Improving on current challenges in cell analysis 

Dr Lindsay Fraser, Chief Science and Operations Officer, and Dr Fernanda Masri, Chief Commercial and Innovation Officer, at Cytomos explore current advances in technology that are helping improve cell analysis within drug discovery.  

The biopharma industry is under increasing pressure to bring novel therapies to market, faster and more affordably. However, securing access to key cell specific data at the right time is a major challenge, frequently resulting in crucial information being compromised at critical stages.  

Since flow cytometry became commercially accessible around 50 years ago, the technology has become a mainstream tool for cell analytics, from cell counting or sorting and biomarker detection to determining pre-defined cell characteristics. However, flow cytometry has a great many limitations. Perhaps most striking is the fact that its two-dimensional approach (based on labels and markers that necessitate pre-definition of the analyses performed) can frequently result in meaningful data going undetected. Such restrictions, along with operator bias and a tendency for the tool to produce ‘indigestible’ data that depend on further analyses and interpretations, combine to make conventional flow cytometry alone unsuitable for quick and unbiased decision making.  

Over the next decade, it is widely anticipated that advanced process analytical technologies (PAT) will greatly enhance the levels of information obtained, and that these newer devices will probably be far more commonly used alongside conventional flow cytometry. In particular, advanced PAT are expected to serve as key drivers for accelerating new product discovery, development and manufacturing.  

The full long-term potential of complex therapeutics, such as monoclonal antibody therapies (mAbs), cell and gene therapies (CGT) and advanced therapy medicinal products (ATMPs), will at last be unlocked by the deployment of these next generation technologies. Cutting-edge inventions combining technology and biotechnology – TechBio – are thought to hold the key to this paradigm shift, thanks to the application of novel technologies in tools such as sensors.  

Addressing key challenges 

By collecting data on intrinsic cellular properties in real-time, and delivering label-free, unbiased, consistent, accurate and reliable predictive cell analytics, next-generation technologies could address key industry challenges such as a lack of process control and understanding, high attrition rates, and difficulties in scaled manufacture (both scale-up and scale-out).  

Key challenges with conventional cell analytics1 include:  

  • Operator bias 
  • Need for complex equipment to deal with ‘indigestible’ data 
  • Requirement for expert data analysts 
  • Constraints of cell markers and labels 
  • Non-scalable technologies 
  • Lack of versatility  
  • Lack of real-time data collection 
  • Lack of process control/understanding 
  • Unstable/unpredictable productivity 
  • Difficult / inconsistent technology transfer  

One approach to unlocking the potential of complex therapeutics is the combination of dielectric spectroscopy and consumer microelectronics, which can provide high speed, scalable and low-cost cell analysis.  

By generating a complex electric field and passing streams of individual cells over the surface of a silicon microchip, the electric field is distorted by each single cell. Measuring the distortions at different frequencies, and using novel techniques to maximise information density, generates a multitude of data in real-time and creates unique, digital cell fingerprints for analysis and characterisation without the requirement for labels. Eliminating the need, complexity and constraints of cell markers and tags enables a streamlining of testing regimes (removing the need for complex equipment such as lasers and optics). This further contributes to helping end-users make key decisions faster, based on complete and comprehensive data.  

The cell fingerprints are generated using the intrinsic properties of the cell rather than proxy data and the digital nature of the fingerprint enables the possibility of integration to automated processes. As the platform provides information on cell properties that other technologies simply can’t, it has the potential to improve cell analytics, benefitting researchers across drug discovery and life sciences. This has the potential to expand user capabilities while offering incredible simplicity of use to create a true leap in value for end-users.   

For example, the elimination of sample preparation (as sensors assess cells directly in culture solution) effectively streamlines sampling, operator handling and technology transfer (as label free). Combined with the provision of real-time data in an objective, simple readout, this approach reduces the potential for bias on the part of the operator, and on the part of the data manager, while eliminating the need for complex downstream analyses. Therefore, the technology allows for earlier, more informed and consistent decision making. 

Conventional technologies are not easily scalable from R&D to manufacture.  However, scalable microchip technology opens new opportunities for integration in a range of form factors without changing the essence of the data. The same technology platform can be used in probe instruments for bioreactors or other cell culture devices, including single use reactors. 

Bringing value to the industry 

Harnessing the power of silicon and consumer electronics brings enormous and exponential economies of scale in sensor manufacturing enabling cost effective monitoring tools for high frequency sampling as well as single use application. These advantages offer huge potential to improve product quality for scaled therapy manufacture and personalised medicines such as ATMPs.  

For example, it will be possible to improve and streamline cell line development and bioproduction processes by enabling end-users to better select robust, high antibody producing cell clones (e.g. for Chinese hamster ovary [CHO] or human embryonic kidney [HEK] lines). 

Meanwhile, improving CGT process control should enable earlier prediction of product failure or success and ultimately positive patient outcomes.  The key to improving CGT processes involves live, cell-specific understanding, which in turn increases the speed and accuracy of decision-making for enhanced process control.  Clearly, a comprehensive, real-time insight into the state and stage of cell populations inside a bioreactor / culture vessel will give CGT developers a clear advantage in terms of responding rapidly to any developments – good or bad. Specifically, real-time data collection permits better live monitoring of: 

  • Growth of cell populations 
  • Cell health 
  • Cell heterogeneity or differentiation  
  • Product purity 
  • Cell functionality

Insights such as these unlock exponential value for the bioprocess industry, enabling rapid decision making and live process control. Therefore, new technologies fit into an evolving landscape of next-generation therapies, biologics and more novel high growth segments which are driving the need for radical improvements in PAT and in-process controls with real-time, automated capabilities.  

It is anticipated that new technologies will be used alongside conventional technologies such as flow cytometry, bringing substantial complementary value. Combining specialist technologies in this way can provide the end-user with a more detailed analysis in order to delve deeper into cell analytics and will allow them to make quicker, more relevant conclusions based on reliable, consistent data.  

A new approach 

Thanks to the integration of consumer electronics that enable affordable, mass access to better and more insightful cell analytics, these technologies are no longer ‘exclusive’ – they are ready to go mainstream.  

For example, Cytomos’ first product, the Celledonia benchtop solution enables label-free, comprehensive cell analysis through its patented real-time AuraCyt platform agnostically translating complex cell data into actionable insights to materially improve cell line development, CAR-T processing efficacy & iPSC productivity. 

By simplifying use and data analyses, and removing critical market barriers, we anticipate that next-generation technologies will accelerate biological drug discovery and development, streamline biologics manufacturing (with real-time monitoring potential), and provide better prospects for delivering automation in the future production of cell and gene therapies. Ultimately, they will help biopharma to achieve the goal of providing better access to safe and affordable medicines and vaccines, delivering life-changing advanced therapies across the world. 

References 

  1. Masri F. Advancing cell analytics: a vision for the future. Genetic Engineering & Biotechnology News, April 2024:36–37.

Biographies 

Dr Fernanda Masri, Chief Commercial and Innovation Officer, Cytomos Ltd.
Dr. Lindsay Fraser (right), Chief Scientific and Operations Officer, Cytomos Ltd.

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