Millrock has been developing lyophilization systems since 1957. Why does Millrock continue to focus on one technology and one market?
Millrock focuses on sophisticated laboratory freeze dryers as well as custom pilot/production systems up to 200 square feet. Our laboratory equipment can be supplied as a basic freeze dryer or with the most sophisticated control systems for developing protocols. The demand for sophisticated/custom lyophilizers continues to increase.
What have been some of the major milestones in lyophilization since 1957?
There have been several milestones in freeze drying equipment. Reliable vacuum pumps and refrigeration systems were the first major milestone in lyophilization. Today’s equipment is substantially more reliable than equipment manufactured 20 years ago. The next major milestone was the introduction of instrumentation such as vacuum and temperature sensors. These have enabled us to gain more insight into the freeze drying process. The most recent milestone is the use of PLC’s and Computers for monitoring and control.
You recently debuted LyoPAT™. Can you tell me about what LyoPAT® does and the motivation behind its development?
Today most of the measuring instruments, such as: TDLAS, NIR, and Mass Specs, are expensive, intrusive, interruptive and provide marginal process improvement. Most are not economically feasible for process control. LyoPAT® was developed to provide an affordable method to obtain detailed information on critical process parameters. The technique enables the user to characterize their existing recipes/protocols and then apply incremental techniques to determine their effect on the process. For example, the user can execute their existing protocol and then apply controlled nucleation and controlled heat flow to determine the effect on Thermal Conductivity of the Vial (Kv), Mass Flow, Product Cake Resistance (Rp), and Product Temperature.
LyoPAT gives the user access to information that did not exist before and on a continuous basis for the entire freeze drying cycle, including; freezing, primary drying and secondary drying. This information enhances the development capabilities of your freeze dryer and provides alternatives for scalability as well as quality control.
Methods using an average measurement of the product in the chamber, such as calculated via pressure rise testing, adjust the temperature of the shelves a few times through the first half of the primary drying process. This process is limited to only the first half of primary drying and only provides a conservative protocol, but is not optimized and does not take into account variations inside the chamber.
Ways that LyoPAT can be used:
- Analyze an existing freeze drying recipe
- See the freezing process in heat transfer terms
- Measure heat flow continuously
- Measure Kv continuously
- Determine your sublimation rate and product resistance
- Determine the optimal application design space
- Vary the shelf temperature and pressure and analyze the product temperature and sublimation rate
- Develop transferrable protocols between the Lab and Production
- Determine the effect of Controlled Nucleation on your Process
- Control the crystal growth rate post nucleation and determine the effect
- Control the product temperature in primary drying without the use of a thermocouple
What is the benefit of applying Process Analytical Technology with the freezing and primary drying phases of freeze drying?
True PAT, meaning a technique that is applied continuously in-process and for all phases of the process. LyoPAT® provides this ability. Freezing is the basis for an efficient and repeatable freeze drying process. The key to freezing is the ability to produce the same ice crystal structure across the batch and inside the vial. LyoPAT provides both FreezeBooster® Controlled nucleation (produces the first 10% of the ice crystal growth) and AccuFlux® heat flow control for controlling the remaining 90% of the crystal growth. The combination has never been in achieved before.
Classic primary drying control is open loop; the shelf temperature and chamber pressure are controlled based on a predetermined profile and it is assumed that the temperature of the product stays below its critical temperature. The result is a very conservative and long freeze drying cycle. Closed loop control of the product temperature is required to both prevent collapse and minimize the length of the freeze drying cycle. The latest control systems use the critical temperature information to dynamically control the shelf temperature, which both protects against collapse and melt-back while optimizing the freeze drying cycle.
What do you think the future of lyophilization might hold?
In the next few years, Process Control and PAT will be the major considerations for freeze dryers. Currently, the freeze drying process is an open loop control with very little monitoring in-situ. So, the processing company may not know there is a faulty run until the freeze drying run is completed. New technologies, such as LyoPAT®, monitor the process and can be used to determine if there have been changes to the process, such as: loss of fluid flow inside the shelf, change in vial type or vial fill, and any change that may affect the process dynamics.
The need for smaller and more sophisticated freeze dryers continues to grow. As technology progresses, drug potency increases and the amount of overall product in each vial is significantly reduced. Thus, smaller vials are being used more frequently and the value of the product is ever increasing. In most cases, the higher potency drugs require safer handling, isolators and some form of sterilization.