Basic Cycle Development Techniques For Lyophilized Products

By J. Jeff Schwegman

In the early days of lyophilization cycle design, it was not uncommon for development scientists to run upwards of 15 to 20 pilot runs to develop a cycle that worked well for their product in commercial manufacturing. In many of these cases, the main criteria for determining if the cycle was acceptable was based on the physical appearance of the dried product (solid, intact cake), the reconstitution time, the residual moisture content, and the stability of the active ingredient (immediately after freeze-drying and after long term storage). While these attributes are still important today and must still be achieved from a lyophilization cycle, modern lyophilization cycle design must also take into account the time that it takes to dry these products.

When talking about cycle optimization, the question that begs to be asked is, why worry about how long it takes to freeze-dry a product if one is achieving product that consistently looks good and meets all of the release specifications? The answer to this question is that it doesn’t matter at all for a company that is only producing several batches of product a year (for example a product with orphan drug status). In these cases it would likely take more time and effort to optimize the cycle than the time savings that could be saved by doing such.

However, for those drug products that are produced regularly on a large scale, cycle optimization is critical for two distinct reasons. The first reason simply comes down to the manufacturing costs. It is well understood that commercial freeze-drying is the most expensive unit operation as part of a complete manufacturing process. This cost increases dramatically the longer the product spends in the freeze-dryer.