The New Scope of Pharmaceutical Lyophilization
A great deal of thought, time and money goes into developing and creating quality pharmaceuticals, nutraceuticals and other products. Therefore, it is not surprising that maintaining the inherent qualities of these compounds is of great importance. Every preservation method and service comes with a price, however, and manufacturers must decide how to preserve quality while still adhering to their budget.
Lyophilization (also known as freeze drying) is often an ideal solution for manufacturers that are attempting to preserve the characteristics of an unstable or delicate product. The process offers a number of benefits that are difficult to replicate, often making its slightly higher price tag well worth the cost. To find out more about the benefits of lyophilization and how the process is evolving, Pharmaceutical Processing spoke with providers of lyophilization machinery and lyophilization contract services.
Products with limited shelf lives, highly potent characteristics, unstable natures and sensitivities to exterior influences are often lyophilized not only to protect them from outside elements, but also to protect them from their own eventual decay.
Lyophilization is used not only for vaccines, but also for blood products,
cytostatics and cosmetic-related products. (Photo courtesy of Optima Machinery Corp.)
“When a product is determined to have a limited shelf life in the non-dry state, a method of drying is considered,” explains Todd Reihbandt from Millrock Technology Inc., a provider of lyophilization systems for applications ranging from the laboratory to cGMP production. “Although not the least expensive method for drying, often freeze drying is the only method available that can maintain the viability of the product being dried.”
Although the steps of lyophilization are sometimes expanded to include the stoppering of vials, or broken down into even more specific stages, the method is typically described as a three-step process that includes freezing, primary drying and secondary drying.
Reihbandt explains that the freezing stage is often the most overlooked, yet it is arguably the most important, since “proper freezing will enable a more efficient and repeatable drying process.” Because proper freezing is essential, Reihbandt stresses the benefits of controlled nucleation, which consistently freezes vials at the same rate and temperature, resulting in “consistent ice structure across the batch.”
The freezing stage is followed by primary drying (sublimination) — typically the longest step — which removes unbound moisture from the product. Secondary drying (desorption) completes the process and “drives the ionically bound water from the material,” explains Reihbandt. Secondary drying can often “result in moisture levels of 0.5 percent,” he adds.
Controlling the Rate of Drying
It is essential to closely control the rate of drying during the lyophilizaton process, since the freezing and secondary drying stages will be affected by an improper drying stage. Stefano Chiaramonti from Patheon Inc., a contract services company that offers extensive expertise in the development and scale-up of freeze-dried products, explains that an overly rapid drying process can result in the dried product being “blown out of the container by escaping water vapor” and the dried product can even “melt or collapse.” Chiaramonti says that these mistakes can result in product degradation and changes to the physical characteristics of the material, therefore making it both “visually unappealing and harder to reconstitute.”
Freeze drying is a reliable way to reduce negative influences on products.
(Photo courtesy of Optima Machinery Corp.)
There are a number of technologies that can help manufacturers avoid these mistakes. Jens Gemmecker from Optima Machinery Corp.’s Klee brand, which offers sterilizable freeze-drying plants (lyophilizers) that are particularly designed to meet the requirements of the pharmaceutical industry, says that a multitude of sensors can help analyze the “gas composition within a chamber.” He also explains that “for achieving a constant quality and homogenous drying properties, the exact temperature control of the shelves where vials are placed, as well as optimized starting conditions for all vials, are decisive.” As an overall rule of thumb, he explains that it is essential that “the machine’s overall concept guarantees a good performance.” He emphasizes the importance of focusing on the complete package, not the individual parts of the process.
Reihbandt says that “controlled nucleation is the best method for accurately controlling the freezing portion of the process,” because freezing without controlled nucleation produces “different crystal structures and inconsistent pore sizes in the product, resulting in longer primary drying cycles.” He also explains that special software, such as the company’s Auto-Dry system, can help control and optimize the cycle, therefore producing a better end product.
The Changing Scope of Freeze Drying
According to Chiaramonti, the lyophilization process is increasingly “used for products which are in early development (phase I and II) in order to increase the stability of the drug and go faster into the clinic.” He explains that clients are “asking to develop liquid and lyophilized formulation in parallel,” so that they can, at a later stage, “switch process in the IND or IMPD files.”
As in other critical processes, control is paramount. “The control of the critical process parameters though lab experiments is required in order to justify … how the manufacturing process has been set up,” says Chiaramonti. “Quality by Design and Design of Experiments are useful tools for this purpose.” Before the process validation runs “the study of the robustness of the lyophilization cycle is required” and “GMP batch tools like DSC or microcalorimetry and the sample thief” help manufacturers characterize the lyophilization cycle and shorten it when possible, he explains.
Gemmecker notes industry changes, as well: “A noticeable trend is the increase in the automation degree and the analysis of the individual steps during the process,” which is “done by using a multitude of sensors placed at the machine, which allows the analysis of the progress as well as the quality during the process.” He also notes that increasingly, “the specifications for new machines display a higher degree of flexibility, and therefore the design has to reflect this as well.”