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The general principle of lyophilization has hardly changed, but significant advances have occurred in process and product attribute understanding.
Lyophilization is a well-established technique within the bio/pharmaceutical industry and is a necessity for certain drug products that include unstable ingredients, require longer shelf-lives, or are temperature-sensitive. The lyophilized drug market is expected to grow at a compound annual rate of approximately 7%, according to market research, mainly driven by increasing regulatory approvals for lyophilized formulations (1).
“The primary benefit of lyophilization is improved product stability,” explains Andrew Morbey, associate director of process development, LSNE Contract Manufacturing. “This can manifest as additional shelf-life at frozen, refrigerated, or ambient storage conditions or as equivalent stability at an increased storage temperature. In many cases, this eliminates the need for cold chain shipping and storage, reducing risk during manufacturing.”
Stephan Reuter, managing director, Optima Pharma in Gladenbach-Mornshausen emphasizes that the greatest advantage of lyophilization is the stable formulation result, which subsequently impacts the success of a development program. “The development of drugs is a very costly and time-consuming process, and always runs the potential risk of not being successful,” he says. “Many substances would not be stable without freeze-drying technology, which creates a durable product and retains effectiveness.”
Additionally, as the formulation is filled as a liquid, there is compatibility with almost all filling lines and little variability occurs as a liquid formulation is amenable to maintaining proper fill weights, asserts Gregory Sacha, senior research scientist, Baxter BioPharma Solutions. “Sterility of the product can also be maintained and achieved,” he says. “The moving parts of the equipment, such as compressors, are located in an equipment maintenance area on the other side of the aseptic manufacturing area. This keeps the area clean and reduces introduction of foreign particles.”
A further advantage of lyophilization lies in the fact that the process requires low temperature and so is suitable for heat sensitive drug substances or those prone to degradation from hydrolysis, Morbey continues. “Other advantages include the ability to reconstitute to the desired concentration at the time of use and reducing shipping costs due to lower finished product weight compared to liquid products,” he notes.
A challenge for lyophilization is that not all molecules are stable as freeze-dried solids. “For example, some cephalosporins remain amorphous and are less stable than when in the crystalline form,” stresses Sacha.
For Morbey, a major disadvantage of freeze-drying is the development of appropriate formulations that are suitable for lyophilization. “Not all liquid formulations are suitable for lyophilization,” he confirms. “The appropriate buffers, cryoprotectants, bulking agents, and tonicity modifiers need to be carefully selected to provide both stability to the formulated drug substance and properties suitable for lyophilization.”
“Volatile compounds, such as acetate buffers, can be removed by high vacuum, which can result in changes of the final product pH,” notes Sacha. Additionally, he specifies that not all solutes can be dried to a form with an acceptable appearance. “For example, formulations prepared with high salt concentrations have low melting points and are difficult to freeze-dry,” he says.
Development of the lyophilization cycle can also be challenging, requiring extensive expertise, particularly for turnkey projects, highlights Reuter.
Each cycle is unique to the formulation and requires expertise to ensure product quality, agrees Morbey. “Most cycles are 24 to 96 hours; however, some products require conditions that extend the cycle length beyond 192 hours. A consistent challenge to lyophilization is the expertise required to develop a cycle appropriately to fit both equipment and product limitations,” he states. “Some lyophilization cycles are not suitable for commercial scale lyophilizers because there is little consideration for refrigeration capacity, system capabilities, or variation in equipment capabilities. Without the awareness of these challenges, there could be considerable impact to the product.”
“There have been few changes to lyophilization equipment, but there have been large changes in understanding and conducting the lyophilization process,” remarks Sacha. “For example, process development was achieved by trial and error and, in some cases, it still is. However, today process development is often approached using the first principles of heat and mass transfer to understand the process.”
Understanding the process involves a thorough thermal characterization of the formulation so that the failure point during primary drying can be known, continues Sacha. Additionally, an understanding of the capability of the equipment, determining the heat transfer coefficient for the specific vial, and determining the resistance to mass transfer of the drying solid are required. “The data are used to develop a design space for primary drying that identifies the most efficient process conditions, as well as the conditions that may lead to failure of the product,” Sacha adds.
Morbey agrees that despite the lack of changes in the lyophilization process over the past 15 years at a commercial scale, the laboratory and academic settings have seen great advances in the understanding of each individual step of the process and the impact on product critical quality attributes (CQAs). “These advancements include controlled nucleation to improve the thermal treatment phase,” he says. “Understanding of container specific heat transfer coefficients, mass flow and heat flux, and implementation of process analytical technology (PAT) devices to aid in primary and secondary drying end point determination have supplemented the development of the drying phases of lyophilization.”
Significant advancement toward the automatic loading/unloading systems have been seen throughout the supporting manufacturing activities, Morbey continues. These advancements have limited the need for operator intervention and, hence, mitigated risks to sterility. And, isolator technology has also advanced, he adds.
“The development of freeze-drying technology is based on product development, since freeze-drying has a massive influence on the product. Therefore, innovations must be adapted to product development,” reveals Reuter. “This reasoning is why the general principle of freeze-drying has not changed in the last 30 to 40 years, but freeze-dryers have become faster and more effective. They are more accurately adjustable, and alternative, more environmentally friendly refrigerants are increasingly being used.”
It is possible to drastically reduce processing time by building a primary drying design space based on the first principles of heat and mass transfer, emphasizes Sacha. “Data obtained through this design space can also be used to support deviations in shelf temperature and chamber pressure that may occur during routine production,” he says. “The technique also demonstrates that the company has a good understanding of the equipment and how the formulation can affect processing conditions.”
“The simulation of processes during freeze-drying and their influence on each other can give a better understanding of the process itself,” adds Reuter. “The integration of the products’ properties in the simulation, which has to be freeze-dried, allows improvements in the process by predicting what the product quality attributes will be at the end of the freeze-drying. So, nowadays it is theoretically possible to define lyophilization process parameters with very high accuracy. If the freeze-drying parameters are defined correctly, the entire process achieves the best efficiency.”
However, verification and qualification of the process are still required, Reuter continues, which leads on to the instrumentation. “A number of new sensors are available now on the market to monitor and control the lyophilization process with very high accuracy,” he explains. “Through these sensors it is possible to save time and energy, and, hence, make the process more efficient.”
The majority of equipment advancements were created to aid in the development, optimization, and characterization of lyophilization cycles so that it would be possible to effectively transfer cycles to commercial‑scale equipment, emphasizes Morbey. “Most drug product manufacturers do not have the luxury of performing lyophilization cycle development activities on the intended commercial‑scale freeze-dryer. Therefore, a comprehensive understanding of the product’s characteristics and equipment is required to ensure product quality is maintained when scaling up to commercial‑scale production,” he says. “Product characterization using modulated differential scanning calorimetry and freeze-dry microscopy is now standard practice. New technologies are being developed to supplement these tests and better understand the product.”
Equipment process improvement for analytical technologies include tunable diode laser absorption spectrometry, heat flux measurements, end of primary drying determination, and in-line mass spectrometry, Morbey continues. “Implementation of these technologies during the development phase, in most instances, has increased the overall time, energy, and cost of development services. However, the benefit is realized through seamless transitions from development scale to production scale,” he notes. “Complete process and product understanding following quality-by-design principles takes time; however, a standardized approach for lyophilization cycle development together with experienced scientists capable of utilizing the available PAT devices can streamline the development process.”
An additional growth factor for lyophilization is the rising proportion of biologics in development pipelines. “The industry evolution toward biologics is making the need for lyophilization more prevalent,” confirms Morbey. “Many biologics are not stable in solution and, as such, need to be lyophilized.”
Morbey iterates that there are even some instances where lyophilized biologic drug products form aggregates on stability. In such cases, it is necessary to revisit the formulation and add surfactants or additional excipients so that the aggregation is inhibited. Formulation scientists should be able to build upon previous experiences to inform development activities prior to the issues arising, he notes.
“The high cost for biologic drug substance development and manufacture translates to smaller drug product batch sizes in order to reduce risk. For lyophilization development scientists, this enforces the importance of formulation and cycle development to ensure minimal product loss,” Morbey stresses. “Some high-volume parenteral manufacturers may be accepting of 90–95% yield from 200,000+ unit batches when producing 30 million units a year. For low volume, high-value lyophilized biologics every dose is important. Unnecessary manufacturing line loss and rejects caused by inadequate lyophilization practices are not acceptable.”
For Sacha, the increased need for lyophilization as a result of the rising proportion of biologics will be a long-term effect unless combinations of excipients are developed that can offer the same, or better, stability improvements as freeze-drying. “The challenge with freeze-drying biologics is that they can be sensitive to the stresses of freezing and drying” he says. “This issue requires study of the biologics’ sensitivity to interfacial interactions and loss of residual moisture to determine if certain protective agents are needed in the formulation.”
Turning the attention to highly potent compounds in general, Reuter notes that the processing of such pharmaceuticals puts special demands on the cleaning concept and construction of pharmaceutical plants so that safety of both the product and human life can be assured. “It is, therefore, important to develop a comprehensive and holistic process for the filling and processing of highly potent substances, including comprehensive pressure and wastewater concepts, for example,” he adds.
“Many of the highly potent molecules are both poorly soluble in aqueous solutions and unstable in solution. There have been a rising number of requests to lyophilize formulations that consist of 100% organic solvent or co-solvents,” Morbey says. “Lyophilization of organic solvent systems provides unique challenges to the development program and its equipment. The handling of the formulation and compatibilities of the material contact and equipment, need to be fully understood.”
Additionally, the development scientist must comprehend how to remove the organic solvents from the cake to residual levels without affecting other product quality attributes, asserts Morbey. “Hopefully, the trend towards higher value biologics and highly potent drugs translates to an increased understanding of the importance of the development activities. As quality-by-design approaches prove their worth, we expect this trend to continue well into the future.”
Despite the fact that not all vaccines need to be freeze-dried, there is an overall positive impact on the demand for lyophilization happening as a result of the current pandemic situation, highlights Reuter. “Freeze-drying is the best way to safely and quickly achieve a successful formulation and facilitates the transport of pharmaceuticals to warmer regions,” he says. “Whether this is a long-term trend, however, cannot be assessed at this point in time.”
“In the short term, product stability for the COVID-19 vaccines will not be an issue in developed countries with cold supply chain capabilities because doses will likely be administered rapidly after manufacture,” Morbey adds. “However, with the potential for additional waves of the virus and the unknown approval timeline, it will be critical to stockpile both vaccines and therapies in order to have product available to meet future demand. I am quite confident that many vaccines are currently being simultaneously developed as both a liquid and lyophilized dosage form.”
The same principle applies to proven anti-viral products, Morbey asserts. “If the liquid presentation is stable for 12 months but the lyophilized presentation is stable for four years, the current demand does not require more than 12 months of shelf-life,” he explains. “However, once the pandemic is under control, shelf life may become prohibitive for maintaining stockpiles to combat new outbreaks. For under-developed countries without cold supply chain capabilities, stable lyophilized vaccine and therapies are needed.”
Sacha remarks on the development of mRNA platforms, which are not necessarily very stable in solution at room temperature. “These platforms may require cold storage that creates challenges for effective distribution around the world,” he states. “There is a potential that lyophilization can simplify the supply chain for these vaccines and facilitate widespread, global vaccination efforts.”
A further impact of COVID-19 is in the form of manufacturing capacity, which is being exhausted, continues Morbey. “Government agencies have acted quickly to buy manufacturing capacity from large contract manufacturers to support mass production of vaccines,” he says. “With reduced liquid manufacturing capacity, drug developers can look to lyophilized presentations as a first step instead of a last resort.”
Two trends are particularly important in Morbey’s opinion to continue gaining traction within the industry—understanding the importance of product specific lyophilization cycle development, and standardization of lyophilization equipment capabilities, controls, and PAT. “Cycle development is critical to ensure product quality and is dependent on the formulation characteristics and freeze-dryer capabilities,” he notes. “Technologies exist to fully characterize and understand product characteristics and develop cycles appropriately. When cycles are implemented on out-dated equipment or poorly controlled equipment, all the development and optimization efforts can be thrown out the window.”
Increasing system complexity, efficiency, and flexibility is a primary trend for Reuter. “As a result, there is an impulse to implement new technologies in the lyophilization system, for example PAT tools—not only for process monitoring but moreover for process control, making the process parameters adjustable within an allowable range,” he says. “Through better process understanding it is possible to significantly reduce the freeze-drying process duration and in combination with highly flexible fill/finish systems, small batches with rapidly changing container types, formats and ingredients can be processed.”
Another trend highlighted by Sacha is a reduction in the size of the lyophilizer itself so that efficiency can be increased. “Smaller lyophilizers may be needed to accommodate smaller volumes of product,” he states. “Biologic formulations are typically processed in smaller volumes than for many small molecule formulations and the formulations are quite expensive. Operating with smaller equipment will reduce loss of material and may improve handling of the product.”
Replacing currently used refrigerants with more environmentally friendly ones is also a consideration of Reuter. “Furthermore, investigating and implementing alternative heat sources, such as infrared or microwave, may also improve system efficiency and make lyophilization more attractive,” he comments. “For some lyophilized products, continuous manufacturing can be beneficial and spray freeze-drying has a positive future for certain application fields.”
“Manufacturing of lyophilized dosage forms is a tried and true process for organizations with this expertise. Significant changes are not needed; however, continuous improvement of equipment controls, PAT devices, and implementation of process understanding at commercial scale will lead to improvements in lyophilization practices industry wide,” Morbey concludes. “With the right equipment, quality systems, and development expertise, the lyophilization process is a low-risk operation with significant benefits to the product.”
1. Coherent Market Insights, “Lyophilized Drugs Market Analysis,” coherentmarketinsights.com, Market Report, July 2019.
Felicity Thomas is the European editor for Pharmaceutical Technology Group.
Vol. 44, No. 9
When referring to this article, please cite it as F. Thomas, “Advancing Understanding of a Traditional Technique,” Pharmaceutical Technology 44 (9) 2020.