Bottlenecks in drug discovery drive the need for automated sample management. In small molecule discovery, hardware and software determine how efficiently samples can be stored and used. The options for automation cover a wide range of platform sizes and throughput capabilities, but today’s key element could be flexibility.
“Big-pharma companies have sample collections of millions of samples,” says Kevin Moore, head of markets and applications at Tecan. “These samples need to be retrieved and processed for high-throughput screening or secondary screening.”
Not long ago, screening steps caused some of the biggest slowdowns in drug discovery. “Over the last decade, we’ve seen that screens with selected subsets of compounds for specific assays have outgrown the number of large library screens,” says Donat Elsener, director of sales and marketing at Hamilton Storage. “This shifted bottlenecks from screening to compound management, making the latter that much more critical to automate.”
Compound-management workflow retrieves a sample from storage, processes the sample to the required tubes or plates with liquid handling, and then moves it along for high-throughput or high-content screening, HTS and HCS, respectively. “Most companies store the sample in tubes,” says Moore, “so they don’t have to thaw an entire plate for a couple samples.”
Methods of moving
To a certain extent, pharmaceutical companies want more from less. “To improve efficiency,” says Chris Grimley, vice president of marketing at Labcyte, “pharmaceutical companies continuously strive to increase high-throughput screening capacity without increasing compound usage or increasing space requirements.” That’s no easy task.
Collaborating with AstraZeneca, Brooks Life Sciences, and Titian Software, Labcyte introduced a new acoustic sample management solution. “The solution, which includes the new Access Dual-Robot System and the Echo 655T Liquid Handler from Labcyte, addresses the needs of customers wanting to perform more targeted screens, or ‘smart screening,’ as a more efficient way to identify leads,” Grimley says. When asked about the key benefits of this technology, Grimley adds, “This new sample-management solution enables an increase in high-throughput screening capacity while extending the benefits of non-contact acoustic liquid handling to the earliest stages of sample management to conserve sample material and preserve sample quality.”
A tube might be retrieved to format the sample in a 96-well plate. “You can have a very big system, where it’s all built in—end to end—and the final plate comes out,” Moore explains. “But there’s a trend for more separate systems.”
Tecan’s Fluent Laboratory Automation Solution can work with up 1,536-well plates. “It automates the sample aliquoting to downstream plates,” Moore says. “The key is a small footprint, but with the most dense number of plates.” The platform also needs to make room for disposable tips, source plates, and empty consumables. “Fluent can change from 96- to 384-well heads on the fly,” Moore explains. “That allows more flexibility in terms of plate format and more walkaway time from the systems.”
Image: Fluent’s ability to change MultiChannel Arm™ (MCA) head adapters from 96 to 384 tips ‘on the fly’ allows for higher throughput and flexibility. Image courtesy of Tecan.
Pharmaceutical companies also get flexibility in selecting a system. Another option is the Verso automated sample storage system from Hamilton Storage. This platform “eliminates compound-management bottlenecks by reliably picking tens of thousands of specific compounds per day and delivering them to screening, all in a hands-free manner,” Elsener explains. “When preselecting promising compounds via virtual screening methods, Verso can easily and quickly recall initial hits for use in hit-confirmation.” He adds, “Random access is key, and Verso supports this with automatically generated pick lists, which can be imported from a LIMS for execution.”
This system can also automate sample management for downstream processes, such as toxicity tests, hit-to-lead optimization, dose-response tests, and more. “There is even a trend to increasingly support clinical studies with automated sample management, which is a natural relationship given that good manufacturing practice/good laboratory practice compliance is often better guaranteed with automated processing and documentation,” Elsener explains.
To provide more options, Hamilton Storage developed compact platforms, such as the Verso S1 SE. “This helps small laboratories and contract research organizations to leverage the same sample-management technology applied in big pharmaceutical labs, but on a smaller and affordable scale,” says Martin Frey, vice president at Hamilton Storage.
By offering various options in size and capabilities, vendors give drug discovery companies an opportunity to build the system that works best for them. Finding the right fit, though, often comes down to trying out the options in a specific workflow.
Image: The Hamilton Verso Picker, part of an automated sample storage system, can pick tens of thousands of compounds a day. Image courtesy of Hamilton Storage.
Software is the director
No matter how fancy and sophisticated robotics gets, the controlling software is the brains of the operation. As Moore says, “One of the keys to sample management is the software.” This includes sample tracking: Where is the sample at the start, how can it be retrieved, how much is needed and where is it going and why?
According to Daniel Addison, senior scientist at AstraZeneca, “The AstraZeneca Compound Management group uses high-performance liquid chromatography-mass spectrometry for structure elucidation and purity determination of the AstraZeneca compound collection.” Manual review and interpretation of the results created a bottleneck, despite building a high-throughput process. So, Addison and his colleagues tested data-mining techniques—including classification using WEKA from the University of Waikato and Pipeline Pilot from Biovia—to automate reviewing the outcomes.
“Results were assessed using criteria including precision, recall, and receiver operating characteristic area,” Addison noted. This approach significantly improved the review of the data. For example, Addison pointed out that a 10-tree random forest technique implemented with Pipeline Pilot reduced manual reviews by 45%, which could increase the company’s monthly capacity from 25,00o analyses to 45,000.
In 2018, Clint Cario, then a graduate student at the University of California, San Francisco, and John Witte, professor of epidemiology and biostatistics at the University of California, San Francisco, described Samasy, which stands for: A SAmple MAnagement System. “We were designing a study that required re-sequencing of tens of thousands of DNA samples that had been archived,” Cario says. “When the practical limitations surrounding the physical management of these samples became clear, we saw an unmet need for a simple tracking system that could be used with liquid-handling robots. This led to the creation of Samasy.”
This web-based, sample-tracking platform is simple and visually intuitive. “Users are able to quickly import existing sample information—for example, in Excel format—and can generate batch files, which can be used in concert with Samasy to direct a liquid-handling robot in the process of sample subset transfer,” Cario explains. “The system tracks samples, plates, and batch attributes and displays this information with color-coded overlays and bar charts.” To download and learn more about this tool, click here. This website includes information on getting started with Samasy and a live demo.
Commercial platforms should be expected to include key software capabilities. The Verso, for example, offers specific features like an application program interface that requires little experience to use. “There’s only one simple interface to implement and users can easily access a real-time overview of compound inventories, document all actions, and easily kick-off a dedicated discovery initiative at their fingertips,” Elsener explains.
Similarly, Tecan has taken the usability of the system to the next level by making the Fluent very simple to operate on a daily base with a touchscreen interface. This system comes with routines that run standard tasks, and users can customize steps and processes as needed.
Keeping samples available and usable creates a key element in turning small molecules into treatments. Getting the hardware and software optimized for a specific process, though, can take some experimentation. As the AstraZeneca example shows, some quantitative assessments can turn into big saving or capacity increases. Getting those boosts, however, only comes from taking the steps to test the options.