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Journal of Biomolecular Screening
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Establishing Quality Assurance Criteria for Serial Dilution Operations on Liquid-Handling Equipment

Ioana Popa-Burke

GlaxoSmithKline, Sample Management Technologies, Research Triangle Park, North Carolina, ioana.g.popa-burke{at}gsk.com

Brian Lupotsky

GlaxoSmithKline, Sample Management Technologies, Collegeville, Pennsylvania

Joseph Boyer

GlaxoSmithKline, Statistical Sciences, Collegeville, Pennsylvania

William Gannon

GlaxoSmithKline, Sample Management Technologies, Collegeville, Pennsylvania

Rob Hughes

GlaxoSmithKline, Sample Management Technologies, Essex, United Kingdom

Paul Kadwill

GlaxoSmithKline, Sample Management Technologies, Essex, United Kingdom

Donald Lyerly

GlaxoSmithKline, Sample Management Technologies, Research Triangle Park, North Carolina

Jason Nichols

GlaxoSmithKline, Sample Management Technologies, Research Triangle Park, North Carolina

Elizabeth Nixon

GlaxoSmithKline, Sample Management Technologies, Collegeville, Pennsylvania

Darren Rimmer

GlaxoSmithKline, Sample Management Technologies, Essex, United Kingdom

Isabel Saiz-Nicolas

GlaxoSmithKline, Sample Management Technologies, Parque Tecnológico de Madrid, Madrid, Spain

Beatriz Sanfiz-Pinto

GlaxoSmithKline, Sample Management Technologies, Parque Tecnológico de Madrid, Madrid, Spain

Sue Holland

GlaxoSmithKline, Sample Management Technologies, Collegeville, Pennsylvania

Since the advent of high-throughput screening (HTS) in the early 1990s, parallel multichannel liquid handlers have become a mainstay in every drug discovery setting. Although several peer-reviewed publications have discussed methods and criteria for stamping multiwell copies, there is very little information about establishing a standard operating procedure (SOP) for standard (microliter-level) serial dilutions of compounds used in dose-response experiments. The authors discuss the 4 main criteria any serial dilution process must pass (accuracy, precision, fold dilution, and outliers) and the process for establishing thresholds for all of these values in a compound management or biological screening laboratory. The thresholds need to be both low enough to be acceptable from a biological potency variability perspective and high enough to allow the instruments to pass the quality assurance (QA) analysis on a regular basis. In this article, the authors suggest suitable thresholds arrived at by a variety of methods, including trend analysis of QA data, survey questionnaire from the main stakeholders (screening scientists, chemists), and published criteria for single-shot stamping. A mathematical analysis of the effect of threshold values on estimated XC50s was performed to ensure that the variability introduced by the serial dilution step is within acceptable overall variability limits.

Key Words: serial dilution • dose-response • liquid handler • quality assurance

This version was published on September 1, 2009

Journal of Biomolecular Screening, Vol. 14, No. 8, 1017-1030 (2009)
DOI: 10.1177/1087057109339938
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