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CASE STUDY: Increasing access for medicinal chemists with LAB2LAB
In the modern drug discovery industry, it is essential for medicinal chemists to have constant access to a wide range of analytical instruments in order to characterize and ensure the integrity of chemical intermediates during a series of reaction steps, to analyze chemical composition after final purification, and for quality control of the compound during storage before or after biological assay. During the synthesis of chemical compound libraries, a number of different specialized, analytical instruments such as HPLC, LCMS, GC/MS, UPLC and sometimes even NMR instrumentation are required.
Such analytical instruments not only require adequate knowledge to ensure efficient use but tend to have high maintenance overheads. It is therefore unrealistic for pharmaceutical companies to install and support instrumentation in every lab and as a result, instrumentation is generally housed in a central analytical lab, supported by specialized analysts. These specialists are trained in machine maintenance and operation ensuring that they are working to the correct specification and that standard analytical methods are adhered to.
With analytical instruments being clustered in a central location, scientists often have to transport their samples between floors or research buildings in order to perform detailed analysis of reaction steps. The need to leave the lab often detracts from the scientist's research flow and uses valuable time. Typically samples are formulated and collated into racks before manually being entered into analytical instrumentation which, in addition, can be a time consuming, error prone and inefficient process. As a result, in order to minimize analysis time between reaction steps, the medicinal chemist is faced with having to use cruder, less informative and costly, lab-based techniques such as HPLC and thin-layer chromatography.
In order to solve the issue of housing analytical equipment in a central unit, TTP LabTech suggested the idea of an automated transport system which is able to send samples to analytical instruments from a remote chemistry lab. It was suggested that by using this system, a medicinal chemist would be able to log in sample details using a PC in their lab and the sample would be transported directly to their chosen analytical instrument. The analytical results would then be returned to their electronic lab notebook (ELN) following processing by instrumentation software.
From this idea TTP LabTech devised LAB2LAB, a pneumatic tube transportation system which is capable of connecting labs from anywhere in the building or across a research site to analytical instrumentation. Using this technology, the medicinal chemist assigns an reference (e,g. an ELN reference) to a bar coded microtube. The scientist places the sample (typically 10-250 uL) in the microtube, scans it and selects one or more analytical methods. The chemist then places the sample in the LAB2LAB sender to transport the vial to the analytical laboratory. The sample may then be sent directly to the most appropriate or available instrument or held temporarily in a buffer until the instrumentation is available. When the selected instrument is available the system presents the microtube to the injection position of the autosampler of the analyzer. The results of analysis is then rapidly returned to the originator's electronic lab notebook and the sample can either be returned to the buffer for further analysis or sent to a collection point or waste.
This system was successfully introduced into the medicinal chemistry group of Novartis's Respiratory Disease Centre (NIBR, Horsham, U.K.) in February 2010. Installation of this system enabled scientists to assess the benefits of remote connection of several chemical laboratories across multiple floors to a central analytical lab located on the ground floor of the building.
In the first phase of installation, six medicinal chemistry laboratories were linked to an Agilent 1100 HPLC for analysis in a central lab. Following this, two Acquity UPLC-MS instruments were linked to LAB2LAB and studies showing a significant increase in productivity were obtained. An example of such a study included a comparison of the time taken for medicinal chemists to submit samples to a single UPLC-MS or two UPLC-MS instruments. From this, it was demonstrated that the addition of a second UPLC-MS instrument to LAB2LAB resulted in a significant reduction in queue time as the number of samples being submitted daily increased (in excess of 100) (See figure below). Data included samples which had been submitted for multiple methods, including methods which would take longer than the standard two-minute reaction monitoring analysis. Additionally, outliers show the effect on queue times as a result of taking an instrument offline for maintenance. In this study it was seen that on a single day where 180 samples were submitted to two UPLC-MS instruments, the average time for the results to be returned into the chemists ELN was 11 minutes, 34 seconds.
In a further study, more than 250 samples were submitted using LAB2LAB by 50 medicinal chemists across six labs. Linking two UPLC-MS instruments to the LAB2LAB network and one HPLC instrument, the average time for results to be returned to the chemists ELN in that day was 30 minutes (with the most results being returned between five and 15 minutes). LAB2LAB was shown to facilitate the sample distribution and queue management, significantly reducing the rate of analysis compared to the traditional manual methods.
Not only does LAB2LAB reduce analysis time but it opens up the opportunity for chemists to use UPLC-MS and other relevant analytical instrumentation to provide detailed information at speeds fast enough to incorporate information from these results into reaction studies, monitoring the integrity of intermediates and enabling the detection of novel entities.
The incorporation of additional analytical instruments (such as Supercritical Fluid Chromatography (SFC) and NMR) into a LAB2LAB network will provide the chemist with a 'virtual instrument' in every laboratory, capable of running a variety of methods on each sample. It is possible to load large numbers of samples directly into the buffer or bulk sender therefore enabling automatic analysis of a compound collection. The ability to retrieve samples from compound store and link them to analytical instrumentation in other laboratories provides the potential for a fully automated solution to drug discovery, adding a new dimension to the efficiency of the drug discovery process. Elimination of the manual transport of samples between laboratories not only reduces health and safety risks but allows scientists to concentrate on science rather than on the laborious process of manually storing and retrieving samples, preparing and transporting them and finally queuing for instrument time.
Drug discovery is a multidisciplinary business and the ability to enhance interactions between chemists and biologists are crucial for the success of modern drug discovery programs today. LAB2LAB has the potential to link scientists working in different disciplines, connecting synthesis to purification, then to compound management and biological assay. This vision of a fully automated system from synthesis to purity to biological testing is a "revolution in compound management" and could help reduce the time taken to develop a new chemical entity into a drug molecule.
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