Introduction

The journey from bench to bedside is a long one in the world of pharmaceutical research, entailing large expense, complex processes and, often, dead ends. It is estimated that the cost of bringing a new drug to the market is around $2.6 billion and takes at least 10 years. And the odds of a drug entering clinical testing ever reaching the market are less than one in eight, and at this point, the costs of failure can be so high as to prevent turning back. At the same time, there are growing pressures within the pharmaceutical industry to reduce costs and increase productivity.

Improvements in analysis within the earliest stages of drug development of drug candidate identification, optimization and selection could both improve success rates and reduce expenditure in pharmaceutical development.

At Pittcon 2018, taking place in Orlando, Florida in February 2018, you can hear about some of the latest developments in technology assisting analysis and automation in pharmaceutical research.

For example, members of the Enabling Technologies Consortium will discuss how collaboration between pharmaceutical companies is helping to overcome shared obstacles in drug development. This includes GlaxoSmithKline, who have teamed up with other pharmaceutical companies to test robotic platforms for accurate, automated dispensing of solids and AstraZeneca who have worked on combined efforts to improve the measurement and prediction of API solubility.

You can also hear from speakers and exhibitors about advancements in high-throughput screening, assisted by the latest developments in automation and robotics. For example, Life Technologies will discuss their SelectScreen service which allows their clients to review the majority of their compound screening data within two days. David Damon from Pfizer will also discuss high-throughput screening of Lewis acids.

At Pittcon 2018, there will also be the opportunity to hear about the latest available technology for liquid chromatography and mass spectrometry. For example, Jonathan Wingfield from AstraZeneca will describe the success of a recently developed acoustic ion generation method to enable a high-throughput mass spectrometry platform.

There will also be presentations from ThermoFisher on paper spray technology, while Waters, Porvair, PharmaFluidics and Restek are among the other exhibitors.

In the next few chapters, you can find out more about what to expect at Pittcon 2018, as well as more of the exciting talks and exhibitors you can meet in Orlando this February.

References

• Larkin M (2015). Breaking bottlenecks in drug discovery and development. Available at:https://www.elsevier.com/connect/breaking-bottlenecks-in-drug-discovery-and-development Accessed: December 2017
• Forum on Neuroscience and Nervous System Disorders; Board on Health Sciences Policy; Institute of Medicine. Improving and Accelerating Therapeutic Development for Nervous System Disorders: Workshop Summary. Washington (DC): National Academies Press (US); 2014 Feb 6. 2, Drug Development Challenges. Available from: https://www.ncbi.nlm.nih.gov/books/NBK195047/
• Welch CJ, Faul MM, Tummala S, et al. The Enabling Technologies Consortium (ETC): Fostering Precompetitive Collaborations on New Enabling Technologies for Pharmaceutical Research and Development. Organic Process Research & Development 2017; 21: 414-419

Chapter 1 – Collaborations on enabling technologies for pharmaceutical research

The pharmaceutical industry faces a number of challenges when it comes to developing new enabling technologies. Liaison between pharmaceutical researchers and academics and vendors can result in successful development and evaluation of prototype inventions and products for use in research. However, these types of collaborations can lead to products designed with only one pharmaceutical company in mind and may not be useful across the industry.

Collaborations between single pharmaceutical companies and academics or vendors also suffer from this issue, while collaboration between pharmaceutical companies – an increasing trend – can be complicated and delayed by the need for complex legal agreements.

In recognition of this, 2015 saw the formation of the Enabling Technologies Consortium (ETC), a collective of pharmaceutical companies collaborating to deliver mutually beneficial solutions to challenges in pharmaceutical manufacturing.

The Consortium was founded with 12 members: AbbVie, Amgen, AstraZeneca, Biogen, Boehringer-Ingelhaim, Bristol-Myers Squibb, Celgene, Eli Lilly & Co., GlaxoSmithKline, MSD, Pfizer Inc., and Takeda.

Currently, the ETC is focused on collaborations addressing “issues related to pharmaceutical chemistry, manufacturing, and control with the goal of identifying, developing, evaluating and improving scientific technologies that enable the rapid and efficient discovery, development, and manufacturing of pharmaceuticals.”

Examples include the development of new instruments, reagents, computer models or research workflows. Transparency is one of the Consortium’s guiding principles and at the conclusion of each project, the results are shared with the rest of the pharmaceutical industry.

At Pittcon 2018, you have the opportunity to hear from the teams who have taken part in ETC collaborations talk about the challenges they’ve faced and the solutions they’ve found.

For example, Matthew Bahr from GlaxoSmithKline will be outlining the work of the High Throughput Experimentation working group which has been comparing potential technologies for the automated dispensing of solids, which still remains a challenge for the industry.

The group tested multiple robotic platforms to compare their ability to accurately weigh powder into vials using a range of powders under different lab conditions at five pharmaceutical companies, collecting a total of 18,000 data points.

We will also be joined by exhibitors Enviroflo, a company who provide balance enclosures specifically designed for the handling of potent powders to pharmaceutical companies around the world and Bettersize whose instruments provide data on powder characteristics like particle size, shape, and distribution.

Also exhibiting at Pittcon are Systec and HNO Mikrosysteme who have technologies for liquid dispensing. HNQ Mikrosysteme market pumps for dosing small amounts of liquid quickly and accurately. They also provide integrated systems like the MoDos (modular dosing system), a tailor-made, ready-to-use pump system for continuous delivery in fine chemical and pharmaceutical production.

Systec, through their Mediaprep instruments, provide automatic media preparators for the preparation of sterile liquid media such as agar culture media, peptone water and buffer solutions. Their optimized automation allows for predictable production of high-quality media, while the filling port allows additives to be added while maintaining sterility.

Regina Black from Bristol-Myers Squibb will be talking at Pittcon 2018 about another ETC collaboration aimed at developing a new generation of supercritical fluid chromatography (SFC) instruments.

This technique is employed ubiquitously in the pharmaceutical industry for rapid small molecule purification, but the “gold standard” instrument has fallen out of production. This has led to questions for pharmaceutical companies about what instruments to replace equipment with that has reached the end of its life. In this talk, Black will discuss the experience of participating in an ETC collaboration that aims to develop new instrumentation that will best meets the needs of its users.

SFC has been widely used in the pharmaceutical industry for around the last 15 years for the measurement and enhancement of purity. The method, which primarily uses supercritical CO2 as a solvent also benefits from green credentials.

Scientists from Waters Corporation, who will be exhibiting at this year’s Pittcon, have shown how using supercritical fluid extraction (SFE) and SFC can increase productivity when extracting compounds from natural products.

The team studied the extraction of a terpene derivative known to have anti-cancer activity from fine-ground plant material. They performed SFE before trialling three different two-step methods of purification: medium-pressure liquid chromatography (MPLC) and high-pressure liquid chromatography (HPLC); MPLC and SFC; or SFC and SFC.

The researchers found that, compared with MPLC+HPLC, MPLC+SFC resulted in a nine-fold increase in productivity. But SFC+SFC resulted in a 16-fold increase in productivity and also benefited from a 90% reduction in solvent use.

Also exhibiting at Pittcon 2018 will be Phenomenex and ES Industries, providers of SFC instrumentation. ES Industries range of GreenSep columns are specifically designed for SFC applications to deliver high-performance SFC separations. Phenomenex, meanwhile, offer a complete range of columns and accessories for HPLC/UHPLC and SFC.

Simon Yates from AstraZeneca will talk about an ETC collaboration that has involved pharmaceutical companies working together to be better able to measure and predict the solubility of active pharmaceutical ingredients and drug intermediates. The sub-team shared data with each other to develop a best practice model and the talk will detail their results so far. They now plan to publish these and seek commercial partners for the development of equipment and software tools.

Also available at Pittcon will be representatives from Distek who specialize in instruments for measuring dissolution, a critical parameter in drug delivery. This includes the Distek symphony 7100, their most advanced instrument, which combines bathless technology with embedded temperature sensors, the ability to run three independent methods simultaneously and a color touch screen display.

References and Further Reading:

• Desfontain V, Guillarme D, Francotte E, et al. Supercritical fluid chromatography in pharmaceutical analysis. Journal of Pharmaceutical and Biomedical Analysis 2015; 113: 56-71
• Lemasson E, Bertin S & West C. Use and practice of achiral and chiral supercritical fluid chromatography in pharmaceutical analysis and purification. Separation Science 2016; 39: 212-233
• McCauley J, Jablonski J, Aubin A, et al. Improving the productivity in isolating a naturally occurring bioactive compound using supercritical fluid extraction and preparative supercritical fluid chromatography. Available at: http://www.waters.com/webassets/cms/library/docs/720005168en.pdf. Accessed: November 2017
• Welch CJ, Faul MM, Tummala S, et al. The Enabling Technologies Consortium (ETC): Fostering Precompetitive Collaborations on New Enabling Technologies for Pharmaceutical Research and Development. Organic Process Research & Development 2017; 21: 414-419

Pittcon Tracks

Chapter 2 – Automation in the Pharmaceutical Research and Development Laboratory

High-throughput screening (HTS) has become a cornerstone of pharmaceutical research in the post-Human Genome Project era. The approach allows the rapid analysis of 1000s of chemical compounds at a time, something which has been instrumental in identifying small-molecule drug candidates, for which genomic research throws up dozens of targets. HTS first gained traction as a drug-discovery tool in the late 1990s and several drugs have since come to the market that owe their existence to the approach.

HTS has a number of advantages for the pharmaceutical industry. The method employs robotics, detectors and software to screen and assay a large number of chemical compounds against a target, sometimes ranging to 100,000 per day. This has created huge potential for accelerating drug discovery, particularly given that chemical synthesis can generate huge libraries of novel compounds.

HTS can reduce the costs of drug development and has facilitated drug discovery efforts in previously neglected disease areas. It also allows for the early determination of compound toxicity.

The emergence of HTS as a critical tool for drug discovery has been underpinned by developments in robotics and automation. At Pittcon 2018, you will be able to meet the companies who are developing the latest technologies for use in HTS. David Damon from Pfizer Inc will discuss the development of workflows for the HTS of Lewis acids. These acids are routinely used in the development of chemical processes to prepare active pharmaceutical ingredients.

Also at Pittcon 2018 will be Life Technologies, part of ThermoFisher Scientific, who have developed an online web portal called SelectScreen, which allows their customers to view real-time screening data. Typically, when scientists outsource compound screening and profiling, it takes around 5-15 days for a report to be delivered to the client. With the SelectScreen workflow, the team at Life Technologies have shown that clients receive 75% of their data on average within the first two days.

This year’s Pittcon will also feature numerous exhibitors providing a range of automated instruments that can be applied in HTS including Metrohm International. Their automated sample preparation system, the 815 Robotic Soliprep, can be used for a range of applications, including in ion chromatography, HPLC, ICP, voltammetry and titrimetric applications to ensure uniform sample preparation at every step. Their scientists have demonstrated that the instrument can be used for the homogenisation of pharmaceutical tablets, as is required for accurately quantifying the ingredients and verifying the active pharmaceutical ingredient.

Beckman Coulter provide a range of integrated automation solutions to assist optimizing lab throughput. Their Biomek automated liquid handlers allow lab scientists to reduce their hands-on time during drug discovery research and can be integrated into complete workflows, including from third party devices, such as bar-code readers, microplate centrifuges and temperature-controlled storage. Beckman Coulter will also be exhibiting at Pittcon 2018.

References

• Janzen WP. Screening Technologies for Small Molecule Discovery: The State of the Art. Chemistry & Biology 2014; 21: 1162-1170
• Lasky D, O’Banion M & Harvey M. Accelerating Delivery of Compound Profiling Data to Enable Faster Discovery Decisions. Available at: https://www.thermofisher.com/content/dam/LifeTech/global/services/pdfs/Accelerating%20Delivery%20of%20Compound%20Profiling%20Data%20to%20Enable%20Faster%20Discovery%20Decisions.pdf. Accessed: November 2017
• Macarron R, Banks MN, Bojanic D, et al. Impact of high-throughput screening in biomedical research. Nature Reviews Drug Discovery 2011; 10: 188-195
• Steinbach A. Sample preparation for tablet analysis. Available at: http://www.metrohm.ru/Downloads/Application/PharmEng/1116743_TA-006_EN.pdf. Accessed: November 2017
• Szymański P, Markowicz M & Mikiciuk-Olasik. Adaptation of High-Throughput Screening in Drug Discovery—Toxicological Screening Tests. International Journal of Molecular Science 2012; 13: 427-452

Chapter 3 – Mass Spectrometry and High Throughput Screening for Drug Discovery

Over the past 20 years, electrospray ionization mass spectrometry has been applied widely across areas including proteomics, metabolomics and imaging. In drug discovery, the qualitative and quantitative approach offers a sensitive, reliable and robust tool for studying molecules of interest at low concentrations, as well as macromolecules that are difficult to study with other techniques.

Electrospray ionization involves spraying a sample using an electrical field, leading to the formation of charged droplets. Following desolvation, the ionized analytes can then be detected with a standard mass spectrometer.

At Pittcon 2018, you can hear Jonathan Wingfield from AstraZeneca discuss a collaboration between the company with Labcyte and Waters to develop a high throughput mass spectrometry platform.

It uses acoustic ion generation, similar in principle to electrospray ionization, which the team refer to as Echo-MS. It involves a modified acoustic liquid handler which ejects a mist of droplets directly from a 384-well assay plate. These are ionized as they pass through a transfer tube which delivers them into the mass detector.

The team have already demonstrated that it could screen 300,000 samples during a single assay, using manual plate loading and they have now adapted it using an automation to feed plates into the system, allowing a screen of around two million samples.

At Pittcon, Wingfield will discuss the high throughput data so far collected using this prototype system as well as present recent work demonstrating how it could be applied in drug discovery.

Waters, whose mass spectrometry devices were used in the prototype will also be exhibiting at Pittcon.

Their MS instruments enable maximal performance in pharmaceutical analysis from pre-clinical testing to clinical trials. Scientists from the company have recently demonstrated how a high-sensitivity method coupling UPLC to tandem MS could be used to study the pharmacokinetics of the asthma drug fluticasone proponate in the blood serum of rats, even though it circulates at concentrations as low as 10 pg/mL.

Porvair, who offer microplates and assay plates for all applications including sample preparation and high-throughput screening, will also be exhibiting at Pittcon 2018.

Liquid chromatography/mass spectrometry in the pharmaceutical industry

Liquid chromatography- tandem mass spectrometry (LC-MS/MS) has become a mainstay at all stages of pharmaceutical development. The expansion of mass spectrometry into the industry was accelerated by the advent of electrospray ionization, a nobel-prize winning achievement that allows for the ionization and analysis of large bio-molecules.

Exhibiting at Pittcon 2018 will be ThermoFisher Scientific who offer a range of LC-MS systems, software and accessories.

Scientists from the company have recently shown the potential of paper spray technology for fluid analysis. The direct-ionization method could provide a simpler and more rapid method for studying blood and urine samples, in clinical research, forensic toxicology and in anti-doping in sport or horse-racing, without the need for extensive sample pre-treatment and chromatography.

The team from ThermoFisher tested the approach using horse urine samples spiked with methamphetamine and other stimulant drugs. Using a triple-quadrupole mass spectrometer, they were able to perform quantitative analysis of seven different analytes.

References

• Ghislain L, Bachman M, Sinclair I & et al (2017). High-Throughput Mass Spectrometry: Direct Acoustic Ionization for Sub-Second Sample Processing. Available at: https://www.labcyte.com/media/pdf/POS-High-throughput-Mass-Spec-SLAS2017-Ghislain.pdf. Date accessed: December 2017
• Gu C, Lin B, Pease J, et al. (2015) Mass Spectrometry in Small Molecule Drug Development. Available at: http://www.americanpharmaceuticalreview.com/Featured-Articles/179230-Mass-Spectrometry-in-Small-Molecule-Drug-Development/. Date accessed: December 2017
• Ho C, Lam C, Chan M, et al. Electrospray Ionisation Mass Spectrometry: Principles and Clinical Applications. The Clinical Biochemist Reviews. 2003; 24(1): 3-12
• Joshi K and Patil D, Chapter 9 – Proteomics, In Innovative Approaches in Drug Discovery, edited by Patwardhan B and Chaguturu R, Academic Press, Boston, 2017, Pages 273-294, ISBN 9780128018149
• Mather J, Graham K, Rodriguez Cabaleiro D, et al. (2012) Quantification of Fluticasone Propionate and Salmeterol Xinafoate in Plasma at the Sub pg/mL Level Using UPLC/MS/MS. Available at: http://www.waters.com/webassets/cms/library/docs/720004340en.pdf. Date accessed: December 2017
• Olin M, Prieto Conaway MC, Kennedy J, et al. Method Development Considerations for Paper Spray Mass Spectrometry – Direct Ionization Technique for Physiological Fluid Analysis. Available at: https://tools.thermofisher.com/content/sfs/posters/PN-64926-LC-MS-Paper-Spray-Horse-Urine-MSACL2017-PN64926-EN.pdf. Accessed: December 2017
• Sinclair I, Stearns R, Pringle S, et al. Novel Acoustic Loading of a Mass Spectrometer: Toward Next-Generation High-Throughput MS Screening. Journal of Laboratory Automation 2016; 21(1) 19–26

Chapter 4 – Recent Advances in Liquid Chromatography

Liquid chromatography-mass spectrometry (LC-MS) was first pioneered in the 1970s, but it continues to be an important method throughout the pharmaceutical industry such as in pharmacokinteic analysis, in proteomics and metabolomics and drug development. As samples become increasingly complex in biomedical research, sample preparation and separation techniques have been adapted and developed to cope with these challenges.

At this year’s Pittcon, you can hear from researchers who have been refining a 2D-LC method for use in polymer conjugated drug development.

Polymer conjugation has become a valuable method in drug development. It works by conjoining the drug of interest to a polymer, such as polyethylene glycol, which then alters its in vitro and in vivo properties. Commonly, the aim is to reduce side effects, such as by targeting the drug to a specific organ or tissue, or to prolong the drug’s lifespan before it is cleared from the body.

However, characterizing polymers using conventional techniques is challenging. Standard HPLC is unable to separate polymer species which may have different properties but only subtle structural differences. Meanwhile electrospray MS results in a highly convoluted charge distribution profile, preventing their identification.

To overcome these obstacles, researchers used 2D-LC on a complex polymer sample mixture to separate degradants and impurities from the polymers. They then followed this up with charge reduction mass spectrometry to deconvolute the polymer distributions to lower charge states, and thus identify the resolved peaks.

The researchers used quadrupole-time-of-flight mass spectrometry (Qtof), a method which offers high sensitivity and high mass accuracy. It has grown more and more popular due to increasing performance characteristics, and the recent expansion of semi-automated instrument control and data processing.

Exhibiting at Pittcon 2018 will be Waters, who offer high-performance Qtof mass spectrometers for comprehensive quantitative and qualitative applications. This includes the Xevo G2-XS, a benchtop Qtof mass spectrometer that offers the highest quality qualitative information alongside class-leading quantitative sensitivity. The technology is able to identify a greater number of components in complex samples than ever before, as well as quantify those of interest even at the lowest levels.

Also exhibiting at this year’s Pittcon will be PharmaFluidics, whose µPAC cartridge can be used to achieve nano-LC separation, decreasing sample preparation, increasing throughput and enhancing analytical results.

Restek, who have been developing and manufacturing LC columns for the last 21 years, will also be exhibiting at Pittcon 2018. They have a range of columns for use in HPLC and UHPLC, including their ultra selective LC column, which offers the widest range of selectivity in the industry, to enhance peak separation and resolution.

Other exhibitors at Pittcon 2018 include Metrohm, whose range of ion chromatography instruments can be applied for routine analysis or in research and development. This important method for determining active and inactive ingredients, impurities, excipients and metabolites in pharmaceutical products can be used for characterising components ranging from trace contaminants up to major pharmacological components.

Also at Pittcon will be Phenomenex who offer a complete range of columns for HPLC and UHPLC, as well as Valco Instruments, who provide injectors, valves, selectors and fittings for use in UHPLC and nano-LC.

References

• Dixon, S. P., Pitfield, I. D. and Perrett, D. Comprehensive multi-dimensional liquid chromatographic separation in biomedical and pharmaceutical analysis: a review. Biomed. Chromatogr 2006; 20: 508–529
• Grigoletto A, Maso K, Mero A, et al., Drug and protein delivery by polymer conjugation. Journal of Drug Delivery Science and Technology 2016; 32: 132-141
• Lin C-K & Lord G. Current Developments in LC-MS for Pharmaceutical Analysis. Biol Pharm Bull 2002; 25: 547-557
• News-medical.net (2017). Trends and Developments of-Ion Chromatography in Pharmaceutical Analysis. Available at: https://www.news-medical.net/whitepaper/20170809/Trends-and-Developments-of-Ion-Chromatography-in-Pharmaceutical-Analysis.aspx. Accessed: December 2017

Conclusion

As the pharmaceutical industry continues to face the challenges of the high failure rate of candidate drugs in clinical trials and the pressure of reducing expenditure, accurate, fast and reliable analytical methods will continue to be essential.

The rise of automation and robotics looks certain to have a major impact on early drug development, including enhancing the speed of screening. Meanwhile advances in spectroscopy methods should allow better characterization of candidate molecules at an earlier stage, giving greater ability to predict efficacy and toxicity and lower the risk of costly failures.

At this year’s Pittcon you can discover how the latest technologies are helping pharma overcome hurdles in early drug development. This includes analytical methods, like multi-dimensional liquid chromatography and direct ionization mass spectrometry, and advances in automation and robotics.

Major players in the industry will be presenting at the Pittcon exhibition, and you can also hear from experts in the field in the impressive range of talks and symposia.

Featured companies joining us at Pittcon this year include ThermoFisher Scientific, Restek, Metrohm, Waters Corporation, AstraZeneca, GlaxoSmithKline, Pfizer and more, all of which will be demonstrating the latest technologies for automation in pharma – join us in February in Orlando, Florida for Pittcon 2018.