Freeze-Dried Future: How Lyophilization Is Unlocking Cool Innovations in Pharma

Walt Pebley, Chief Scientific Officer, OFD Life Sciences

The process is sublime. We all assume that skipping a step in any process can yield suboptimal results. In this case, however, intentionally bypassing the liquid phase of water by going directly from ice to vapor stabilizes a compound without sacrificing its effectiveness, if done correctly. This sublimation is key to freeze-drying or lyophilization, a process that continues to evolve through innovation to play a greater role in biopharma, medtech, and life sciences.

While the technology isn’t new, many of its current applications are. Gone are the days after World War II when freeze-dried instant coffee became so popular that it was found in most homes across the United States.1 Coffee has come a long way since then and so has lyophilization. Today, experts use lyophilization as a strategic tool to improve product stability and preserve sensitive compounds throughout the pharmaceutical and medical device industries. Innovations in lyophilization mean these products can reach a greater number of patients by minimizing cold chain and special handling requirements, further expanding their use globally.

Another essential aspect of lyophilization is its ability to retain the integrity of complex molecules. Improving and retaining shelf life is an obvious benefit, but not if it comes at the cost of lower effectiveness of a vaccine, biologic, or other complex formulation. Optimal freezing and lyophilization cycles need to be very controlled and precise, taking into account temperature, pressure, and other parameters, simultaneously. Pharmaceutical and device manufacturers as well as regulatory authorities require strong assurances and robust evidence that the company they trust to lyophilize their products can, in fact, perform this multi-stage process without compromise while being repeatable during scale-up.

Maintaining Potency and Performance

Many products feature molecules that are sensitive to heat, oxygen and moisture. Maintaining the physical structure of these complex formulations remains of paramount importance in preserving their efficacy. Lyophilization helps mitigate degradation and improve product performance in many cases better than other drying technologies, like spray-drying.

Cold chain distribution adds complexity, costs, and concerns about product waste to the delivery of these products, particularly in socioeconomically challenged nations. Lyophilization helps to alleviate these challenges by producing products that can be stored at either room temperature or standard refrigerated temperature for extended periods of time, including in resource limited settings.

Multiple Applications

When the Inca used freeze drying to preserve potatoes as chuño 900 years ago, they could never have imagined how many applications the process would evolve to encompass.2 Today, lyophilization supports innovation in multiple industries. In addition to a growing number of biologics, for example, biopharma relies on lyophilization to boost the storage time and transport of sensitive components like mRNA and peptides. Real advantages include minimal yield loss and the ability to scale up the process as needed.

There are also many consumer health products like probiotics and supplement ingredients that benefit from this process. For example, active ingredients such as enzymes, proteins, and phytonutrients – plant-based products marketed as antioxidant and/or anti-inflammatory – can retain their potency for longer when the manufacturing process includes lyophilization.

A Precise Process Requires Expertise

The success of lyophilization depends on the quality and precision of this complex, multistep process. It starts with developing a deep understanding of the ingredient(s) to ensure the outcome meets the expectations of desired bioavailability, product stability, and regulatory requirements. The next step is using optimally designed lyophilization chambers to facilitate product drying at the right rate, temperature, and pressure. At the appropriate low pressure, for example, the primary drying process removes any moisture in the frozen product through sublimation. A secondary drying step removes residual water, often from five percent down to less than one percent. Both steps are essential for product stabilization and extended shelf life.

Managing pressure and moisture removal during this process necessitates continuous adjustments based on temperature, moisture levels, product surface area, and heat flux. If pressure is too high, it can cause the product to collapse; too low and the process takes more time. Even after conditions are properly controlled, it remains essential to visually inspect the product and test it for factors such as residual moisture and reconstitution time to maintain quality.

Realities Driving Innovation

Emerging industry trends are guiding the expansion of lyophilization. Decentralized patient care, for example, calls for development and availability of more shelf-stable vaccines, therapeutics, and medical devices. Public health officials worldwide want to minimize cold-chain product storage and transportation requirements to save money, reduce waste, and allow greater global distribution of essential medical products. Lyophilization can accomplish both, as well as encourage investment in current and future single-dose, shelf-stable formulations.

Pipelines are filled with active ingredients featuring a much wider variety of modalities than in recent years, including proteins, peptides, and polymolecular compounds, and developers are also being driven by patient centricity to find new ways to deliver drugs that were developed as injectables. Formulators who have largely had the same set of tools to work with for years welcome a technology like pharmaceutical bulk lyophilization, which can not only be used to stabilize and preserve molecules, but also to create amorphous dispersions in a process ideal for heat-sensitive molecules which delivers maximal yield. This is especially welcome considering the complexity and high cost of API in pipelines.

Historically, lyophilization has been an empirical process, meaning success could only be measured by testing the finished result. More recently, process analytical technology allows freeze-drying to be more data-driven and controlled through continuous feedback. Tools like spectroscopy can be used to measure moisture content, wireless sensors to track temperature and pressure, and incorporate machine learning systems to predict cycle abnormalities and optimize batch outcomes.

Challenges and Misconceptions

Even with all the advances in lyophilization technology, some pharmaceutical and medical device leaders hold common misperceptions around cost, complexity, and scalability. Adding stability and shelf-life to your product extends its life and global reach, crucial factors to consider when looking at costs from a holistic R&D to clinical or everyday use perspective. Uniquely, the scale of the process remains nimble. The creation of stable, long-lasting lyophilized products can be ramped up easily to meet demand.

A Freeze-Dried Future?

Formulation scientists, R&D leaders, and commercial teams will continue to take advantage of lyophilization where it matters most – in production and wider availability of essential vaccines, therapeutics, and medical devices designed to make a difference in people’s lives and outcomes around the world.

Lyophilization will continue to advance, accelerated by technologies like artificial intelligence and machine learning that can uncover new applications, along with human-driven progress we’ve yet to even imagine. Freeze drying is not frozen in time; it’s an essential current and futuristic strategy.

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