High-Throughput Screening to Assess Biophysical Properties Of Therapeutic Proteins in Early Development

During candidate selection, limited material is available for biophysical characterization.  In this Q&A interview, Martin Lemmerer, Integrated Biologics Profiling at Novartis, joins Amber Scorah of Pharma IQ to talk about how they assess and pick winners, the advantages of a high-throughput automation platform enables compared to a conventional setup, and the techniques they are using to assess biophysical properties of a molecule.

A Scorah: During candidate selection, limited material is available for biophysical characterization. How do you assess and pick winners?

Martin Lemmerer: We pick winners based on physical chemical characteristics of a molecule. The characteristics of a molecule enable us to assign a candidate to different risk categories. The thresholds of the risk categories are based on past experience. The candidate with the most favorable characteristics will move forward in the pipeline. We set up experiments in various buffer systems and different excipients. We then assess characteristics such as solubility, turbidity, viscosity and molecule-molecule interactions through determination of the 2nd viral coefficient. We try to establish a model to predict biophysical properties of proteins using the data we have collected. For example we try to correlate viscosity to the second viral coefficient.

A Scorah: What are the advantages a high-throughput automation platform enables compared to a conventional setup?

M Lemmerer: An automated platform frees up a scientists precious time. Human errors are eliminated, by applying automated liquid handling. Small volumes can be pipetted by the robot with high accuracy. We also avoid repetitive work for our analysts through automated liquid handling.

A Scorah: What other advantages are there to this approach?

M Lemmerer: Redundant work for the analyst such as preparing numerous buffer-excipient mixtures can be done by the liquid handler. Higher efficiency and throughput can

be achieved by utilizing automation. Automated liquid handling also cuts cost; the robot can be run overnight or over the weekend.

A Scorah: What techniques are you using to assess biophysical properties of a molecule?

M Lemmerer: We utilize UV-Vis spectroscopy to determine solubility and turbidity. Furthermore, by applying dynamic light scattering we measure the diffusion coefficient and the viscosity of a molecule. The tests are all done in a high-throughput approach. We use 384well plates to minimize the material consumption and to be able to process a higher number of samples. For all measurements mentioned above we are using automated sample preparation. Furthermore, for the assessment of the data we have developed a semi-automated Excel file to process the data in a timely manner.

Visualization of a big data set is often a significant problem. Spotfire software enables us to overcome this issue. Furthermore, to convey the results of the screen to the project teams we are utilizing risk rated heat maps.

A Scorah: For what uses has this screen been implemented?

M Lemmerer: The screen is mainly used to assess manufacturability of early stage biologics. We collect valuable information such as a strategy for purification development and formulation development by the testing numerous buffer conditions. Furthermore, problematic candidates can be identified through the screen. We have already eliminated potential candidates which were supposed to go into full development. Thus "fail early" is desirable, since the candidate goes into development, the costs increase significantly.

Martin Lemmerer will be speaking in-depth on this topic at the upcoming IQPC Protein Formulation Development Summit, September 11 and 12, 2012 in Boston. For more information go to www.proteinformulationsummit.com/.

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