Lyophilization was first developed in the 1940s, and has been a mainstay of the pharmaceutical industry ever since. The fundamental free-drying methods are fairly straightforward and have remained relatively static over the decades, leading some in the industry to take lyophilization cycle development for granted. In fact, lyophilization is beguilingly complex, and compared to other processes it can be costly and time-intensive.
With the growing demand for biologics there is a greater need for advances in lyophilization cycle development than ever before, as the sublimation process is especially well suited for preserving the structure and potency of protein and peptide drugs. The drive to improve the accuracy and efficiency of lyophilization processes while also reducing their cost led to the formation of the Advanced Lyophilization Technology Hub (LyoHUB) at Purdue University in 2014. In the five years since, innovations in lyophilization cycle development have changed both the methodologies involved and the mindsets behind them.
After remaining fairly static for generations, the process of lyophilization cycle development is undergoing a number of technological innovations.
Less than two years ago, LyoHUB released their Lyophilization Technology Roadmap. Based on both academic and industry input from over 100 leading lyophilization experts, this ten-year technological plan intends to revolutionize a process that has remained relatively unchanged since it was used to preserve the stability of penicillin during World War II. Their most immediate concerns are advancing process models for primary drying and the development of more precise, sensitive instrumentation and sensors.
Among the roadmap’s long-term goals are the development of inline quality monitoring equipment and technology that allows for more close-loop processing.One recent innovation is a miniature mass spectrometer. In addition to the obvious benefits that come from economy of space, these miniature devices monitor both the primary and secondary drying, detect the presence of silicone oil, and come equipped with sensors to identify vacuum leaks. While they are still in the prototype phase, the obvious potential here is exciting.
Not all innovations in lyophilization technology are so dramatic. Some recent advances in lyophilization cycle development are as seemingly simple as condensers and vapor port designs that are better suited for high vapor loads. Refrigeration systems are another arena where minor changes to size and design have yielded vast improvements in reliability and accuracy.
Developing new heating methods may be the next frontier, as volumetric or infrared heating technologies are more accurate and easily monitored than current methods. Cold-plasma and hydrogen peroxide are being investigated as potential alternatives to steam sterilization. Spray-freeze drying may help scaleup for bulk APIs, and more efficient container and closure systems with embedded pressure sensors and temperature gauges have the potential to alter the industry. Of all the many developing advances in lyophilization cycle development, though, few are as intriguing as the field of process analytical technology (PAT).
Process analytical technology (PAT) provides vital tools for lyophilization cycle development in general and closed-loop controls in particular.
One of the main hurdles in lyophilization cycle development has been the inability to directly measure the critical process parameters as they are happening and make adjustments accordingly. Process analytical technology (PAT) promises to change that, allowing for real time monitoring and control of residual moisture, product temperature, and drying rate at every step of the lyophilization process. Beyond the obvious improvements these tools would bring to process control in general, they are absolutely essential to make the jump from open-loop processing to the far more efficient closed-loop control. In addition to reducing the time it takes to process drugs, closed-loop control can also be far more energy efficient and ensures a more consistent, higher quality product.
A new wireless, multi-point temperature system recently designed and evaluated by a team Purdue showcases the potentials of PAT to transform lyophilization cycle development. Testing the sensor array during the lyophilization of sucrose and manntiol solutions yielded exciting results—their new equipment seemed to accurately track the sublimation process and displayed results that closely matched predictions based on simulations. While more testing of this particular device is required, the possibilities of real time monitoring appear to be on the cusp of realization.
New approaches to lyophilization cycle development necessitate a reevaluation of old methodologies and mindsets.
Changes in technology always necessitate a change in viewpoint. Considering how consistent the methodologies of lyophilization cycle development have remained up until quite recently, it is not surprising that certain entrenched ideas may be hard to dispel. Just as a better understanding of vacuum levels, drying processes, critical temperatures have improved the accuracy and efficiency of lyophilization cycle development in the past, maintain an open mind to the ongoing innovations in the field will ensure best practices prevail.