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Technical advances in process understanding and control must be accompanied by a change in mindset.
Since its introduction to the pharmaceutical industry in the 1940s, lyophilization (freeze-drying) has been a mainstay for manufacturers to stabilize products and ensure they are durable and safe for as long as possible. In recent times, lyophilization has experienced a surge in interest, which has been attributed to the rising proportion of biopharmaceuticals being developed and manufactured that are generally unstable in aqueous form (1).
Essentially, lyophilization is the ability to remove water while maintaining chemical or biological function, explains T.N. Thompson, president, Millrock Technology. “It is a three-step process involving freezing, primary drying or sublimation, and secondary drying (sometimes referred to as desorption),” he continues. “Freezing is the most important step of the entire process. If the product is not frozen properly, then the primary drying process can be inefficient or impossible.”
“Ultimately, lyophilization is a stabilizing process that is used to preserve the long-term safety, strength, and quality of pharmaceutical products, especially for parenteral biologics,” confirms Alina Alexeenko, from Purdue University in Indiana, and coâdirector of the Advanced Lyophilization Technology Hub (LyoHUB)-an industryâled partnership aimed at advancing the science and technology of lyophilization.
Currently, there are an increasing number of biological drugs in development or being approved by regulatory bodies worldwide (2). “Many drugs are unstable in solution,” continues Elizabeth Topp of Purdue University, co-director of LyoHUB. “These drugs are often marketed in solid forms to preserve their potency and prolong their shelf-life. This is particularly true for biologics.”
It is this growth in biologics that has contributed to the rising importance for lyophilization, they specify. “Unlike other drying methods, lyophilization removes water in a relatively gentle way that helps to preserve the structure and activity of peptide and protein drugs,” says Topp.
“For biopharmaceuticals, the increasingly complex molecular formats are very unstable in solution,” agrees Sajal M. Patel, associate director, MedImmune. “Lyophilization offers a well-established process that can deliver stable products for parenteral delivery.”
The well-established process of lyophilization is considered by many to be both time- and cost-intensive, and has been described as fundamentally unchanged (3). However, according to some experts, these descriptions may not truly reflect the progress that has been made in the lyophilization process over the past few decades.
“The physics may not have changed but our knowledge of the process, equipment, and instrumentation has improved significantly,” Thompson stresses.
An improved understanding of the freeze-drying process has led to improvements in the equipment design, Thompson continues to explain. “One such improvement includes the refrigeration systems, which are now properly sized and far more reliable,” he says. “Others include condensers that can effectively handle high vapor loads, vapor port designs that don’t choke the vapor flow, sterilization methods for GMP processing, loading and unloading automation, and isolators, to name a few.”
Not only have there been advances in the instrumentation and control of the process, but also knowledge of the process itself has improved, Thompson adds. “Our understanding of the product critical temperature has improved, for example, which has enabled us to optimize the shelf temperature and chamber pressure to maintain the product just below its critical point while maximizing the sublimation rate,” he notes. “Also, the freezing methodology has changed. We now understand that the method of freezing effects the crystal structure in the product.”
Understanding of the drying process has also improved. Primary drying, for example, would periodically step up the shelf temperature over time in the past, which resulted in long drying cycles that were susceptible to failing. “We now know that the sublimation rate at the beginning of the cycle can be driven very fast, but as the dry layer builds up in the vial, the sublimation rate is reduced and the product temperature increases, so the shelf temperature needs to be reduced,” he adds. “So, today, it is not uncommon to have a high shelf temperature initially and then reduce it for the majority of the cycle, which reduces the primary drying time significantly.”
Knowledge of the vacuum level and its effect on the product temperature has also improved. “In the old days, many freeze dryers did not have a method for vacuum control, and often primary drying was attempted at pressures as low as 5 millitorr. It was believed that the lower the chamber pressure the better,” Thompson notes. “Today, we understand that the chamber pressure should typically be between 60 and 200 mT for the maximum sublimation rates and for proper process control.”
“The literature widely describes lyophilization as time-consuming and expensive,” says Patel. “However, both time and expense are relative. It may seem obvious to compare lyophilized drug products to liquid drug products; however, this is an inappropriate comparison as lyophilization is considered when solution stability is unacceptable.”
Because many biopharmaceutical products are unstable in solution, time and expense spent on lyophilization could be negligible when considering the total cost of manufacturing biological drugs, Patel explains.
“Regarding optimization of the lyophilization cycle time, there are several publications in the literature addressing this topic,” he adds. “Significant progress has been made over the past three decades in terms of heat and mass transfer understanding during the lyophilization process to allow development of the shortest possible lyophilization cycle without impacting product quality attributes. Recent publications (4) demonstrate the application of single-step drying (wherein primary and secondary drying is performed in a single step) that can significantly reduce the lyophilization cycle time.”
For Alexeenko, a key reason as to why lyophilization is time-consuming and expensive is that it is currently a batch process with open-loop controls. “An open-loop process is performed using a fixed and often quite conservative recipe,” they say. “Conversely, closed-loop processes use immediate feedback from process sensors.”
“Processing times for many existing freeze-dried products were developed when our process knowledge was limited, resulting in very long freeze-drying cycles, often lasting a week,” notes Thompson. “However, with our current knowledge of freezing and primary drying process dynamics, the processing times can be dramatically reduced-often to less than 24 hours.”
Overall, industry’s goal for lyophilization is to be able to achieve high quality, lower cost, and more readily available lyophilized products, according to Alexeenko and Topp, who led the development of the Lyophilization Technology Roadmap (5), which was released by LyoHUB in September 2017.
“The roadmap, funded through a grant from the US National Institute of Standards and Technology, was the culmination of two years of workshops and meetings involving over 100 contributors who identified lyophilization needs in products, process, equipment, education, and regulatory interface,” they add. “It identifies two broad areas of effort needed to move toward improving lyophilization: advancing lyophilization technologies and techniques and strengthening the industry foundation.”
Technical innovations will be required across all areas of lyophilization, including the lyophilized products, the lyophilization process, and the lyophilization equipment, they note. “The full implementation of these technical innovations will depend on a strong industry foundation, which will require that the interface between the industry and regulatory agencies be strengthened and that a well-trained workforce be developed and maintained.”
For Thompson, significant improvements to assist in the efficiency of lyophilization would come if closed-loop control was employed based on the product temperature rather than the shelf temperature. “Today, the control process is open loop-the shelf temperature is set and controlled and the chamber pressure is set and controlled, but no adjustments are made during the process based on the critical process parameters,” he says. “The semiconductor industry uses closed-loop control on all of their processes to maintain consistent quality levels. The pharmaceutical industry needs to begin to adopt the same type of process control to ensure quality and reduce processing times.”
A technique that has been discussed and researched for some time is that of controlled ice nucleation. However, uptake of this technique from a commercial standpoint has been slow. “When controlled nucleation was first introduced it was over-marketed as a methodology to reduce primary drying time,” states Thompson. Although it is a technique that is widely available in laboratory freeze dryers, he adds that there are certain road blocks to its implementation within mainstream production.
“There have been significant advances in using controlled ice nucleation in research and development, with over 250 publications on controlled ice nucleation since 2010 (about half of them in the past three years). However, there is still a need for integration of ice nucleation technology in validated manufacturing processes,” agrees Alexeenko.
Patel also concurs with the challenge of availability of controlled ice nucleation at the production scale. “It’s difficult to modify existing freeze-dryers, and new facilities are reluctant to adopt the technology with the argument that controlled nucleation is ‘nice to have’ but not a ‘must have’,” he says. “Controlled nucleation cannot be implemented in early development because there are not many manufacturing facilities that have controlled nucleation capability.”
“The major benefit for controlled nucleation is to produce a consistent ice formation across the batch at the beginning of the freezing cycle,” summarizes Thompson. “Consistency across the batch improves the quality of the finished product. I believe that the best way to justify implementation of controlled nucleation is to improve the quality and consistency of the finished product. If it also reduces process times, it is an added bonus.”
Experts agree that process analytical technology (PAT) is important in the advancement of lyophilization. “PAT is an integral part of the lyophilization process design, development, optimization, and scale-up,” emphasizes Patel. “The information gained about the process performance and the understanding of parameters that could potentially impact product quality are key to building quality within the product rather than testing quality at the end of the process.”
PAT is also vital for industry to achieve closed-loop control in lyophilization, notes Alexeenko. “Many new PAT solutions are being developed and applied now, especially for direct measurement of product temperature, in-situ measurement of lyophilization rate, and tracking non-aqueous solvents in complex formulations,” she adds.
Thompson, however, stresses that the definition of PAT needs to be clear. “PAT is a technology that provides direct measurement of the critical process parameters in real time for process monitoring and control,” he says. “Users need to understand that many of the PAT tools being offered by manufacturers provide information based on indirect measurements and calculations based on assumptions. Many of the tools provide ‘batch average’ information, which does not provide the resolution needed to understand the process variations across a batch of vials.”
A rather controversial topic that has been the subject of much debate over the years is that of cake appearance. “The common misunderstanding is that the end user demands a good look and feel for a lyophilized product or that in certain markets, ‘pharmaceutical elegance’ is critical,” explains Patel. “However, there are no data to support any of these misunderstandings. On the contrary, some of the experiences shared within the industry suggests otherwise (6).”
In partial agreement, Thompson states that cake appearance is very subjective and in fact, a poor cake appearance is not an indicator of an improperly freeze-dried product or poor drug substance. “However, a doctor who takes a vial and is adding water before injection would be very concerned if the cake appeared to be collapsed. They cannot be sure whether the product was exposed to high temperatures or the seal on the vial was compromised,” he says. “New studies show that in some cases, product that has collapsed during freeze drying may result in more stable product that can be fully reconstituted (7). The challenge is whether the doctors in the field will trust the product.”
“Our knowledge and understanding of lyophilization has evolved significantly over the past three decades, particularly in terms of impact of formulation and process on product quality, and active research in the field would further enhance our understanding of the lyophilized drug product,” summarizes Patel.
“However, our progress in the field of lyophilization demands a change in mindset,” he states. “Lyophilization is an established process to deliver a sterile product with existing infrastructure.”
There are several innovations in lyophilization already under development, notes Topp. “These include continuous lyophilization, which could increase the efficiency and throughput of the process; wireless sensors, which would allow for better control of the process and support continuous processing with closed-loop control; computational monitoring, which would allow for better design of lyophilization equipment and facilitate scale-up; and analytical methods, which are enabling more rapid development of lyophilized products and can support manufacturing by evaluating the effects of process deviations on the product,” she asserts.
“With these advancements, as well as those in PAT tools, lyophilization can be monitored and controlled to minimize processing time and cost,” adds Patel. “But, more importantly, lyophilization can deliver a quality product that is stable for commercialization.”
1. Research and Markets, “Lyophilization Services for Biopharmaceuticals, 2017–2027,” report ID: 4229083, April 2017.
2. F. Mirasol, BioPharm Int., 31 (3) 14–17 (2018).
3. PharmTech, “Experts Set a 10-Year Roadmap for Optimizing Lyophilization,” Sep. 14, 2017, accessed Jan. 3, 2019.
4. S.K. Pansare, and S.M. Patel, J. Pharm. Sci., Nov. 20, 2018. pii: S0022-3549(18)30725-1. doi: 10.1016/j.xphs.2018.11.021. [Epub ahead of print].
5. LyoHUB, “LyoHUB Roadmapping,” pharmahub.org, accessed Jan. 3, 2019.
6. S.M. Patel, et al., J. Pharm. Sci., 106 (7) 1706–1721 (2017).
7. E.E. Etzl, G. Winter, and J. Engert, Pharm. Dev. Technol., 19 (2) 213–222 (2014), DOI: 10.3109/10837450.2013.769567.
Vol. 32, No. 4
When referring to this article, please cite it as F. Thomas, “Changing Perceptions: An Understanding of Lyophilization Advancements," BioPharm International 32 (4) 2019.