Lyophilization (freeze-drying) has become one of the most popular methods for preparing pharmaceutical formulations. When done correctly, this procedure provides longer shelf-life, greater stability and temperature tolerance, and sometimes even enhanced solubility and bioavailability; particularly for injectables.
The lyophilization process begins in a drying chamber, which reduces the water fraction of the formulation, while a cooling system reduced the temperature. Condensers and vacuum equipment then bring the formulation back up to a higher temperature in a controlled manner, after which it’s placed into an aqueous solution. For best results, all these steps must be completed in a sterile environment.
Some of the most popular applications for lyophilized drug forms are the vaccine, peptide and liposome markets, which have all seen an explosion of growth over the past several years. As lyophilized drugs become more common, guidelines for good laboratory practices (GLP) continue to grow more precise. Here are a few of the areas in which GLP guidelines are particularly crucial when lyophilizing pharmaceutical formulations.
Carefully controlled freezing
Lyophilized drugs must be frozen at extremely precise rates. If freezing occurs too quickly, a greater number of small ice crystals can form, creating resistance to water vapor and lengthening the drying process. Freezing that occurs too slowly, on the other hand, can lead to the formation of fewer, larger ice crystals, creating a coarser pore structure, which also extends the drying time.
In fact, variations in the size and number of ice crystals can significantly affect the formulation’s structure. Excess crystalline formations can damage or destabilize the active pharmaceutical ingredient (API), ruining entire batches of lyophilized product before the problem can even be detected.
What’s more, water that cools too rapidly may lead to supercooling, which can also structurally disrupt the compound. Supercooling can also impact the compound’s physical attributes, causing it to form a “skin” that prevents water vapor from escaping.
Precisely calibrated drying
After the freezing stage is complete, the lyophilized product is then placed in a vacuum, and put through primary and secondary drying processes. First, the pressure in the condensation chamber is lowered, and the heat is gradually increased. If the product dries too quickly, it may escape the chamber with escaping gases; or it may simply melt, rendering the entire batch useless.
Once this primary drying stage is complete, the secondary drying stage reduces residual moisture on the product’s surface. Every product requires different moisture and temperature conditions in the secondary drying stage. These conditions depend on the formulation’s eutectic (melting) point, which is determined in turn by its peptides, proteins and other components, as well as by excipients included in the formulation.
It’s equally crucial to maintain precise control over the chamber pressure. Many manufacturers have turned to automated systems to manage the pressure of the drying chamber, because it can often vary unpredictably, and even a tiny fluctuation can ruin a batch of product late in the drying process.
Balanced heat transfer
Throughout the primary and secondary drying stages, heat must be efficiently transferred through the walls of the vial from the shelf heating element, so it can increase the temperature of the product. This means the angle between the wall and the vial’s bottom surface must be carefully chosen, to make sure heat is proportionately distributed and the risk of breakage is minimized.
One way to improve the balance of heat transfer is to add an inert gas (for example, nitrogen) to the drying chamber. This gas will help spread heat through the chamber and vial, allowing more heat to be transferred into the product, speeding up the drying stages while reducing the energy and work required to complete them.
As lyophilization procedures have grown more efficient and precise over the past few years, GLP now dictates specific pressures, temperatures, drying times, and even vial properties for an ideal product. Many pharmaceutical developers and contract manufacturing organizations (CMOs), in turn, have introduced an increased amount of automation and digital control. Computers typically handle the actual loading of vials in today’s lyophilization facility.
Even so, the need for updated GLP remains clear. While vacuum pumps have achieved greater energy efficiency, many remain unable to handle significant amounts of water vapor. Quite a few labs remain continue to sterilize their equipment by hand, and remain unaware of proper sterilization procedures. Thus, GLP for lyophilization will continue to develop over the coming years.
In addition to being a writer and speaker, Raymond E Peck is the Founder and CEO of VxP Pharma Services and VxP Biologics, both based in Indianapolis Indiana.