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Autumn/Winter 2012 Join our mailing list and download the latest and previous copies of our quarterly newsletter.
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Innovative Solutions

"How Low Can You Go" - Small Molecule Bioanalysis


Quantification required for a basic drug and two metabolites to support a clinical study. Highly potent drug with a Cmax of 4 pg/mL. Existing methodologies had a LLOQ of 1-2 pg/mL and did not adequately describe the absorption and elimination phases. The customer asked “How low can you go?”  - Target LLOQ 100 fg/mL.

Approach

As part of the streamlining method development process, we have developed new pre-determined strategies for analysing compounds based on their chemistry and sensitivity requirements, we like to call it the “considered approach”. This involves the use of well understood solid phase extraction (SPE) mechanisms to isolate analytes from the endogenous matrix components coupled with orthogonal chromatographic separations using sub 2 micron particle size analytical columns or sub 3 micron fused core analytical columns. 

We have developed open access robotics to fully automate all our online and offline sample preparation. We have also simplified the use of laboratory reagents, which now consists of fifteen generic reagents which can be used for sample preparation and chromatographic separation. We feel all of these elements put together are a key to aid quality, speed, and cost of future bioanalysis.

To achieve the 100 fg/mL LLOQ in human plasma we used the “considered approach”; analyte chemistry was exploited in combination with orthogonal extraction techniques. The method utilised an offline mixed mode cation exchange solid phase extraction (SPE), an online C2 SPE followed by C18 chromatography.

Outcome

Method validated to current regulatory standards and applied to early clinical studies, enabling previously unobtainable pharmacokinetic (PK) data to be generated, ensuring rapid progression of the clinical program.

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