Methods For Determining Equipment Capability Of Freeze-Dryers

By Gregory Sacha, Ph. D.

Parenteral drugs are typically administered in solution form when the product demonstrates acceptable stability; however, there are instances where the long-term shelf life of a drug solution is not ideal. One effective solution to enhance stability is lyophilization, which transforms the drug into a solid form. This drug manufacturing process involves freezing the formulation, then drying the frozen ice under vacuum and removing any unfrozen residual water. The pharmaceutical freeze-drying technique is continually evolving, driven by advancements in understanding product characteristics, process conditions, and equipment efficiency.

During the development of a lyophilized drug product, a graphical design space is established to illustrate the relationship between process variables and the physical attributes of the product (see Figure 1 at the end of the document below). This design space incorporates parameters intrinsic to the drug product as well as those related to the container and equipment used. The blue trace in Figure 1 indicates the freeze dryer’s capability to support mass transfer during sublimation.

Understanding the capabilities of freeze dryers is crucial for successfully scaling up the lyophilization process from lab to full manufacturing. A key limiting factor in any freeze dryer is a phenomenon known as “choked flow,” which occurs when the velocity of water vapor in the duct connecting the product chamber to the condenser approaches 360 m/sec, or the speed of light. It is vital to have data on this phenomenon to design efficient lyophilization cycles.

Currently, literature on choked flow in freeze dryers is limited. Patel et al. identified the ratio of chamber pressure to condenser pressure as an indicator of choked flow, establishing a threshold of 2.5; any pressure ratio exceeding this value signifies the occurrence of choked flow. Additionally, Kshirsagar et al. employed computational fluid dynamics modeling to predict choked flow, achieving results that aligned closely with experimental findings.

This white paper outlines two experimental methods for determining choked flow: the minimum controllable pressure method and the choke point method.