Publications

Screening methods are a high throughput common approach for accelerating method development for chromatographic separations. Using this approach, several method conditions can be screened in serial or parallel to reduce or eliminate timely method development. However, as the numbers of method conditions are increased, inevitably the amount of time to review and select the optimal condition increases. An automated flexible and dynamic method selection package was implemented to analyze and review both SFC and HPLC screening conditions.

Supercritical Fluid (SFC) and High pressure liquid (HPLC) chromatographic systems were interfaced to single quadrupole mass spectrometric detection. The SFC and HPLC systems consisted of Agilent 1100 LC-MSD’s which include quaternary or binary pumping components, autosampler, Diode Array Detector (DAD) detectors and G1946D MSD Systems. The SFC system also included an Aurora Fusion A5 unit to condition carbon dioxide for use in these experiments. The automated software utilized Analytical Studio Express and Analytical Studio software from Virscidian with customized data interpretation and results visualizations.

The software was validated against a statistically relevant batch of real world discovery phase pharmaceutical chemistries utilizing 6 SFC and 4 HPLC screening methods. In our initial evaluations of the screening results, the system implementation was able to guide the user to select the best method better than 80% of the time for both SFC and HPLC, though we are still currently optimizing selection criteria and do expect improvements. A target of better than 95% in both cases is the ideal goal for the project once it goes into routine operation. The subsequent methods were purified and the success rate of the purification was found to meet or exceed our corporate needs for purified compound for downstream operations. Additionally, the increase in throughput for lab personnel resulted in an overall drop in turnaround time by 15 – 20% though this is still being optimized. Figure1 shows the visualization of an example analysis and results visualization from the approach. This approach was taken to enable our laboratory to use the best in class instrument, automation and software elements in order to deliver the optimize solution. During the presentation we will provide an overview of the system, its implementation, available performance figures, the challenges which were faced and some of the approaches that have been used to solve these issues.

Selective scoring and visualization of the practical separation method conditions for SFC-MS and HPLC-MS methodologies using advanced data evaluation criteria.

Support of Medicinal Chemistry, Compound Collection and our Synthetic Chemists requires our laboratories to deliver purified, confirmed chemistries for downstream activities. Historically sample turnaround times were both variable and often longer than all departments were happy with. Using both internal and external expertize, the entire end-to-end workflow has been revisited, refined and automated with screening results and purified materials now being turned around in 24 hours. This presentation focuses on the challenges there were faced and how these were practically solved and the automation environment that was required to deliver to the project needs.

Synthesis samples from both manual and automated synthesis environments are screened using a combination of low resolution Agilent Single Quadrupole and Agilent 1290 Tof instruments. Purification is accomplished using a mixture of both Waters and Agilent MS directed auto-purification systems. Purified substances are then analyzed for target validation, sample purity and sample homogeneity using a number of Waters uPLC/MS Single Quadrupole instruments. Data are all analyzed using an automated client-server software environment from Virscidian Inc.

The system has now been in operation since summer 2010 and been used in over 50,000 sample analyses. At each stage the results are assessed in the same software application environment against specific evaluation criteria that are appropriate to the stage of the sample. A number of common evaluation criteria across all stages include accuracy of data processing across all detectors but most importantly for the detector(s) used to confirm Area% of the target. Additionally accuracy of target determination and accuracy of the automated results interpretation are also critical. Our preliminary data suggests that once an optimal data processing method is generated for an instrument, that no additional reprocessing of results is required. Indeed where automated results interpretation failure exists, the sample quality is typically not appropriate for further assessment. Indeed the level of results review has dramatically reduced from 100% review of all samples across all phases, to just the samples that are flagged for review and a general low percentage review of the remaining results for quality control purposes. During the presentation, we discuss the challenges that were faced in implementing such a system, an overview of the system that is currently in production usage and expectations for future enhancements to allow for additional automation improvements.

Cross platform integration and automation for a seamless high accuracy system of purified compound production in 24 hours.

Part of our drug discovery philosophy is to commence our lead evaluation with purified lead compounds that have been confirmed for presence and minimum acceptable purity prior to biological activity screening. The goal of a recent quality and performance improvement program was to reduce the time taken to analyze our lead compounds for target presence and purity, purify where necessary and then confirm the dried fraction(s) for target presence and final purity. On starting this improvement project our turnaround times were variable and typically required in excess of 3 – 4 days depending on the laboratory workload. Our goal was to be able to complete the entire turn-around time in 24 hours. Such a target required us to reevaluate our workflow in detail, increase levels of automation, increase quality of the automatically produced analytical results, decrease the time required for results review and reporting in each stage of the process. This presentation aims to describe how we collaborated with an external software company with extensive domain experience and our internal teams to achieve our primary objectives. We discuss the areas that required particular attention and how we have stepwise improved the hardware and software infra-structure with commercially available products, fine-tuned our workflow, optimized the integration of hardware, samples, sample information, and our existing company infra-structure in a cost effective manner.

Screening high volumes of analytical results for quality and consistency of results when it comes to library compound management QC, small to medium automated synthesis support and purification of targets is tedious and costly in terms of required experienced manpower. Our laboratories for analyzing incoming samples are comprised of a heterogeneous array of instrument types and instrument vendors. Our goals at the start of the project were multi-fold. Improve quality of results, reduce the number of false positive results, reduce the number of samples requiring manual reprocessing, and decrease the throughput time from initial QC, purification and post purification QC. Automate the processing of raw data and to create a single consistent output of results that are integrated with our existing inter/intra departmental workflows and corporate infra-structure. In this presentation we would like to share our practical experiences in achieving our primary goals, some of the challenges that we faced prior to implementing the automated approach and how the new workflow has impacted the departmental workflow in a positive way. Already we have seen the cycle time from initial QC of samples to final QC of purified fractions reduced from a variable number of days to around 24 hours.