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Process Validation and Screen Reproducibility in High-Throughput Screening

GlaxoSmithKline R&D Pharmaceuticals, Screening and Compound Profiling, Tres Cantos, Spain, isabel.coma{at}gsk.com

Liz Clark

Screening and Compound Profiling, Harlow, UK

Emilio Diez

GlaxoSmithKline R&D Pharmaceuticals, Screening and Compound Profiling, Tres Cantos, Spain

Gavin Harper

Computational and Structural Chemistry, Stevenage, UK

Jesus Herranz

Computational and Structural Chemistry, Tres Cantos, Spain

Glenn Hofmann

Screening and Compound Profiling, Upper Providence, Collegeville, Pennsylvania

Mark Lennon

Discovery Statistics, Stevenage, UK

Nicola Richmond

Computational and Structural Chemistry, Stevenage, UK

Manuel Valmaseda

Information Technology, Tres Cantos, Spain

Ricardo Macarron

Compound Management, Upper Providence, Collegeville, Pennsylvania

The use of large-scale compound screening has become a key component of drug discovery projects in both the pharmaceutical and the biotechnological industries. More recently, these activities have also been embraced by the academic community as a major tool for chemical genomic activities. High-throughput screening (HTS) activities constitute a major step in the initial drug discovery efforts and involve the use of large quantities of biological reagents, hundreds of thousands to millions of compounds, and the utilization of expensive equipment. All these factors make it very important to evaluate in advance of the HTS campaign any potential issues related to reproducibility of the experimentation and the quality of the results obtained at the end of these very costly activities. In this article, the authors describe how GlaxoSmithKline (GSK) has addressed the need of a true validation of the HTS process before embarking in full HTS campaigns. They present 2 different aspects of the so-called validation process: (1) optimization of the HTS workflow and its validation as a quality process and (2) the statistical evaluation of the HTS, focusing on the reproducibility of results and the ability to distinguish active from nonactive compounds in a vast collection of samples. The authors describe a variety of reproducibility indexes that are either innovative or have been adapted from generic medical diagnostic screening strategies. In addition, they exemplify how these validation tools have been implemented in a number of case studies at GSK. (Journal of Biomolecular Screening 2009:66-76)

Key Words: high-throughput screening • pharmacological screening validation • process variation • reproducibility • screening tests

Journal of Biomolecular Screening, Vol. 14, No. 1, 66-76 (2009)
DOI: 10.1177/1087057108326664


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