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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
From separation systems to reactor technology, new tools are increasing the feasibility of continuous API production.
Flow chemistry for the production of small-molecule APIs is recognized to offer significant benefits, particularly for processes that involve hazardous reagents or that are highly exothermic. The ability to provide greater process control combined with the use of minimal quantities of reagents at any one time increases the safety of such processes, in many cases enabling the production at commercial scale of valuable compounds that cannot be manufactured practically in batch mode. Continuous processing is new to API manufacturing, however, and additional tools and technologies must still be developed to make this promising approach a practical, widespread reality.
A few solutions that have been recently introduced or are under development to facilitate the adoption of flow chemistry for API manufacturing are described as follows.
Continuous processes are required not only for the reactions used in the synthesis of small-molecule APIs, but also for the unit operations connecting reactions. The development of continuous work-up solutions is one area that has been lagging.
Zaiput Flow Technologies was founded at the end of 2012 to commercialize liquid-liquid separation/extraction technology suitable for continuous processing that was developed by Andrea Adamo while working at the Massachusetts Institute of Technology. The company’s core capability, according to Adamo, is engineering innovation in the context of fluid-related operations.
Zaiput’s membrane-based separation technology exploits the concepts of hydrophobicity and hydrophilicity and unlike traditional devices does not require gravity to achieve separation. Differences in the wetting properties of two liquids (or a gas and a liquid) on the porous membrane allow for separation of immiscible solutions, even for solutions with compounds that have the same density. One material wets the membrane, filling all of the pores (the wetting phase). Application of a controlled-pressure differential “pushes” the wetting phase through the pores while leaving the not-wetting phase behind.
“This technology is the only solution available for continuous manufacturing because these devices can be operated in a pressurized line to enable multistep synthesis without interruptions,” Adamo, who is the CEO of the company, asserts. He adds that the systems have excellent scalability and thus provide a single solution from the bench to the plant, reducing the time and money needed for optimization and scale up.
Zaiput has sold its technology to pharmaceutical companies around the world, and even sent devices into space on the International Space Station. The technology was included in the CRS-13 Mission in December 2017 to confirm its ability to perform in zero-gravity conditions. The devices were found to successfully separate immiscible liquids in space while under remote operation and observation.
The company has an ongoing collaboration with Snapdragon Chemistry, a contract-development company focused on facilitating the adoption of flow chemistry and is starting one with the “Medicines 4 All” program operated by Virginia Commonwealth University (VCU) with support from the Gates Foundation. “Zaiput has innovation at its heart, and we are always looking for new additions and new ideas,” Adamo asserts.
For continuous manufacturing, where many of pieces of equipment have to be operated, monitored, and adjusted simultaneously, automation is essential. Automation has long been available on plant-scale but is now coming into the pilot plant and laboratory, according to Matthew M. Bio, president and CEO of Snapdragon Chemistry. “With laboratory automation enabled, flow chemical process development is accelerated through automated experimentation. At the pilot scale, automation is being applied to ensuring safety and consistent product quality,” he explains.
In-line process analytical technologies (PATs) such as infrared (IR) spectroscopy, Raman spectroscopy, and bench-top nuclear magnetic resonance are also being developed specifically for flow chemistry applications, according to Bio. “In the lab, in-line PATs are providing rich data sets that can be mined for process understanding, while in the pilot plant, they provide real-time process monitoring and enable feedback control of continuous processes.”
Automated flow systems, coupled with embedded in-line PAT, are being used at Snapdragon to automate the discovery and development of continuous manufacturing processes. “We are able to rapidly define process design spaces through automated process characterization,” says Bio. The company is also developing autonomous process development tools where optimization algorithms are used to discover optimal reaction conditions. The data derived from these flow systems can be used for machine learning applications.
Flow chemistry is often performed in microreactors, small reactors with small volumes and high throughputs. Anton Paar, in conjunction with pharmaceutical companies such as Janssen, Patheon, Astra Zeneca, and Lonza, has used additive manufacturing to produce a microreactor as part of the international research project “CC Flow.” Initial research and simulations were performed by Professor Oliver Kappe and his team at the University of Graz.
The reactor was designed for the difluoromethylation of a lithiated nitrile with fluoroform (CHF3), a known greenhouse gas. “Three prototypes were developed before the final design and the perfect internal and external dimensions were determined,” explains Stefan Pfanner, specialist for additive manufacturing and direct metal laser sintering at Anton Paar.
The reactor was produced via direct metal laser sintering using 316L stainless-steel powder with dimensions of 164 mm by 93 mm by 3 cm (thickness). Stainless-steel was chosen based on the chemical, mechanical, and thermal stability and thermal conductivity required for the reaction, according to Pfanner. A serpentine cooling core is surrounded by reaction channels that have an inner diameter of 0.8 mm and a total length of four meters. There are four inlets, two defined reaction zones, and one outlet.
Anton Paar plans to develop various tailor-made reactor types for different industrial requirements, according to Gunter Kole, business area manager for analytical and synthetic chemistry at the company. “One of the advantages of 3-D printing is that any type of design can be produced, which has not been possible in the past with conventional manufacturing technologies,” he notes.
In November 2017, Corning and the University of Liège in Belgium announced the establishment of the first lab in Europe qualified for use of the Corning Advanced Flow reactor (AFR) (1).
The lab is located in the university’s Center for Integrated Technology and Organic Synthesis (CiTOS), which provides customers with continuous-flow demonstrations, experimental trials, feasibility testing, and chemical reaction process development services. Other labs have previously been qualified in the United States and China.
Earlier in 2017, Angelini Pharma installed Corning’s AFR technology at its Aprilia facility for use in API manufacturing (2). The company started with a pilot line (G1 glass and G1 silicon carbide) in 2015 and decided to switch to the G4 production reactor shortly afterwards. The production reactor meets pharmaceutical quality and FDA requirements. The company uses flow chemistry to perform reactions it could not do previously on a commercial scale in batch mode (2).
The AFR technology is specially designed to enable the conversion of batch chemical processes to continuous processes. The reactors consist of engineered fluidic modules that integrate heat-transfer and mass-transfer into a single piece of equipment. As a result, they offer at least 100 times enhancement in mixing, 1000 times improvement in heat transfer performance, and efficient scale-up from the lab to full-scale production, according to the company (1). Processes, therefore, can benefit from increased efficiency, scalability, yields, and quality with reduced performance variability and cost.
Another change in technology that is impacting continuous manufacturing today, according to Bio, is the approach to scale up and the design of production facilities for continuous manufacturing. He points to Eli Lilly’s Kinsale plant in Ireland as an example of a new approach to pharmaceutical drug-substance manufacturing in which the use of small-footprint modular components in fume hoods results in a flexible facility where process trains can be easily reconfigured for multi-product applications. “The reduced size and cost of continuous manufacturing equipment together with the ability to adjust output by numbering out and numbering up will enable responsive supply chains for pharmaceutical API,” Bio states.
Snapdragon has developed a scalable-by-design approach to flow chemical process development. “We have invested in the development and characterization of laboratory reactors that mirror the performance of production-scale reactors. Our custom software platform FlowChem WebApp continuously logs data from these reactors and interacts with a suite of [Internet-of-Things] IoT-enabled flow components for automated experimentation and even autonomous, algorithm-driven, reaction optimization. These tools allow for rapid translation of laboratory results to production scale,” says Bio.
Snapdragon has also invested in the development and scaling of photochemical processes, recently completing the design and construction of a production-scale 5 kW flow photoreactor that is built to work with a range of different wavelengths and is able to operate under pressure for gas/liquid photoreactions.
Pumping technologies for flow chemical applications, particularly at lab and pilot scale, are still inadequate, according to Bio. “The syringe pumps typically used in laboratory flow demonstrations don’t accurately mirror the performance of plant-scale pumping technologies, but to develop plant-ready processes, pump performance characteristics must be taken into account,” he explains. Some manufacturers are beginning to look at this issue, though. The Tacmina Smoothflow technology is particularly useful for developing flow processes with organometallic reagents, according to Bio. Snapdragon has been working with Tacmina to evaluate this pump in flow chemistry applications. The company is also evaluating microannular gear pumps as another scalable pump technology for flow chemistry.
1. Corning, “Corning and University of Liège Announce First Advanced-Flow Reactor Qualified Lab in Europe,” Press Release, Nov. 3, 2017.
2. Corning, “First Industrial Use of AFR Technology in Italy,” Press Release, March 2017.
Vol. 42, No. 6
When referring to this article, please cite it as C. Challener, “New Tools Outline Advances for Continuous API Processing" Pharmaceutical Technology 42 (6) 2018.