Expanding the analytical toolbox for biopharmaceutical characterisation

Biopharmaceuticals are highly complex molecules due to their large size and structural heterogeneity. Analytical characterisation of biopharmaceuticals can be challenging and a final drug substance can be composed of a mixture of variants that can have an impact on stability, function, efficacy and safety.

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The Challenge

During product development and manufacturing the Critical Quality Attributes (CQAs) of the molecule need to be characterised in detail using a range of analytical tools, including properties such as:

  • Post translational modifications, for example glycosylation

  • Aggregation profiling through a range of sizes from soluble to visible particulates

  • Charge related variants

  • Conformation

  • Structural heterogeneity

  • Stability

There continues to be a need for improved analytical methods for biopharmaceutical characterisation. Firstly, HDX methods have limited time resolution of several seconds, reliant on the speed of manual pipetting or a liquid handling robot. Weakly protected regions of polypeptides exchange in the millisecond time scale and valuable data may be missed. Next, there are challenges around data interpretation for conventional CD, as it is limited to demonstrating conformational comparability which is fundamentally subjective and prone to error.

Current protein aggregation profiling methods are dependent on the use of disparate orthogonal techniques, making analysis time consuming. Finally, there is a need for rapid, efficient and reliable tools for glycan analysis to improve efficiency and reduce the costs associated with biopharmaceutical development.

Inputs

  • Provided access to CPI’s state-of-the-art bioprocessing facilities and analytical equipment 
  • Shared expert technical and industry knowledge around the analysis of biopharmaceuticals 
  • Collaborated on publicly fundedR&D projects 

Outputs

  • Demonstration of a prototype for an improved platform forHydrogen Deuterium Exchange(HDX) analysis
  • Supported the development

    of a new analytical platform to allow a quantitative approach toCircular Dichroism (CD)

  • Development of analytics for rapid and high throughput analysis of glycosylation

  • Development and supply of aggregation standards

Outcomes

  • Acceleration and de-risking of a range of new analytical tools for biopharmaceutical characterisation
  • Improved analytical characterisation of biotherapeutics will ultimately lead to improved safety for patients

How CPI helped

CPI used our expertise and facilities to support the development and testing of a number of new analytical tools for biopharmaceutical characterisation as part of a number of Innovate UK funded collaborative projects, including:

  • Demonstration of a prototype for improved HDX analysis. The prototype allowed automated analysis in the lower millisecond time range with high accuracy and reproducibility to facilitate and improve the study of conformational dynamics of polypeptides

  • Demonstration of the value of a quantitative CD spectroscopy system to remove subjectivity when comparing overlaid spectra and provide information on changes in protein structure

  • New analytical platforms to streamline aggregation profiling

  • Development of a novel analytical platform, enabling rapid and high-throughput analysis of the glycan profile of a biopharmaceutical

Summary

The structural and functional complexity of biopharmaceuticals makes analytical characterisation challenging, and there is a need for advanced analytical tools to improve understanding of critical quality attributes. Through CPI’s commercial and technical expertise we were able to support a number of partners with the development of industrially viable analytical technologies for biopharmaceutical development and manufacture.