Benefits of an automated GLP final report preparation software solution.

The final product of analytical laboratories performing US FDA-regulated (or GLP) method validation and bioanalysis studies is the final report. Although there are commercial-off-the-shelf (COTS) software/instrument systems available to laboratory managers to automate and manage almost every aspect of the instrumental and sample-handling processes of GLP studies, there are few software systems available to fully manage the GLP final report preparation process. This lack of appropriate COTS tools results in the implementation of rather Byzantine and manual processes to cobble together all the information needed to generate a GLP final report. The manual nature of these processes results in the need for several iterative quality control and quality assurance events to ensure data accuracy and report formatting. The industry is in need of a COTS solution that gives laboratory managers and study directors the ability to manage as many portions as possible of the GLP final report writing process and the ability to generate a GLP final report with the click of a button. This article describes the COTS software features needed to give laboratory managers and study directors such a solution.

An integrated bioanalytical platform for supporting high-throughput serum protein binding screening.

Quantification of small molecules using liquid chromatography/tandem mass spectrometry (LC/MS/MS) on a triple quadrupole mass spectrometer has become a common practice in bioanalytical support of in vitro adsorption, distribution, metabolism and excretion (ADME) screening. The bioanalysis process involves primarily three indispensable steps: MS/MS optimization for a large number of new chemical compounds undergoing various screening assays in early drug discovery, high-throughput sample analysis with LC/MS/MS for those chemically diverse compounds using the optimized MS/MS conditions, and post-acquisition data review and reporting. To improve overall efficiency of ADME bioanalysis, an integrated system was proposed featuring an automated and unattended MS/MS optimization, a staggered parallel LC/MS/MS for high-throughput sample analysis, and a sophisticated software tool for LC/MS/MS raw data review as well as biological data calculation and reporting. The integrated platform has been used in bioanalytical support of a serum protein binding screening assay with high speed, high capacity, and good robustness. In this new platform, a unique sample dilution scheme was also introduced. With this dilution design, the total number of analytical samples was reduced; therefore, the total operation time was reduced and the overall throughput was further improved. The performance of the protein binding screening assay was monitored with two controls representing high and low binding properties and an acceptable inter-assay consistency was achieved. This platform has been successfully used for the determination of serum protein binding in multiple species for more than 4000 compounds.

Validation of a high-throughput absorption, distribution, metabolism, and excretion (ADME) system and results for 60 literature compounds.

A high-throughput analytical system for the support of absorption, distribution, metabolism, and excretion (ADME) was constructed in collaboration with Gubbs Inc. to commercialize corresponding software. We sought to quickly build and validate this system for microsomal clearance assessment using 60 commercially available non-proprietary compounds that are non-DEA-restricted in addition to 36 proprietary Millennium compounds that had already been assessed using a low-throughput infrastructure. The system was constructed such that a approximately 45 second total cycle time was achieved injection-to-injection. Software was successfully coded to enable the analyst to submit multiple batches, and modify multiple methods very quickly for use with Applied Biosystems Analyst 1.3. After acquisition the software was used to simultaneously integrate multiple injection chromatograms, regress the data, and calculate clearance such that all of the data could be easily and immediately reviewed by both bioanalytical and enzymology personnel. Unfortunately, despite an exhaustive search of the literature, we were unable to find a large number of non-proprietary compound data for validation, so we provide such a source of data here. Results are presented for the 60 literature compounds that were assessed. A good correlation was observed between literature results for 16 compounds that we were able to find and the results obtained using the system. The Millennium proprietary compounds that we assessed using both low- and high-throughput approaches also correlated well. We present here a system for the support of high-throughput in vitro ADME analysis and also present the results of 60 non-proprietary, non-DEA-scheduled compounds to facilitate the validation efforts of others. Finally, we present commercially available software to facilitate high-throughput ADME systems in the community.