Optimizing Lyophilization Cycles (Freeze Drying) by Removing “Trial and Error”

An innovative new technology promises to eliminate the “trial-and-error” element from developing lyophilization processes, allowing users to optimize lyophilization cycles and guarantee a smooth transfer from laboratory to production scale.

The process of lyophilization involves drying a product in a frozen state under vacuum to optimize product stability, reducing the effects of degradation and oxidation, and to improve the shelf life of the product.

The process has been used to preserve products such as water-damaged documents, biologicals, tissue preparations, bacterial cultures, and therapeutic; and food products, such as antibodies vaccines, proteins, and drugs. The ongoing discovery and development of protein-based therapeutics has been driving an increasing need for enhancements in freeze-drying process development.

Process Development Challenges

Two major challenges in lyophilization today include developing an improved lyophilization cycle and overcoming the scale-up issues that arise from lab and production/pilot-scale unit cycles. Gaining insights into the lyophilizer performance and the properties of the product are crucial for successful freeze-drying.

Various products that are freeze-dried, such as protein-based therapeutics, are in short supply and can be very costly to produce. Lyophilization is a process that requires extensive time and energy, and can take days or even weeks to complete.

The process of lyophilization cycle development can be shortened to develop an optimized lyophilization cycle that can accelerate development time, increase efficiency and thus minimize time-to-market, and save valuable product. The most efficient drying cycle should be enabled by the transfer of an improved lyophilization cycle from the development stage to the production scale, thereby further increasing the return on investment.

In the lyophilization process, the product is first frozen to a temperature at which a rigid solid is formed by all formulation components. The next step is primary drying, which involves the removal of up to 95% of the frozen water or ice. Controlled temperature shelves are employed during primary drying to provide the energy for sublimation of ice.

In turn, it is necessary to control the pressure in the chamber such that it is possible to add heat to the product to enable sublimation of water, without resulting in instability or melting of the already dried product matrix. The sublimated water vapor from the product enters the product chamber and the pressure differential between the condenser and the product chamber makes the sublimated water travel to the condenser.

Subsequently, it is frozen onto the plates or coils in the condenser, thereby assisting the condenser to stay in a low-pressure condition in relation to the product chamber (1). Any water that was not removed at the time of primary drying is removed during a secondary, desorption drying stage.

The crucial parameters in the development of a lyophilization cycle — and consequently successful freeze-drying — are knowledge of the stability of the active pharmaceutical ingredient, the collapse temperature of the formulation, and the characteristics of the excipients (2).

Apart from the characteristics of the formulation, system geometry, shelf temperature, the product container, and chamber pressure all have critical roles in developing the lyophilization cycle. Various lyophilization processes are developed through a “trial-and-error” process that usually leads to non-optimized lyophilization cycles that might not carry well from the laboratory to production scale-up.

Accelerating Lyophilization Cycle Development

SP Scientific has commercialized a technology — SMART Freeze-Dryer™ Technology — for speeding up and streamlining the lyophilization cycles development. The technology, which was developed through a collaboration between the University of Connecticut and Purdue University and partially funded through the Center for Pharmaceutical Processing Research (CPPR), runs on a LyoStar II System (see Figure 1) and offers new as well as experienced lyophilization researchers a means of developing optimized lyophilization cycles with a decrease in average cycle development time of up to 78%, based on independent testing results.

The technology minimizes the process of average cycle development to one or two runs, as against the traditional sequence of six to eight runs, thus reducing development time and minimizing materials costs by one-third or more. This provides the development researcher with more time for analyzing other factors that assist in an optimized lyophilization cycle, for example, excipient choices and parameter extremes, as well as their consequent impact on the freeze-dried product.

Figure 1

The underlying principle of the technology is the use of manometric temperature measurement (MTM). This ensures precise calculation of the product temperature at the sublimation interface, by eliminating the need to place thermocouples or other temperature sensors in the product vials. It is crucial to measure the product temperature at the sublimation interface to determine the accurate parameters to prevent “melt back” or product collapse during primary drying.

The traditional technique for evaluating product temperature at the time of a freeze-drying cycle is to position a few selected temperature sensors in vials. However, it has to be noted that this may have an impact on the freezing and drying behavior of the samples by bringing about ice nucleation or functioning as a thermal pathway.

These problems render the placement of a thermocouple inside a vial a poor representation for what actually takes place in most of the vials present in the product chamber. Moreover, thermocouples or temperature sensors positioned in vials are placed near the bottom of the vial, and not at the sublimation interface.

Hence, they do not give a precise measurement of product temperature at the sublimation-ice interface (1). At times, it would be challenging to place the thermocouples repeatedly in the same position, and they have their own inherent flaws across their temperature range.

The MTM technique involves placing an isolation valve between the product drying chamber and the freeze-dryer condenser. Before running a SMART lyophilization cycle, the important input parameters are the number of product vials, the fill-volume of the vials, whether the product is crystalline or amorphous, and the eutectic point or collapse temperature of the product.

When the lyophilization cycle is carried out, the isolation valve closes automatically and rapidly, and the increase in pressure is measured for 25 seconds at regular intervals at the time of primary drying. The raw data is gathered and employed in the MTM equation to compute the product temperature at the ice surface interface, the thickness of ice, the dried layer resistance, and the mass transfer and heat flow.

Subsequently, this information is used to automatically adjust the vacuum set points and the shelf of the lyophilizer at the time of freeze-drying, thereby realizing and maintaining the product temperature accurately at the target temperature through the entire lyophilization cycle.

Practically, acquiring optimal MTM data requires a minimum product surface area of greater than 300 cm2 or three-quarters of a sample tray. Other needs are the placement of the sample in an aqueous solvent, a relatively leak-free lyophilization system, the recommended solids being between 3% and 15%, and the optimal vial fill being one-third the volume of the chosen product container.

Critical Parameters in Cycle Development

One of the crucial parameters for successful development of the lyophilization cycle with the help of the SMART Freeze-Dryer Technology is the temperature at which the product has to be maintained through the entire primary drying stage.

This critical temperature is ascertained from the collapse temperature (Tc) or the glass transition temperature of the product (Tg) (3). In general, these values are determined using freeze-dry microscopy or differential scanning calorimetry (DSC). The accuracy of the input parameters for creating a SMART lyophilization cycle will govern the quality of the MTM fit and hence the ensuing lyophilization process design.

Figure 2 illustrates the steps in the operation of the SMART Freeze-Dryer Technology. The software automatically selects an initial temperature and pressure based on user input. Upon moving to primary drying, MTM measurements get started and are fed into the SMART algorithms to ascertain the product temperature at the sublimation surface.


The software offers real-time data on the ice thickness, product resistance, and heat transfer flow at the time of primary drying (see Figure 3). These process measurements can be used to automatically adjust the shelf temperature and drying chamber pressure to maintain the optimal product temperature through the entire primary drying stage. Subsequently, the termination of primary drying is detected and then the process automatically advances into secondary drying. When the process ended, an optimized lyophilization cycle is delivered, together with all the process data.

The SMART Freeze-Dryer software provides real-time data on product resistance, ice thickness, and heat transfer flow during primary drying.

Figure 3. The SMART Freeze-Dryer software provides real-time data on product resistance, ice thickness, and heat transfer flow during primary drying.

The outcomes of two case studies of process development savings accomplished by using SMART Freeze-Dryer Technology are illustrated in Figure 4. Both the laboratories reported breaking even on their investment in new technology within a period of three months. Primary savings were accomplished through the potential to ensure an optimized lyophilization cycle following only a few experimental runs.

The average time developing the cycle was reduced by 78% or 62 days. Development savings, essentially in the form of active ingredient material costs and labor, averaged $40,029. Considering an average of eight development programs in a year, the average annual savings are $320,232.

Results from two case studies of process development savings that were achieved by applying SMART Freeze-Dryer Technology.

Figure 4. Results from two case studies of process development savings that were achieved by applying SMART Freeze-Dryer Technology.


Apart from enabling an optimized freeze-drying cycle, SMART sample data output also offers the MTM data to the user to gain better insights into the freeze-drying process and troubleshoot freeze-drying protocols.

The FDA has been encouraging pharmaceutical manufacturers through its process analytic technology (PAT) initiative (4,5) to gain insights into and control process parameters to ensure the quality of product manufacturing by design. SMART Freeze-Dryer Technology is a PAT tool for the identification and reporting of crucial parameters at the time of the product freeze-drying formulation process that can be later monitored at the time of the freeze-drying production to preserve product quality.

Developments are ongoing to enhance the technology as a PAT tool. These enhancements will enable MTM measurements to be gathered on standard or existing freeze-drying cycles. Researchers can run their standard freeze-drying cycles and gather MTM data such as product temperature calculations, resistance measurements, and heat-flow calculations. This supplementary data will offer considerable benefits in trouble-shooting currently used freeze-dryer cycles, and validating variations or adjustments to legacy protocols.

The need for enhanced techniques in freeze-drying process development is increasing continuously — specifically with the continuous progress in protein-based therapeutics. This, in combination with the FDA’s PAT initiative, renders the development of tools like SMART significant in creating robust freeze-drying protocols, and offering the critical data required to find out parameters that have to be monitored and controlled at the time of product production.


  1. Tang, X., Nail, S.L., Pikal, M.J. Evaluation of Manometric Temperature Measurement, a Process Analytical Technology Tool for Freeze-Drying: Part I, Product Temperature Measurement. AAPS PharmeSciTech 2006, 7(1), E1-E9.
  2. Tang, X., Pikal, M.J. Design of Freeze-Drying Processes for Pharmaceuticals: Practical Advice. Pharmaceutical Research 2004, 21(2), 191-200.
  3. Gieseler, H., Lee, H., Mulherkar, B., Pikal, M.J. Applicability of Manometric Temperature Measurement (MTM) and SMART Freeze Dryer Technology to Development of an Optimized Freeze Drying Cycle: Preliminary Investigations of Two Amorphous Systems. 1st European Congress on Life Science Process Technology 2005, October 11-13, Nuremberg, Germany.
  4. U.S. FDA Center for Drug Evaluation and Research, http://www.fda.gov/Cder/OPS/PAT.htm
  5. Gieseler, Henning, PAT for freeze drying: cycle optimization in the laboratory. European Pharmaceutical Review 2007, Issue 1, 62-67.

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Last updated: Nov 2, 2018 at 11:20 AM

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