50 Years Later, Consortium Looks for Freeze-drying Overhaul

Lyophilization, also known as freeze-drying, is a critical technology for the food industry, pharmaceuticals and biotech. However, the process, which removes water from products at low temperatures and low pressure, is expensive, time-consuming and has remained unchanged for the last 50 years.

Now, Elizabeth Topp, the head of Purdue’s Department of Industrial and Physical Pharmacy and Alina Alexeenko, Associate Professor of Aeronautics and Astronautics, are coming together to lead a consortium that will address top priorities facing the technology. The consortium, LyoHUB, includes equipment manufacturers, the Food and Drug Administration (FDA) and end users, who each bring a unique perspective to both the challenges and opportunities lyophilization poses.

Different industries, same need
Lyophilization is important for products that are sensitive to heat but whose integrity would be lost by heating them. For example, the food industry uses the process to produce the dried fruit found in cereal.

“You can imagine if you tried to dry the strawberry by cooking it or essentially boiling it to get the water off,” Topp told Laboratory Equipment. “You’re going to destroy a lot of the flavor components of the strawberry because they’re going to be ruined by the higher temperatures.”

The same thing is true of pharmaceuticals, such as vaccines, where the molecule would be destroyed by heat. Instead of heating, lyophilization freezes the material but does so in a low-temperature, low-pressure environment, where water is pushed directly into the vapor phase, removed from the material by sublimation, and collects on condenser coils. Through this process, food and pharmaceuticals can be essentially desiccated, without using high temperatures. Lyophilization is increasingly becoming important for the biotech industry as well, Topp said, as recombinant protein drugs are a big part of the market, and more and more people are looking at using tissues and cells as therapeutic agents—materials that would be destroyed by heating.

Alexeenko’s background is in the area of rocket propulsion/space science. At first it may seem like an unusual pairing—an aerospace engineer working on a process for foods and pharmaceuticals—but surprisingly, the conditions found inside a lyophilizer are similar to those in outer space.

“That flow of vapor that’s happening at low temperature and low pressure is happening in exactly the same regimes that are considered for rocket propulsion in outer space,” Topp said.

In that sense, Alexeenko likes to say that lyophilization is rocket science.

Why focus on lyophilization?
Being such a complex process, why focus on lyophilization and not some other unit operation? For one, there are many aspects that can be improved.

“Lyophilization is what we call a fill-finish operation,” said Topp. “So it’s the last operation that many products see before they’re packaged and shipped out the door. It’s also one of the most time-consuming and energy-inefficient processes that pharmaceutical manufacturing encounters.”

A lypho cycle can last anywhere from a couple of days to almost a week, so throughput is slow and can cause a bottleneck in the production of many pharmaceutical products. The degree of instrumentation is poor, and the process is run in batch mode instead of continuous mode, which causes additional inefficiencies, Topp explained.

So why has lyophilization technology been stagnant for 50 years? According to Topp, up until this point there were a number of disincentives to process innovation. On the pharmaceutical side of things, the FDA not only regulates the final product, but also the process. Once a company clears the hurdle of obtaining FDA approval on how a unit operation is run, it is often never changed for the lifetime of the drug product—in the interest of time, convenience and money.

“Other disincentives are the fact that unlike some parts of the chemical process industry, pharma has traditionally been a low-volume, high-value-added kind of product,” Topp explained. She compared it to gasoline, which is a high-volume, low-value-added product, where the margins are slim and therefore process inefficiencies matter.

Now, however, process inefficiencies are becoming more important because the public is increasingly concerned about the cost of drug products. “So anything that we can do to try to make processes more efficient and to lower the cost of producing pharmaceuticals, ultimately is in the best interest of the public and also of the industry,” Topp explained.

Unique perspectives
One way the consortium will address the many aspects of lyophilization innovation is by recruiting members from across industries, what Topp refers to as the “lypho value chain.”

“We’re really trying to build a network of people that are not just one part of this lyophilization process, but really across the process, across things that have to do with everything that it takes from getting a lyophilized product from product idea all the way out the door.”

That includes equipment manufacturers, researchers who lyophilize food or pharmaceuticals, excipients, or those who make sugars or salts that are used to help formulate a product that is lyophilized, academia participants to contribute ideas, and the FDA since it regulates both the product and the process.
Instead of creating challenges, Topp believes having an array of interests involved in the project provides interesting opportunity.

“Now we’re bringing people on board to look at the project and look at this process who come from different perspectives, who have engineering perspectives, who have instrumentation perspectives, and they come with a background that is coming from other technologies.”

This creates an atmosphere of not being burdened by doing things as they’ve always been done in a specific industry.

“They come with innovator perspectives and I think that’s a really great opportunity,” Topp said.

Technology ‘roadmapping’
To figure out what goals and projects are most important to researchers, Topp and Alexeenko just finished a workshop where they focused on what Topp called technology “roadmapping” to set priorities for improving the process over the next decade.

Some of the priorities discussed at the workshop had to do with shortening cycle time, and moving from batch mode to continuous lyophilization. As of now, once material is put in the lyophilizer, the door is closed and scientists must wait. When the door opens, it’s done.

“People would like to develop a continuous process so that a material is moving through the lyophilizer in a nonbatch way, so that material goes in one end and product is collected out of the other end,” Topp said.

One priority that surprised Topp was education: “A lot of our participants really felt that education was critical.” Materials to introduce how lyophilization works and hands-on training for people like FDA inspectors were things members were interested in.

From that idea came one of the first items the consortium will be tackling—best practices papers. The papers would have the weight of the consortium behind them Topp said, and they would essentially say, for example, ‘here’s the best way to develop a formulation for a lyophilized protein drug product’, ‘here is the best way to put process instrumentation in a lyophilizer.’

Having the consortium also helps identify target project areas that might not be recognized if only members of academia were working on the project. For example, one member’s company is interested in getting biotech drug products to low and middle income countries. In this instance, it means the process needs to be done at a much lower cost with much less weight in packaging so vaccines can make it to the country without a lot of heavy glass containers.
In the same way, and another important piece of the puzzle, is having the regulatory agencies involved.

“We can do lots of technical innovation, but we need to hear from the regulatory agencies whether these kinds of innovations would be acceptable,” Topp said.

Innovating short- and long-term
Another exciting aspect of the consortium is a demonstration center that opened at the end of October as a small pilot-scale facility. Member companies can come together to conduct process innovation in a hands-on way.

“For example, if company X wants to work with company Y in improving the design of a chamber in a lyophilizer or improving the design of containers for lyophilization, they can do that in a place that is not owned by either party,” Topp said. “This becomes a place where people can freely change manufacturing processes, take things out, put things in, modify, and show other people what they’re doing in order to advance the technology.”

From the project, Topp said she hopes for two different types of things. One is to make improvements to the existing lyophilization process by reaching goals such as making it faster, better and more reliable. The other is a more revolutionary change.

“I hope for the incremental changes that are more immediate and can be applied in the very short term, as well as the more transformational technology changes that will have people saying, ‘I can’t believe we used to do it like [that], now we have this faster, more efficient way of getting to the same end point.’”