Standing Up for Microcalorimetry

Making sure you have an optimal set of analytical techniques at your disposal is crucial whatever your research focus, but can be particularly challenging in sectors that are experiencing rapid change, such as biopharmaceutical development. Biopharmaceuticals and biosimilars are still relatively young drugs when compared to their small-molecule counterparts – and they can behave unexpectedly during manufacture.

The biopharmaceutical sector has been climbing a steep learning curve, but at last we are gaining a better understanding of which properties to monitor and how to measure them. That said, there is still room for improvement. Today, the main concerns in drug development focus on bioactivity and efficacy, stability, ease of delivery, safety and immunogenicity. What (and how) to measure when it comes to understanding these factors is still open to debate, especially as requirements can change throughout the drug development pipeline. Instrument manufacturers continue to work hard to commercialize new technologies to meet the industry’s needs – and today there are many analytical solutions to choose from.

Techniques that can stay the course from formulation through to manufacture are highly desirable. In my view, orthogonality – the application of alternative techniques based on different measurement principles – is essential to secure understanding and provide the thoroughness needed to progress through development with confidence. Biopharma development is already expensive and mistakes waste precious resources.

One technique that I think is underutilized in the industry is microcalorimetry. Microcalorimetry involves the measurement of the very small heat changes that occur when a drug interacts with a target site or a protein unfolds, for example, and can help deliver information about those interactions and behaviors. Modern microcalorimetry instrumentation can detect temperature changes of as little as a millionth of a degree, which allows users to observe and quantify changes with just 10 µg of sample. But how should the biopharma community apply the technique to get the best (and most useful) results?

With isothermal titration calorimetry (ITC), heat changes are measured when a ligand, such as a drug candidate, is progressively added to a biomolecular target. The resulting heat profiles generate a wealth of information that can be used to understand molecular interactions, aiding hit selection and lead optimization. ITC, therefore, lends itself to drug discovery.

In contrast, differential scanning calorimetry (DSC) detects protein unfolding/conformational change triggered by the application of a temperature ramp, thereby quantifying stability. Stability is a defining issue throughout biopharmaceutical development through to the point of drug delivery – from early screening through to quality assurance and control, and for biosimilar development. The value of the data provided by DSC therefore remains high throughout the drug pipeline.

DSC can usefully accompany a biopharmaceutical product from its earliest origins all the way to the shelf. Instrument developers must ask themselves how best to adapt DSC technology to meet requirements at every step. Current systems consume relatively little sample and are automated for higher sample throughput – important benefits, of course, that fit the technique for screening applications. To realize DSC’s broader value, however, we need to ask some searching questions:

• How can we analyze DSC data as precisely as possible to maximize sensitivity? 
• How can we accelerate and ‘de-skill’ the analytical process to make DSC more suitable for the manufacturing environment?
• How can we streamline DSC to dovetail seamlessly with orthogonal techniques, such as dynamic light scattering, which also have an established role in stability assessment?

If we can answer these challenges, DSC will be able to deliver to its full potential and build on its role as a constant companion throughout drug development and into commercial manufacture. However, more generally, these two examples highlight the need to really understand the potential of a technique to fully exploit its value. ITC boosts productivity primarily by generating a wealth of information to accelerate a single step of development – drug discovery – while DSC is a core tool across the development cycle. I believe we need to explore and embrace techniques in both camps to develop biopharmaceuticals safely and effectively.