The Rising Iceberg of Lyophilized Innovations

Parenteral drug development and manufacturing within the bio/pharma industry is growing, due, in part, to the rising number of therapeutic biologics being developed and approved. As a result of this market trend, lyophilization services for bio/pharmaceuticals are also experiencing greater demand (1,2).

Lyophilization, or freeze-drying, has been used for healthcare products for over eight decades and enables the preservation of aqueously unstable products (3). “Freeze-drying or lyophilization in pharma requires the removal of water from a frozen drug as dry powder,” confirms Shaukat Ali, PhD, FAAPS, senior director, Scientific Affairs and Technical Marketing at Ascendia Pharma. “[The technique] is required for maintaining the stability, structure integrity, and a longer shelf life and efficacy of [numerous drug] products.”

Promising applications

“Lyophilization holds several promising applications in the biopharmaceutical sector, significantly enhancing the stability and usability of products,” adds Greg Sacha, associate director, Research & Development at Simtra. “One of the most promising applications is the ability to significantly extend the shelf-life of biopharmaceuticals. When correctly formulated, biopharmaceuticals can be frozen and dried without compromising their efficacy. This process stabilizes the product, preventing degradation over time, which is a common issue with liquid formulations.”

Prolonging the shelf life and ensuring the stability of biologics and biopharmaceutics is key, continues Ali. “Lyophilized formulations help enhance the product stability of biologics both for therapeutics and vaccines including proteins, antibodies, enzymes, polypeptides, DNA, siRNA [small interfering RNA], mRNA [messenger RNA], oligonucleotides, antibody-drug conjugates, liposomes, polymeric and lipid nanoparticles, among others,” he says.

Additionally, Sacha points out that lyophilization can help to reduce the need to store products at low temperatures. “This [application] is particularly advantageous for global logistics, as maintaining a cold chain can be both costly and complex. Freeze-dried biopharmaceuticals can be stored and transported at room temperature, simplifying the supply chain and reducing costs,” he notes.

“Overall, lyophilization offers significant benefits in terms of stability, storage, and logistics, making it a vital process in the development and distribution of biopharmaceuticals,” Sacha specifies.

Specific limitations

Not all molecules can be lyophilized, however, and there are specific limitations associated with the technique, Sacha warns. “[For example], some molecules, like certain cephalosporins, degrade during freezing and drying,” he says.

Another limitation can be the requirement of long drying times and precise temperature control as a result of very low molecular critical temperatures, Sacha adds. This limitation is particularly difficult at full scale, he highlights.

“Longer primary and secondary drying time could be an impediment in mass production of lyophilized products,” agrees Ali. Additionally, scale-up of lyophilization can be challenging as a result of the stringent requirements for freeze-dried processes and products, he states.

Volatility is a further limitation to lyophilization, notes Sacha. “Some molecules are volatile under the shelf temperature and vacuum conditions used during freeze-drying, meaning they can be removed as a vapor from a solid during the process,” he specifies.

Furthermore, achieving uniformity and quality of a lyophilized product can be limiting, Ali remarks. “The product’s uniformity depends upon multiple factors and is often controlled by fine tuning the process parameters,” he says.

Impact on potency

A lack of control over the uniformity of lyophilized products can impact the potency of certain drug products, Ali asserts. For example, in a study by Bennett et al. (4), the potency and stability of live varicella-zoster virus (Oka strain) vaccines were found to be negatively impacted by a longer controlled vacuum preparation method, Ali states.

Interfaces should be kept in mind for lyophilization, Sacha continues. “Biopharmaceuticals can interact at the container/solution, solution/air, and ice/solution interfaces, leading to unfolding and aggregation,” he says. “Aggregation results in the loss of the active molecule and, consequently, a loss of potency.”

The use of cryo- and lyoprotectants is also crucial, Sacha stresses. “These protectants, such as amorphous sugars, provide necessary water and hydrogen bonding, preventing the unfolding and aggregation of the biopharmaceuticals during freezing and drying,” he says.

Excipients play an important role in stabilization of drugs and are commonly used as cryoprotectants, adds Ali. “Sugars, amino acids, surfactants, and polymeric excipients are commonly used as stabilizers and lyoprotectants,” he specifies.

“Without proper protectants, biopharmaceuticals can be over-dried, leading to destabilization and reduced potency. Amorphous sugars help maintain the structural integrity by preventing over-drying,” states Sacha. “Proper formulation and the use of appropriate protectants are essential to maintain the potency of drug products during lyophilization.”

Key advancements

However, advancements in the field of lyophilization have emerged that are helping to enhance efficiency and product quality, Sacha asserts. “One significant advancement is the implementation of quality by design (QbD) in the development of primary drying cycles,” he says. “This approach involves applying fundamental principles of heat and mass transfer to comprehensively understand the freeze-dryer and the thermal characteristics of the product. By doing so, it removes the guesswork from the development process, ensuring that primary drying conditions keep the product temperature well below its critical threshold.”

Controlled ice nucleation techniques represent another notable advancement for Sacha. “By controlling the nucleation of ice during the freezing step, variability between vials on a shelf and across different shelves is significantly reduced. This innovation is particularly impactful for amorphous products, as it can dramatically shorten primary drying times and improve product uniformity,” he explains.

“Recent advancements in freeze drying technology and process optimization parameter using controlled devices and equipment designs have been made for more efficient and to achieve reliable pharmaceutical dosages,” agrees Ali. “For instance, in improving the refrigeration system, state-of-the-art condensers are designed to handle high vapor loads to facilitate the efficient vapor flow during lyophilization. In addition, sterilization methods, automation, and isolators are all considered for improving the lyophilization process.”

Companies have also innovated with lyo beads, which are spherical freeze-dried solids, that have proven useful with products that are difficult to freeze in conventional vials, Sacha continues. “The spherical shape of lyo beads provides excellent flow properties and efficient freeze-drying due to their relatively small size,” he says.

“Moreover, there have been advancements in microwave-assisted freeze-drying,” Sacha asserts. “This technique can substantially reduce primary drying times without adversely affecting the product. By integrating microwave energy, the drying process becomes faster and more efficient, preserving the product’s integrity.”

What’s next?

Sacha expects that a few key advancements will form the future focus for lyophilization. One such advancement will be reducing the footprint of lyophilization systems, he says. “Developing more compact lyophilization systems to handle smaller volumes of biopharmaceuticals efficiently is increasingly important for personalized medicine and small-batch production,” Sacha confirms.

The implementation of continuous lyophilization processes will also be important in the future, Sacha specifies. “This approach aims to streamline production and improve efficiency,” he says.

There has been a recent emphasis on continuous freeze-drying technology that allows real-time monitoring, confirms Ali. “Process analytical tools (PAT) such as near-infrared spectroscopy (NIR) and Raman spectroscopy are very promising methods for monitoring inline quality attributes. Both techniques are highly sensitive and complementary to each other,” he states.

Through automation, it will be possible to reduce contamination risks and remove the potential of human error, Ali continues. “For example, advanced freeze-drying sensors and PAT allow better control of the process in primary and secondary drying processes under controlled nucleation regime by QbD for robust continuous manufacturing of lyophilized drug products,” he remarks.

“Ongoing improvements to make lyophilization more efficient, such as optimizing energy use, reducing cycle times, and enhancing automation and control systems [will be explored],” summarizes Sacha. “[All] these advancements will help meet the evolving needs of the biopharmaceutical industry, enhancing both scalability and efficiency.”

References

1. Nova One Advisor. Biologics Market Size, Share and Trends Analysis Report by Source (Microbial, Mammalian), by Product (mAbs, Recombinant Proteins, Antisense and RNAi), by Disease Category, by Manufacturing, by Region, and Segment)—Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2024–2033. Market Report, April 2024.
2. The Insight Partners. Lyophilization Services for Biopharmaceuticals Market Report 2023–2028. Market Report, September 2023.
3. Trappler, E.H. Application and Insights for Lyophilization of Parenteral Products. In Practical Aseptic Processing Fill and Finish, Volume 1, Lysfjord, J. Ed.; Parenteral Drug Association, 2009; pp. 31.
4. Bennett, P.S.; Maigetter, R.Z.; Olsen, M.G.; et al. The Effects of Freeze Drying on the Potency and Stability of Live Varicella Virus Vaccines. Dev. Biol. Stand. 1992, 74, 215–221.

About the author

Felicity Thomas is senior director for Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 48, No. 7
July 2024
Pages: 16–17

Citation

When referring to this article, please cite it as Thomas, F. The Rising Iceberg of Lyophilized Innovations. Pharmaceutical Technology 2024 48 (7).