SBIR-STTR Award

Cell culture bioassays are perceived as laborious and imprecise even after substantial development efforts. These bioassays are used broadly in the biotechnology industry to measure protein or vaccine products in development and for lot release. Imprecise assays and slow assay development contribute to slow product development. Common practice in cell culture bioassay ignores statistical and regulatory guidance by failing to utilize proper randomization and not accounting for group effects (caused by multi-channel pipettes). In addition, the lack of attention to location effects within the assays combined with simplistic analyses of assay data compromise the precision and efficiency of cell culture bioassays. We propose a modern standardized approach to cell culture bioassay using statistical design and analysis linked to laboratory robots, which will address randomization, location effects, serial dilution, and grouped dilution. The larger program goal is to build a turnkey cell culture bioassay system using statistical software and a laboratory robot. The work described in this proposal will use 1) standardized designs and analysis, 2) linear or nonlinear mixed split- or strip-plot models for bioassay analysis, 3) recent developments in laboratory robotics that make randomization practical (both hardware and software), and 4) new code for modeling serial dilution error (developed under EPSCoR funding, Lansky 2004). The combination of methods, once developed, should reduce the coefficient of variation from high single digits or substantially higher to low single digits, reducing the need for replication by a factor of four to ten or more. Most importantly, by building a turnkey robotic and analysis bioassay system, this level of assay performance will be made broadly available to the biotechnology industry as well as to non-profit researchers

Abstract Cell culture bioassays are often laborious and imprecise even after substantial development efforts. These bioassays are used broadly in the biotechnology industry to measure protein or vaccine products in development and for lot release. Imprecise assays and slow assay development contribute to slow product development. Common practice in cell culture bioassay ignores statistical and regulatory guidance by failing to utilize proper randomization and not accounting for group effects (i.e.; as caused by multi-channel pipettes). In addition, lack of attention to location effects within the assays, combined with simplistic analyses of assay data, compromise the precision and efficiency of cell culture bioassays. Lansky Consulting LLC will develop a standardized approach to cell culture bioassay using laboratory robots followed by modern statistical analysis. This combination will address the need for randomization, location effects, serial dilution, grouped dilution, and multiple sources of variation in assay response. The work described in this proposal will demonstrate the performance gains associated with: 1) standardized designs (including designs that require robots for randomization), 2) linear and nonlinear mixed split- or strip-plot models for bioassay analysis, and 3) advances in implementation of this modern standardized approach to bioassays. The precision gains from the combined package of modern bioassay methods will be shown to reduce the need for sample replication by an order of magnitude or more. Both simulated data and long-term lab experiments with bioassays will be used. The benefits of these new methods include lower assay costs, rapid application to new assay systems, and easy access to best practices in design, implementation, and analysis. Most importantly, by building a turnkey robotic and analysis bioassay system, this level of assay performance will be made broadly available to the biotechnology industry as well as to non-profit researchers. Project Summary Narrative Bioassays are critical measurement systems for both development and lot release of pharmaceutical protein and vaccine products. Easy access to high performance bioassays will enable faster and better informed development of biotechnology products. Improved bioassay technology will bring unique, important protein and vaccine products to market more quickly to address pressing medical needs.

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