In general, how has lyophilization technology advanced over the last five years? How have these advances helped pharmaceutical manufacturers?
Zak Yusoff, PMP Senior Product Development Manager SP Scientific, a Division of SP Scientific
Substantial advancements in lyophilization technology have occurred in the last five years namely as a result of research related to the lyophilization process and the incorporation of this knowledge into development tools and equipment design. These advances have resulted in new ways to approach product development or product remediation. One particular example is the use of Manometric Temperature Measurement (MTM) technique during the lyophilization process to accurately determine product characteristics such as product temperature at the sublimation interface, dry layer thickness, product resistance, sublimation rate and other important data across a product batch under certain process conditions. An SP exclusive technology is SMART Freeze-Dryer™ which utilizes the MTM measurement to optimize the primary drying process. With this technology, the system can accurately run the freeze drying cycles based on data provided during the routine MTM measurements conducted during the primary drying process and adjust the shelf temperature accordingly so the critical product temperature is not exceeded during the freeze drying process. SMART Freeze-Dryer™ was developed through partnership between University of Connecticut and Purdue University and partially funded by Center for Pharmaceutical Processing Research (CPPR). Use of other non-invasive technologies such as tunable diode laser absorption spectroscopy (TDLAS) system to measure and monitor product temperature and other product characteristics is another technology that is offered by SP. The technology can be used as a tool to determine primary and secondary drying times. Not only can the TDLAS system be used for process monitoring, it can also be used to determine choked flow condition which can impact the ability of the cycle to be scaled up and provide an understating of equipment capability. Determination of heat vial transfer coefficient (Kv ) can also be easily conducted in one experiment run using this technology, offering time and cost saving benefits that impact the product development effort and are easily scaled up into any freeze dryer.
Replacing a trial and error approach, with a more scientific approach and documenting supporting data has identified critical aspects of the process and product that need to be emphasized during development, scale up, and technology transfer. This knowledge and understanding has helped many products to be developed and transferred more efficiently, yielding financial savings, reduction of waste and better documentation to support a regulatory review process as the product moves from development to clinical phases, and eventually commercial manufacturing.
Controlled ice nucleation is another example where an aspect of the lyophilization process, in this case the freezing process, which could not be efficiently controlled in the past can now be managed. The degree of supercooling, where the product freezes at a much lower temperature than the thermodynamic freezing point, can now be controlled and results in uniform freezing within all vials regardless of placement in the chamber in a shorter time period. In SP’s case this technology known as ControLyo™ Technology employs the use of pressurization and depressurization to induce ice nucleation. The wide spread, prevalent use of this technology by companies for R&D has yielded proven benefits in product development that can be readily scaled to production environments.
As more and more development is performed incorporating these and other technologies, companies are benefiting from and adopting these technologies as part of their standard development process.
Are there significant differences between R&D lyophilization processes and larger scale processes? What should a pharmaceutical manufacturer keep in mind when scaling up a lyophilization process?
There are differences that must be considered between development and production freeze dryer, some of which could have a significant impact on the scale up process. While SP tries to minimize the design differences in build and finishes, there are some elements that cannot be consistently engineered simply because of constraints such as space limitation.
These differences must be considered when designing lyophilization cycles in early stage development. In most cases, R&D freeze dryers are more efficient due to their compact nature. R&D freeze dryer refrigeration can handle the typical process demands. On the other hand, a production freeze dryer may be limited in temperature ramping capability due to its size or have limitations in shelf temperature and pressure control.
The condenser surface area must be appropriately sized for sufficient surface area to condense the water vapor sublimed during the lyophilization process. More and more products such as highly concentrated monoclonal antibodies are being developed with aggressive sublimation rates. Transferring such cycles into a production freeze dryer could be a challenge due to the potential choked flow condition if the vapor port is not designed appropriately. The heat transfer must also be characterized because the differences in surface thickness, surface emissivity, and wall insulation can impact the process. Production equipment capabilities and limitations must be understood and operational qualification must be thoroughly conducted.
Controlling the degree of supercooling in a production freeze dryer is one of the most important aspects of scale up that is often overlooked. The level of particulate count in a laboratory environment compared to the low level of particulate count in an aseptic environment could result in higher degree of supercooling which can affect the ice crystal formation in a clean room environment. By utilizing ControLyo™ Technology the nucleation process can be induced at a higher, defined temperature resulting in larger, more porous ice crystals.
These are just some considerations. As good practice, a formal or informal failure mode effort analysis (FMEA) should be performed in order to address any potential risks associated with the process and to mitigate the effects. More research must be done on a manufacturing scale to understand critical factors that have strong dependencies during the scale up process.
In particular, can you tell me about SP Scientific’s recent advances in lyophilization technology, including the addition of ControLyo™ Technology? What specific issues or concerns of pharmaceutical manufacturers does this technology address?
As discussed previously, ControLyo™ Technology has been proven for scale-up and really addresses the supercooling effect or temperature when a liquid freezes. Manufacturers utilize an annealing process, but this process has limited benefits or applicability to formulations with crystalline components or some partially crystalline components. And, for amorphous products annealing may not be beneficial. These types of products, as well as those which are sensitive to prolonged exposure to high temperatures such as vaccines, can gain benefits when freezing is done quickly, in a controlled manner.
Other benefits such as improved reconstitution time, improved cake appearance, shortened primary drying time, batch homogeneity, maintaining long term stability and maintaining low moisture content have been reported in many scientific papers.
Does ControLyo™ easily lend itself to scale-up? Can a pharmaceutical manufacturer rely on this technology as it scalesup through clinical trials and finally commercial production?
We have observed controlled nucleation protocols developed in R&D freeze dryers are easily scaled up in subsequent freeze dryers regardless of equipment size and using the same parameters used in process development as long as the equipment is pressure rated to ASME or PED certified to a pressure vessel standards. Parameters developed in R&D freeze dryers can be easily used in pilot scale and commercial scale freeze dryers. SP has installed ControLyo™ on several units in the field that have this capability ranging from 20 ft2 to 110 ft2.
SP has collected over 26 pressurization and depressurization cycles on a commercial freeze dryer installed with ControLyo™, and have not observed any issues with the integrity of the equipment. Freeze dryers are designed to withstand numerous steam sterilization processes which employ clean steam, a more corrosive gas than the inert nitrogen or argon used in ControLyo™ Technology.
Regulatory agencies are well versed in the process and have evaluated and published work using ControLyo™. This is encouraging and certainly opens doors to more discussion on how the technology could benefit product submission for faster approval. Moving forward, manufacturers need to strongly consider the substantial advantages to incorporating proven process controls into their manufacturing process knowing that uncontrolled processes could result in heterogeneous products that vary from batch to batch or within a batch itself.
Looking ahead, can you describe some of the technology that will be needed for lyophilizing potent/toxic compounds, products that have very high dollar values and products that might be stored in containers other than glass? Is SP Scientific actively looking at these issues and ready to offer solutions to the industry?
Issues of containment, product safety and personnel safety need to be balanced when planning and designing for overall manufacturing and production including the lyophilization process. Keeping personnel safe is of the utmost importance to the process. Ideally, having a process that can contain the product within an isolated environment would be the perfect solution so exposure to personnel will be minimized and the final product is protected from exposure to external elements. Product safety is also critical to ensure patients are getting products that are safe and the process maintains sterility assurance.
Human intervention in an aseptic process is a hot subject. Minimizing human intervention can minimize the potential of aseptic breach due to introduction of microorganisms into the product. Recent SP advances include investing in new technology not just for freeze dryers, but also for ancillary equipment that supports the lyophilizer and the overall manufacturing process. SP partners with some of the best in the industry to provide solutions to the process such as auto loading and unloading systems for freeze dryers, and stays current with the industry by engaging with organizations such as Center for Pharmaceutical Processing Research (CPPR) and through strong collaborations with industrial partners and universities.
Over the last few years, SP has handled novel container closure requirements that differ from the traditional vials, syringes, bulk tray, or 96 well plate applications being utilized by most customers. Newer requirements often require adaptations or development of new processes and designs, and a recognition that changing a container closure will also impact how the product will behave under the processing conditions. The heat and mass transfer characteristics which will affect the sublimation rate need to be fully understood and studied extensively to ensure the process can be easily scaled from R&D into commercial manufacturing. These process requirements are critical in understanding the technology transfer of a product from one freeze dryer to another.
SP Scientific is prepared to address changing customer requirements on a case by case basis to ensure a solution that offers design practicality, incorporates the most effective technologies and meets stringent final product requirements, specific quality attributes, and is in tandem with other process equipment that will work in conjunction with the freeze dryer. Occupational health and safety requirements are also an integral part of the solution. Our expertise and understanding of lyophilization and current trends allow us to work closely with our customers to identify critical parameters and concerns during the design stage to ensure an engineering and equipment solution that maximizes return.