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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Integration of new modeling and analytical tools with flow chemistry are notable trends.
A key focus of the pharmaceutical industry today is increasing efficiency and productivity to reduce cost and time to market. These issues are being addressed across the entire development lifecycle, including in API development labs. From improvement of existing technologies to the introduction of more advanced analytical instruments and modeling software, development labs are focused on increasing speed of optimization and reducing issues during scale up.
Innovation in API development labs is taking place at all pharmaceutical companies. Adam Kujath, senior director of global manufacturing sciences and technology at Alcami, points out how this innovation is being driven largely by smaller pharma and biotech companies. “Speed is the most important thing for these organizations as they work to get into and through the clinic as quickly as possible. Therefore, most investments are not necessarily for exotic new technologies, but rather expansion and improvement of those that drive more efficient throughput,” he comments. Examples include robotic screening equipment, parallel reactors, and more advanced in-line analytics to support process characterization.
Flow chemistry for the synthesis of APIs is an important trend in the industry, according to Rui Loureiro, director of R&D process chemistry development for Hovione. “Flow chemistry enables the implementation of chemistries that previously were not possible due to a lack of technology. As a result, chemists are gaining access to new methods for producing new and more complex molecules,” he says. It can also dramatically reduce scale-up times because the same equipment can be used in the lab and for production, just for longer periods of time and/or in multiple copies.
A side benefit of the interest in flow chemistry is improvements in process analytical technology (PAT)-including nuclear magnetic resonance (NMR) spectroscopy and high-performance liquid chromatography (HPLC)-are being developed to allow their use for continuous manufacturing, according to Loureiro.
Not only advances in equipment technology, but the ability to integrate different aspects of API development laboratory initiatives is helping to speed up activities. Access to a growing selection of miniaturized probes with high resolutions allows researchers to more quickly gain a better understanding of how crystals are formed and how polymorphic forms can be controlled, according to Jerod Robertson, a senior process chemist at Hovione.
He points to smaller probes for focused- beam reflectance measurements and particle vision and measurement from Mettler Toledo as examples that allow performance of crystallization studies in smaller reactors using smaller quantities of expensive API. “Using less material is important since at the beginning of development there normally aren’t significant amounts of product available, but the shape and size of the obtained crystals should be understood as in-depth as possible because these parameters can significantly impact process development down the road to reaching the commercial phase,” Robertson explains.
Most notable for Alcami when it comes to equipment advances has been the integration of multiple systems, according to Kujath. “When a piece of equipment capable of performing automated, high-throughput synthesis or crystallization experiments is directly integrated with direct sampling for multiple forms of analysis on the same system, it drives efficiency, such as the Bruker D8 Discover HTS2. Better, more robust data sets can be obtained, making tools such as design of experiments more accessible for earlier development activities and thereby allowing Alcami to create stronger early clinical processes,” he observes.
Advances in software are equally important as improved equipment and technology. “Software packages are becoming more intuitive, which is important as the databases behind them grow,” Kujath notes. “Scientists today build on the developments of those who came before them, and the software packages that exist today are making that information more accessible for application on a daily basis,” he adds.
At Hovione, using the simple but effective Dynochem (Scale-Up Systems) and Visimix (VisiMix Ltd.) software packages for optimizing scale up and mixing processes and equipment have been great tools for chemists responsible for the scale-up of API syntheses. “The use of Dynochem has enabled Hovione to achieve faster development of unit operations such as solvent swapping, and it has also been a great tool for understanding reaction mechanisms, including those that lead to impurity formation,” Loureiro says. Such understanding helps the development chemists implement effective control strategies that ensure product quality. The use of tools such as Visimix provides chemists with a greater understanding of effects like mass transfer and mixing and how they can impact product quality, according to Robertson. This information can be used to gain insight into how reactions will run at scale or when they are changed from one piece of equipment to another.
Hovione is also leveraging software designed for ab initio calculations, such as Gaussian calculations. “These types of software are very important because they provide chemists with a better understanding of the possible transition states that can be formed during the different steps in an API synthesis route. This information is helpful for identification of pathways that lead to impurity formation,” says Loureiro.
The software packages used at Hovione mainly help with modeling. The information that is obtained on process kinetics and impurity formation is used to determine the optimum control strategies, according to Robertson. The company also uses software such as SuperPro Designer (Intelligen) for batch process simulations and computational fluid dynamics software for modeling the scale up of processes when moving from the lab to large-scale production.
The algorithms used in modeling tools are becoming more accurate and predictive in part because the data behind them continue to grow, according to Kujath. Alcami has seen that they are as a result useful for further refining processes.
As importantly Kujath notes that while the new predictive synthesis applications being developed in academia are not yet widely used in industry, they hold tremendous future potential in reducing time and materials spent in early screening work. He also expects further development of applications of predictive models like solvent maps, which through principal component analysis enable scientists to make more data-driven decisions in solvent and reagent selection.
As the pharmaceutical industry moves toward continuous manufacturing, work is also progressing with respect to in-line process analytical technology for use in both the production plant and development labs, according to Kujath. “These new tools not only provide more rapid feedback on experimental results, but are being effectively used to establish proof of concept for scale up at Alcami,” he observes.
For Hovione, advances in two technologies in particular are speeding of development work: bench-top NRM systems and ultra-high-pressure liquid chromatography (UHPLC).
Traditional NMR systems were quite large and carried high capital and consumable costs. Newer benchtop systems are much less expensive and do not carry the running costs of older machines because they do not require the use of liquid helium for cooling, according to Robertson. “Although they are much smaller, the new bench-top NMRs still provide high resolution and allow chemists to follow reactions that previously were not analyzed due to lack of immediate access to NMR instruments,” he says.
Hovione has found that it is possible to more quickly gather information about impurity formation that was possible before. In addition, the bench-top NMR is used in place of gas chromatography to quantify solvents in distillations more quickly and cheaply. Loureiro also notes that the bench-top NMR system can be connected to flow reactors for continuous monitoring of product formation, providing real-time data and enabling faster process development.
While UHPLC is not new, it is not yet widely used throughout the industry. Many projects that Hovione accepts come with HPLC methods. “We often work with our clients to improve and where possible further convert them using a quality-by-design approach to UHPLC methods,” comments Loureiro.
Both Kujath and Loureiro expect to see more focus on the development of continuous- flow chemical processes going forward. “New small-molecule entities as a whole are becoming more potent. Chemical synthesis already carries inherent risk with potential high energetics, flammable solvents, and other safety management challenges. Coupling that with the need to continually be more cost effective, it simply makes sense to apply this concept whenever possible,” asserts Kujath.
Adds Loureiro: “We think that the continuous manufacturing of APIs still has some space to be further improved. Several people are working on the downstream steps, which still require further development before fully continuous processes can be implemented from addition of the starting raw materials to packaging of the final API.”
Vol. 42, No. 10
When referring to this article, please cite it as C. Challener, “Efficiency Demands Drive Advances in API Labs,” Pharmaceutical Technology 42 (10) 2018.