. We were a little skeptical because these are very challenging formulations with very low concentration formulations. We did some experiments that ultimately were very successful. All of this demonstrates the important nature of industry collaborating with national laboratories and academia. This work is really pushing the boundaries of what the technology can achieve; it’s exciting to see how far we can take this.

The technology is now being trialled in other areas in partnership with Prof Newton’s team, such as checking cough medicines. In recent years, there have been hundreds of deaths attributed to cough medicines contaminated with diethylene glycol and ethylene glycol (1).

What high impact stories can you share?
 

RS: There have been instances where we intercepted highly dangerous substances at borders using our handheld Raman systems. Some of these substances are unregulated, but incredibly harmful. With the internet fueling the popularity of these kinds of dangerous substances, it’s invaluable to detect them early. We’ve intercepted signals at borders worldwide, identifying them as new or previously unknown threats, and then worked with local authorities to understand and respond appropriately. This capability of keeping harmful materials off the black market genuinely reduces potential harm. Another example that stands out involved a large container of materials that could be used to produce date-rape drugs.

Moments like these remind us how impactful our work can be.