Increasing R&D Efficiency from the Bench Up: A Strategic Look at Simplifying Laboratory Operations

By Richard Lake, Pharmaceutical Market Development Manager, Restek Corporation

My shipmates, we, towards that dark tunnel must sail. – OK, I admit, that’s probably overly dramatic, but sailing through these dark economic times will certainly prove to be an odyssey of its own. Today’s economic climate seems to be more than just a normal cyclical downturn, such as those the industry has experienced in the past. Multiple factors are culminating in a perfect storm that is driving us into an extremely dynamic marketplace. Many believe it is likely that we could experience a wholesale restructuring of our industry. Let’s look, for instance, at two well-known and over-riding market facts—the threat of looming patent expirations coupled with the decreasing number of new drug approvals. These two factors are spawning substantial mergers and acquisitions, in attempt to diversify drug portfolios and minimize the effects of future revenue losses caused by reduced sales of products with expiring patents. This has changed the face of the industry, and it is likely to keep changing. What will the pharmaceuticals landscape look like when we emerge from the dark tunnel? What will be our new normal?

Adapting to a Dynamic Market
As Francis Bacon warned, “He that will not apply new remedies must expect new evils.” We must prepare ourselves for these new market dynamics by pragmatically reviewing and improving our practices, from synergistic business strategies all the way to streamlined R&D operations. Big Pharma accounts for well over half of the industry’s expenditures on research and development and changes there ripple throughout the industry. As Big Pharma adopts a strategy of cutting portfolios and putting more emphasis on biologics as a means of making R&D more efficient, this becomes a driver for other market changes. Competition among CROs and CMOs is increasing in response, as they vie for shares of this shrinking market. Overall, industry trends are making operational efficiency become a matter of survival and, as a result, cost-cutting exercises and synergistic business operations are being developed and applied where needed. While these are effective ways to focus our business practices in response to a changing marketplace, we can further improve long-term profitability by switching our view from 30,000 feet above to an on-the-ground look at the lab bench level. In this article we will discuss some simple laboratory, not business, practices that can increase research efficiency and subsequently reduce drug development timelines – simple, practical remedies for the drug pipeline.

Designing Data Quality
Definitive work doesn’t occur by accident and the increased emphasis by regulatory agencies, namely the FDA, on process analytical technology (PAT) and quality by design (QbD) is driving changes at the bench. This initiative, implemented through a draft guidance that outlines a system for designing, analyzing, and controlling manufacturing processes, is consistent with the belief that quality is built into a product through design, and is not simply an emergent property of testing. This requires analytical methodology that can accurately, efficiently, and reliably measure the quality of our manufacturing processes. Experimental design and data quality are fundamental; efficient lab practices can help us improve data quality, which is the precursor to achieving the overriding goals of QbD, regulatory compliance, and pipeline productivity. Let’s look at some specific examples of how efficient laboratory operations contribute to data quality.

Implement Smart Technology
Design of experiment (DOE) is a popular statistical approach designed to quickly and systematically evaluate process optimizations and validations. This is an excellent example of an efficient development strategy. However, when we seek operational efficiency beyond experimental design and focus more on the actual laboratory elements, the first and most fundamental consideration is the technology used. The technological investments we make must be focused on both data quality and lab productivity. While systemic tools, such as laboratory information management systems (LIMS), build in quality and control, chromatographic systems also can have a dramatic impact on lab operations, data quality, and ultimately pipeline efficiency. When we consider chromatography technology there are three areas of development that are most significant to the pharmaceutical industry. They are (1) the implementation of fast LC through ultra-high pressure liquid chromatography (UHPLC), (2) the increased applicability of sophisticated analyte detection, such as LC mass spectrometry (LC/MS) and charged aerosol detection (CAD), and (3) the development of novel column chemistries. These three factors are major contributors to the development of pharmaceuticals and are substantial considerations in supporting the goals of both effective QbD and improved operational efficiency.

Of these three factors, novel column chemistry is the most powerful and cost-effective, as it contributes to both better asset utilization and accelerated method development. Consider its effect on UHPLC, a technology that is fueling exciting new growth potential by speeding up chromatographic separations and accelerating analytical time tables. UHPLC, when coupled with novel column chemistry and MS or CAD detection, can improve data generation rates as well as overall data quality. UHPLC, LC/MS, and novel column chemistry should be viewed as complementary advances that should be dovetailed together, not as separate technology choices.

A timely example of how strategic column and platform choices can be combined to affect overall operational efficiency is in providing the adaptability needed to address the recent acetonitrile shortage. Acetonitrile is probably the most commonly used organic solvent in the pharmaceutical laboratory. During the recent shortage, some labs were notified that it was being rationed, often below their consumption levels. Even when an adequate supply could be obtained, costs rose significantly — in some cases up to 6 or 7-fold. In hindsight, labs that had already implemented UHPLC and novel chemistries for efficiency reasons were also much better positioned to minimize the impact of the acetonitrile shortage. Solvent consumption can be reduced by 10-fold with UHPLC, a benefit further enhanced by novel chemistries, such as the Biphenyl phase, which perform well in alternate solvents and allow easy switching of method development practices to more available and cost-effective organic solvents.

Improve Asset Utilization
It is easy to see that the choices we make in platform technology have a direct impact on our productivity. These are capitol expenditures that are often carefully considered prior to purchase. However, to maximize analytical laboratory efficiency, consumables must also be evaluated — a calculated choice in LC column today extends the lifetime, performance, and profitability of the instrument asset tomorrow. Choosing an optimal separation mechanism, one in which the proper column is utilized, allows the use of mobile phases that are more advantageous to system performance. For example, a Biphenyl column can improve MS system performance, due to its enhanced performance with high organic content mobile phases.

While we often think of resolution as the primary factor contributed by the analytical column, it is not always the most important one. For example, when using an MS detector, resolution may not be as important as simple retention, since the mass spectrometer can identify compounds based on unique ion transitions. In this case, choosing a column that is highly retentive and using a higher organic content mobile phase to elute the compounds is advantageous as this can improve desolvation efficiency, ionization, and thus lead to higher MS sensitivities. Another reason for choosing highly retentive phases for mass spectrometry is to eliminate unwanted adduct formation or charge competition from matrix interferences that are less retained by the analytical column. In practice, the C18 is the most commonly used column at the bench and other phases are often not used to their maximum advantage. While C18 columns are excellent at retaining hydrophobic solutes, they fail when retaining hydrophilic solutes and novel column chemistries can offer better performance in many situations. For example, the Biphenyl phase is capable of retaining both hydrophilic and hydrophobic aromatics better than conventional C18 and phenyl phases, resulting in better mass spectrometer asset utilization. Using a highly retentive column with higher organic content mobile phases for MS analyses is an excellent example of how novel column chemistries can contribute to more effective asset utilization.

Accelerating Method Development
Once proper technology has been implemented, we need to evaluate method development strategies and implement process improvements. Method development continually ranks in surveys as one of the most challenging and time-consuming issues associated with the use of HPLC. Thus, a procedure that is gaining popularity in the pharmaceutical lab is the utilization of column switching systems for method development. In this approach, rather than tediously scouting various columns individually, a systematic approach can be created using existing instrumentation and automating the process of switching between test columns. Using this approach we can determine the best separation option for data quality quite literally overnight. By screening a wide range of column phase chemistries, including alkyls, phenyls, and embedded polar groups, as well as a limited number mobile phase combinations, many HPLC separations can be achieved with high data quality on even the most basic HPLC systems. It is important though, that a variety of column chemistries be evaluated in order to maximize the chances of success with difficult separations. Adopting a logic-based screening strategy can improve the efficiency of method development and the quality of the final method, while minimizing the costly and time-consuming trial and error that is often associated with development.

Although pharmaceutical labs are dominated by LC, there are also critical GC applications and choosing the optimal column for GC is just as important as it is in LC. The primary criteria governing the usability of GC columns include deactivation, bleed (thermal stability), and selectivity. Often, the column chosen is either habitually selected or chosen for just one or two attributes, based largely on the chemical nature of the target analytes. Impurity determination is a common GC application in pharmaceuticals testing and, because of the chemical nature of the molecules commonly analyzed, midpolarity columns are often required to get the desired selectivity. However, more polar columns often have low thermal stability and therefore generally can’t be used in high temperature separations or in GC/MS applications. An exception to this limitation is the Rxi®-624Sil MS column, which is an example of a column designed specifically for the needs of the pharmaceutical industry. By incorporating proper, neutral deactivation and using a proprietary silarylene bonding chemistry, this column offers an ideal selectivity for impurity analysis, with the added properties of high thermal stability and neutral deactivation. The high temperature tolerance of this column means very little column bleed is observed, making it particularly useful for MS applications. The neutral deactivation allows the Rxi®-624 Sil MS column to produce excellent results for both acidic and basic active pharmaceutical ingredients (API). Choosing a robust, universal column, such as the Rxi®-624 Sil MS column can substantially improve the efficiency of GC method development for pharmaceuticals by increasing the number of times you choose the right column first.

Conclusion
Undoubtedly, the market we serve, as pharmaceutical scientists and leaders, is changing. Regardless of the shape it takes, we must start to consider how we will adapt to the upcoming change. Normal business practices need to be reconsidered, from both 30,000 feet above as well as at the bench itself. There is no such thing as small change. As Thomas Huxley once said, “Economy does not lie in sparing money, but in spending it wisely.” Maybe this is the mantra for sailing safely through the current economic storm.

Richard Lake is the Pharmaceutical Market Development Manager at Restek Corporation. He is responsible for overseeing the development and application of chromatographic products for the pharmaceutical industry. He has over 13 years of experience including positions as lead chemist, LC and GC method developer, stability manager, and study director for pharmaceutical studies.