Achieving Reliable, Trustworthy Data for the Drug Discovery and Development Industry
A drying pipeline. Exorbitant costs. High attrition rates. Over the past decade a lot of negative attention has been focused on problems within the drug discovery and development process. The good, perhaps less widely-discussed news is that identification of these problems and their underlying causes has slowly been fostering big changes in how pharma, biotech and even academic teams find and bring new drugs to market. One company at the heart of all this change is XenoTech, a global Contract Research Organization (CRO) and product provider working to help drug discovery and development teams make critical decisions about their large and small molecule compounds.
XenoTech’s Mission
Officially, XenoTech’s mission is “to lead collaborations with the world’s principal researchers and scientific experts, advancing life-enhancing therapies with unparalleled insight and interpretation through high value products and bespoke services.” Less formally, their goal is to make the world a safer, healthier place by generating high-quality, reliable and reproducible data. In the process, they’re also helping their clients reduce costs and better understand risks inherent within the drug development life-cycle.
“The drugs we’re working on are the future of the market,” says Robert Grbac, Senior Scientist at XenoTech. “Ultimately, we are affecting people’s lives through studies conducted at XenoTech.”
The Beginnings of a World Leader in Drug Metabolism Research
Highlighted in Kola and Landis’s widely discussed 2004 opinion piece1, the early 2000s were a time of worry and introspection for the drug industry. Costs were skyrocketing, timelines growing and the regulatory burden increasing. Kola and Landis’s analysis found what many in the industry were already starting to suspect—problems with safety and efficacy in the later stages of development were two of the biggest causes of attrition in the clinic (data from the year 2000).1 The obvious solution would be to save money and time by identifying candidates with safety liabilities and efficacy problems as early in the process as possible.
One avenue already being explored by a small but growing number of pharma teams at that time was to use data from in vitro drug metabolism studies in an attempt to better predict human drug-drug interactions. As high-throughput technologies matured and the business pressures to identify safer, more effective candidates earlier in development grew, the demand for these types of pre-clinical in vitro studies exploded.2
Enter XenoTech.
Andrew Parkinson, Ph.D., founded XenoTech in 1994, when he saw that development teams needed a partner to conduct drug metabolism studies. As a professor studying xenobiotic metabolism at the University of Kansas Medical Center, he’d been receiving more industry requests to study drug metabolism than his lab could handle. His solution was to form XenoTech, which had exactly the right core competencies in place to help a growing number of drug makers obtain in vitro pre-clinical safety data before moving to the clinical phase.
Xenobiotic n. or adj. A substance not normally found in the body, such as a drug or other chemical compound. First used in 1965 by H.S. Mason, et al, in Federation Proc XXIV. 1172 “Microsomal mixed-function oxidations: the metabolism of xenobiotics.” 3
Fast forward to today. XenoTech is a global leader in drug metabolism, partnering with development teams in the drug, nutraceutical, food additives and cosmetics industries to conduct over sixty different types of assays.
“It would be nice if one application satisfied the majority of clients, but everyone’s study is just a little bit different. So we have to be flexible and accommodating to ensure return business,” says Grbac.
As technology changes and drug makers push to get safety and toxicity answers even earlier in the process, XenoTech has evolved and entered into the early drug discovery arena. Their newest launch, the Discovery Plus Suite, provides core screening assays ranging from CYP Inhibition, Metabolic Stability, Plasma Protein Binding, CYP Induction and Bi-permeability assays.
XenoTech: All About Quality
“The data we gather is used by our clients to decide where to go next in their discovery and development programs and navigate the regulatory process, so it’s imperative that the data we produce are accurate and reliable,” says Grbac. “We want there to be as few false positives or negatives as possible, because we are one of the last stops before a compound goes into human trials.”
With so much riding on the data they deliver, data quality, reliability and reproducibility are absolutely critical to the XenoTech team. They push their assays to be as precise and accurate as possible, starting by having instruments that routinely transfer volumes within 6% accuracy and 3% precision for volumes 10 µl and over, and 9% accuracy and 4.5% precision for anything less than 10 µl (read Artel’s “Lab Report 4: Defining Accuracy and Precision” to learn more about these measures of data quality). When volume transfers are this reliable, the data produced by the resulting assays are much more likely to fall within favorably narrow precision and accuracy windows. XenoTech’s internal standard operating procedures (SOPs) require replicate samples to be within 20% standard deviation, a very stringent specification.
Achieving this level of consistency is dependent on having well-maintained, automated liquid handlers. With ten Tecans running a wide range of applications, monthly maintenance and volume transfer verification are very important. Not only does the team need to be sure they can trust their instruments are transferring, say, 10 µl and not 9.8 µl, they need to be able to tell if a robot is starting to drift out of spec. Each day a single Tecan is down translates into $10,000 in lost revenue.
Utilizing Artel Technology to Ensure Quality Data
To keep instruments operating within specifications and minimize downtime, Ryan Mueller, Automation Scientist and Engineer at XenoTech, performs monthly volume verification checks using the Artel MVS®. In four hours, he’s able to verify the performance of all ten liquid handlers—down from forty-plus hours when the team was using gravimetric methods for volume verification. The data on every instrument is saved, all the way back to 2008 when XenoTech first brought Artel in house. This ensures they can track performance over time and predict when one of the instruments is starting to drift off spec. By identifying potential problems before they happen, Rob and his team can better manage assay workflow while replacing worn parts and minimizing costly downtime.
“Sometimes when we start seeing anomalous data from our liquid handlers, we’ll troubleshoot with the Artel system, and if we have to replace any parts we’ll perform a post-change verification with Artel. Between troubleshooting and monthly maintenance, we might be “Artelling” an instrument three times in a single month,” says Mueller.
More recently, XenoTech’s automation team implemented the new software, which has made tracking instrument performance even easier. Instead of having to manually enter individual instrument data into a giant spreadsheet—which was prohibitively time-consuming—they now upload all their existing Artel volume measurements to the software, which allows them to see individual instrument data already plotted and graphed. Trends are even easier to spot, streamlining their ability to take cost-saving preventive maintenance actions.
“Once we brought Artel into the lab, we realized we could push to small volumes. We typically work beyond the liquid handler’s specifications, and we can do this because we have Artel to verify their performance,” says Grbac.
With Artel in place, XenoTech was able to miniaturize many of their assays, moving from 48-well plates in 2008 to 96- and 384-well plates in today’s assays. Increasing throughput while maintaining quality means faster timelines for their clients and more efficient processes overall.
XenoTech: In Conclusion
One of the constant challenges the XenoTech team faces is keeping up with the rapid pace of change in the industry and regulatory requirements. For example, as assays move from using subcellular fractions and microsomal proteins to being cell-based, they’ve needed to redevelop many of their assays, and even create new ones. Whether using monolayer cells, suspension cells, or new three-dimensional matrices, the XenoTech team is constantly exploring and innovating to provide clients with the most informative data possible.
At the end of the day, the XenoTech team needs to deliver quality data in a timely fashion. With the throughput and timelines they need to meet, there’s typically no time for repeating a study or a set of samples—everything has to run correctly the first time. Starting with rigorous maintenance and attention to instrument performance and continuing with careful assay design, execution and data analysis, XenoTech is able to deliver unparalleled data that helps drug developers make critical decisions. They go home satisfied that they are doing their part to make the world safer one drug at a time (or sixteen if you are running a Discovery Plus panel)!
References:
- Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery. Vol 3, 711–716 (2004).
- Hofer, C. Perspectives for ADME/Tox Integration in the Discovery Process; Winter 07.Drug Discovery World
- xeno-, comb. form. OED Online
About XenoTech
XenoTech is a premier provider of in vitro drug metabolism and drug-drug interaction studies to pharmaceutical companies worldwide. We have unparalleled experience in evaluating drug candidates as substrates, inhibitors and inducers of drug-metabolizing enzymes. Core capabilities include Enzyme Inhibition, Enzyme Induction, Drug Metabolism, Drug Transport and Analytical Services.
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