With lyophilization now a prevalent method for stabilizing unstable compounds, the task for pharmaceutical scientists is to develop an efficient process that results in an effective product. One goal is reducing lyophilization cycle time, which may involve modifying the cycle, the product, the package, or a combination of the three.
A review of the current cycle is the starting point for modification. Some cycles incorporate long freezing hold times at -40 to –45°C. Often these long hold times are the result of scheduling convenience for the original cycle developer, since there are no standard time lines. The appropriate time should be determined by test and data. Through investigation, we may discover that we can reduce the cycle, dramatically in some cases, from five days to three days or even less. The lyophilization cycle scientist will verify through thermal analysis the temperatures at which the product freezes and melts. It is also important to monitor both the shelf temperature and the product temperature, because in the primary drying phase (when product temperature and shelf temperature are equal) further drying results in inefficient use of energy and time. This is a point where efficiency can often be enhanced.
In the secondary drying phase, which may take from two hours to two days or longer, the amount of adsorbed moisture is decreasing. A similar monitoring process that defines the relationship between product temperature, shelf temperature, and pressure may again reveal an excessive expenditure of time and, consequently, the opportunity exists to shorten this step as well.
Modifying the Product
A review of preformulation data may reveal product physical or chemical parameters that may be changed, such as the solvent system. In many cases, it is possible to increase the concentration of active drug substance, reducing the amount of solvent sublimed, which in turn reduces the time that it takes for the primary drying phase. This decision must be based on the preformulation data. If the customer has already maximized the concentration, there is no need to explore this avenue.
Modifying the Package
If the customer is not committed to a specific vial size, the manufacturer may be able to design a more optimum cycle. Increasing vial size increases surface area, which will increase the sublimation rate without affecting the cake quality. After the decision has been made to reduce the lyophilization cycle, a lab-scale batch should be run for verification. A 20-vial run, for example, in a laboratory freeze-dryer avoids jeopardizing large amounts of raw material in the pilot or manufacturing process. Once the test run has proven the effectiveness of the changes, the manufacturer writes up a new cycle for the production equipment.
SP Pharmaceuticals has discovered that pursuing these steps for an optimum cycle can reduce considerable time off the lyophilization cycle, and result in major savings after one or two commercial lots.
SP Pharmaceuticals LLC is a privately owned company specializing in manufacturing small-volume parenteral drugs and developing new pharmaceutical products and formulas on a contract basis. SP emerged from the management buyout of Pharmacia & Upjohn's small-volume sterile injectables division.
Thomas R. Kovalcik is a senior scientist in the Pharmaceutical Research Department of SP. A graduate of Duquesne University and the University of Iowa, Kovalcik previously managed product development at Curatek Pharmaceuticals. At SP, he is responsible for lyophilization and vacuum drying cycle development, liposomal formulation development and processing, and compatibility screening and testing.
For more information: Thomas R. Kovalcik, SP Pharmaceuticals LLC, 4272 Balloon Park Road NE, Albuquerque, NM 87109. Tel: 505-345-0500. Fax: 505-761-9229.