Agnes Shanley is senior editor of BioPharm International.

Agnes Shanley

Lyophilization, or freeze drying, was a crucial development in pharmaceutical manufacturing, because it allowed heat-sensitive vaccines, antibiotics, and protein-based drugs to be dried safely. The process results in powders with long shelf lives that can be reconstituted at the point of use. Its strategic importance continues to grow, as injectable biopharmaceuticals become a more prominent part of the overall drug market. In 1998, lyophilized pharmaceuticals accounted for 11.9% of all new injectable or infusible drugs, but, by 2015, they made up half of all such new drug introductions (1). 

	Yet, the basic pharmaceutical freeze-drying process has seen little change since it was introduced in the 1940s (lyophilization made a considerable difference during World War II in allowing medicines such as penicillin [Photo] to be shipped long distances and remain stable). According to experts who work in the field, lyophilization remains one of the most time-consuming and expensive of pharma’s unit operations, with energy efficiency of less than 5%, dominance of open loop processing, and lack of inline quality monitoring technology (2).  

	To help reduce variability and develop more uniform, consistent, and efficient lyophilization processes, the National Institute of Standards and Technology funded the Advanced Lyophilization Technology Hub (LyoHUB) as part of its advanced manufacturing technology consortium in 2014. Based at Purdue University, its members--14 pharmaceutical manufacturers and equipment vendors, as well as universities, independent consultants, and scientists with regulatory agencies--are developing more modern approaches to lyophilization equipment design, analytics, instrumentation, training, and control. The group launched a demonstration facility at Purdue University in 2016 to facilitate R&D and pilot testing. In September 2017, LyoHUB released a 10-year technology roadmap for pharmaceutical freeze drying (2), The roadmap reflects the opinions of more than 100 industry and academic experts whose views were elicited, analyzed, and summarized using methods developed at Cambridge University (3). 

	LyoHUB members currently view the development of sensors and instrumentation, and process models for primary drying as key short-term priorities for the industry. They have also been focusing on publishing “best practices” papers in -open-access journals, to get beyond what scientists describe as the “Because it has always been done this way” hurdle. One of the first white papers describes best practices for process monitoring (4). 

	Part of the reason why pharma may still be on a learning curve in understanding lyophilization is because the process is so complex compared with other pharma operations. “Lyophilization involves complex heat and mass transfer,” explained Alina Alexeenko, Purdue University professor of aeronautics and astronautics and co-director of LyoHUB, in an April 2017 webcast (5) on the use of modelling in lyophilization. Some heat-transfer processes are pressure dependent and others can be very sensitive to differences between container types and even to the finishes on the surfaces of vials, she noted.  

	LyoHUB is advocating greater use of modeling and simulation, including advanced modeling tools such as computational fluid dynamics (CFD), which can offer more detailed views of what’s happening in the equipment than sensor information alone, showing important details about vapor concentration and temperature and pressure distribution, Alexeenko said. 

	For example, Alexeenko recalled one industrial-scale lyophilizer design. Using modeling, esearchers found that a relatively short section of clean-in-place and steam-in-place piping, which accounted for only 3% of the equipment’s area, was causing a 20% reduction in vapor flow rate and overall throughput. 
	Among other goals mentioned most prominently in LyoHUB’s roadmap are:

		Development of continuous or semi-continuous processes based on technologies. Over the past few years, the food industry has moved to continuous operations, resulting in gains in product uniformity. LyoHUB members expect the same to be possible for pharmaceuticals. 

		Use of improved heating methods involving infrared heaters or volumetric heating via microwave, which would allow for closer control of the process.

		Use of spray-freeze drying, particularly for making bulk APIs.

		Alternative sterilization methods, such as hydrogen peroxide and cold-plasma sterilization. Steam sterilization, using steam at temperatures above 120 °C, can result in equipment wear. In addition, the typical sterilization process can take more than six hours to complete. LyoHUB members plan to evaluate lower-temperature alternatives.

		Establishment of standards for characterizing lyophilization equipment performance, which would facilitate scaleup using different vendors’ equipment.

		Better process control, especially during the primary drying stage, during which the ice crystal structure is set, and with it, mass transfer and drying rates. Currently, control is based on traditional open-loop approaches. As a result, such variables as -product temperature, drying rate, and residual moisture content are not monitored directly, so any deviations from optimal levels may not receive enough attention. 

		Development of process analytical technology (PAT) tools, which will be required for closed-loop control. 

		Improved container and closure systems. Currently, product is freeze dried in glass vials with rubber stoppers. LyoHUB is evaluating the use of plastics and developing data on the chemical and physical interactions between pharmaceuticals and containers. Among other plans, the group is considering using vials or stoppers that have been embedded with sensors to monitor temperatures and pressures during processing and transport. 

	Farther off in the future, LyoHUB is evaluating freeze drying’s use with novel therapies such as cell- and gene-based therapies. Below are some recent developments that have taken place within the roadmap’s focus areas.

	Spin freezing and miniature mass spectrometers

	For the past few years, RheaVita, based in the Netherlands, has been working on a continuous lyophilization process based on spin freezing. Collaborating with Ghent University, researchers have developed a prototype to develop comparative process data (6). They recently presented a model and theoretical design space for the continuous process (7).

	In November 2017, Atonarp, an instrumentation company in Toykyo, and IMA Life North America commercialized a lyophilizaton-monitoring platform based on research that the two companies did with Pfizer (8). Driving the technology is Atonarp’s miniature mass spectrometer, which is said to take up less than half a cubic foot of space. The device offered benefits in monitoring the presence of silicone oil (a sign that heat transfer fluids are leaking from lyophilizer shelves). Researchers also used the device successfully to detect endpoints for primary and secondary drying and to detect vacuum leaks. 

	Other process-monitoring solutions developed for lyophilization include IQ Mobil’s Tempris wireless temperature-monitoring technology, as well as Millrock Technology’s measurement platforms based on heat-flux sensing (9). Coriolis Pharma has evaluated heat-flux sensing as a PAT technique for lyophilization (10) and found that it provided more insights into drying thermodynamics and allowed them to use a “vial heat-transfer coefficient” to monitor product temperature throughout primary drying. 

	Advances are also being seen with Tunable Diode Laser Absorption Spectroscopy (TDLAS). One platform that has been optimized for pharma freeze drying uses a spectrometer from Physical Sciences, Inc., and SP Scientific’s LyoFlux analyzer. 

	1. M. Arduini, “Freeze Drying Market Analysis,” Presentation at IMA Aseptic Processing Symposium, Amherst, NY, September 2016.
	2. LyoHUB, 

Roadmapping at Cambridge University’s Institute for Manufacturing

,” ifm.eng.cam.ac.uk.
	4. S. Nail et al., 

, 18 (7), October 2017, Springer.com.
	5. Siemens webcast, “

CFD Methods and Lyophilization: Advancing Manufacturing Processes to Match Growing Demands

, April 27, 2017.
	6. DeMeyer, L. et al., 

, 496 (1), 75-85 (2015).
	7. DeMeyer, L., et al.,  

, 532 (1), 185-193 (2017).
	8. A. Rhoden, “

The Utilization of Mass Spectroscopy for Equipment and Process Modeling in Lyophilization

,” a presentation made on Sept.12, 2017, at IMA’s Process Symposium.
	9. N. Huls, “

Real-Time Temperature and Heat Flux Measurements for Lyophilization Process Design and Monitoring


	Volume 41, Number 12
	December 2017
	Pages: 46-47, 53

	When referring to this article, please cite it as A. Shanley, “Modernizing Lyophilization," 

Articles

A technology roadmap aims to drive and consolidate improvements in a process that has remained unchanged for more than 70 years.