Next-Generation Compound Delivery Platforms to Support Miniaturized Biology.

Recent advancements in science and engineering are revolutionizing our understanding of an individual's disease, and with this knowledge we are gaining an increasingly sophisticated understanding of how discovery can be transformed to deliver personalized medicines. To reach this future state, we must reengineer our approach to enable the use of more relevant human cellular models earlier in the drug discovery process. Stem cells and primary human cells represent more disease-relevant models than immortalized cell lines; however, due to both availability and cost, their use is limited in lead generation activities. Miniaturization of cellular assays below microtiter plate volumes will enable the use of more relevant cells in screening, but this would require a change in how test molecules are introduced to the biology. With these shifting paradigms, Discovery Supply teams at GlaxoSmithKline (GSK) are modernizing our sample handling approaches. Various emerging technologies such as microarrays, nanowells, and microfluidic devices could bring fundamental changes in conventional sample handling support as we transition from microtiter plates to well-less platforms. The discussion here is exploratory in nature and reviews ongoing proof-of-concept experiments. Our ultimate goal is to industrialize the sample management platforms to support future miniaturized biological assay systems.

Compound management: guidelines for compound storage, provision, and quality control.

The scientific discipline of compound management has developed significantly over the last decade, as witnessed by the large number of conferences dedicated to this topic. The key elements of compound management include (1) the management, storage, and processing of both solids and liquids; (2) compound delivery and interface with key customers; (3) performance of instruments and automation that support these operations; (4) analytical techniques used for quality assurance; and (5) sample informatics, including registration, routing, and compound quality data. This article incorporates guidelines, best practices, and experimental protocols for these key aspects of compound management. Curr. Protoc. Chem. Biol. 3:141-152 © 2011 by John Wiley & Sons, Inc.

Applications of adaptive focused acoustics to compound management.

Since the introduction of lithotripsy kidney stone therapy, Focused Acoustics and its properties have been thoroughly utilized in medicine and exploration. More recently, Compound Management is exploring its applications and benefits to sample integrity. There are 2 forms of Focused Acoustics: Acoustic Droplet Ejection and Adaptive Focused Acoustics, which work by emitting high-powered acoustic waves through water toward a focused point. This focused power results in noncontact plate-to-plate sample transfer or sample dissolution, respectively. For the purposes of this article, only Adaptive Focused Acoustics will be addressed. Adaptive Focused Acoustics uses high-powered acoustic waves to mix, homogenize, dissolve, and thaw samples. It facilitates transferable samples through noncontact, closed-container, isothermal mixing. Experimental results show significantly reduced mixing times, limited degradation, and ideal use for heat-sensitive compounds. Upon implementation, acoustic dissolution has reduced the number of samples requiring longer mixing times as well as reducing the number impacted by incomplete compound dissolution. It has also helped in increasing the overall sample concentration from 6 to 8 mM to 8 to 10 mM by ensuring complete compound solubilization. The application of Adaptive Focused Acoustics, however, cannot be applied to all Compound Management processes, such as sample thawing and low-volume sample reconstitution. This article will go on to describe the areas where Adaptive Focused Acoustics adds value as well as areas in which it has shown no clear benefit.

Stability through the ages: the GSK experience.

It is common knowledge in the pharmaceutical industry that the quality of a company's compound collection has a major influence on the success of biological screening in drug discovery programs. DMSO is the widely accepted solvent of choice for storage of compounds, despite the hygroscopic nature of the solvent, which can lead to stability issues. Other factors that can affect compound stability (e.g., degradation, precipitation) include concentration of compound, intrinsic compound stability, presence of reactive contaminants, storage format-related factors (vessel, sealing, etc.), storage conditions (temperature, humidity, freeze-thaw technique and cycles, etc.), and storage time. To define the best practice for the storage and handling of solution samples, GlaxoSmithKline has undertaken stability experiments over more than a decade, initially to support the implementation of new automated liquid stores (ALS) and, subsequently, to enhance storage and use of compounds in solution through an understanding of compound degradation under storage and assay conditions. The experiments described used a number of technologies, including hyphenated liquid chromatography, electrospray mass spectrometry, flow chemiluminescence nitrogen detection, nuclear magnetic resonance, and Karl Fischer titration.