Greg Sacha, Ph.D., Associate Director, R&D
Drug products that are unstable as liquids can be frozen or freeze-dried (lyophilized). While frozen products require specialized transportation and storage facilities, a room-temperature or refrigerated lyophilized product is significantly easier to store, as well as distribute, and has a longer shelf life. In this article, Dr. Sacha, Associate Director, R&D, highlights the advantages and challenges of product lyophilization, the development of lyophilization processes on site at Baxter BioPharma Solutions’ Bloomington, Indiana, plant, and the importance of continuing research.
Lyophilization is widely used in the pharmaceutical and biotech industry for small molecule drug products, vaccines, antibodies and other biological material. What are the key advantages of this stabilization method?
Lyophilization can allow for temperature-sensitive drug products to be stored for longer periods of time, and at higher temperatures, compared to a similar liquid presentation of the product, since they are stored in a dry state. Lyophilization is also advantageous for oxygen- and/or air-sensitive products, as vials can be backfilled with nitrogen and stoppered under a partial vacuum.
Many products that are lyophilized can be stored in refrigerated conditions or even at room temperature, once freeze-dried, but if those same products were not lyophilized, then they would likely require temperatures of -20 °C or lower to remain stable for the lengths of time expected for commercial products.
Why does lyophilization often provide the highest probability of technical success?
Primarily, stability. Solid-state reactions occur much more slowly than liquid interactions. A great example is aspirin. Its half-life is only 50 hours if prepared as a solution. That would not allow sufficient time to manufacture, package and distribute it before half of the content was degraded. That is the reason aspirin is sold only as a solid.
Biologics often have strict temperature requirements to ensure that the product remains stable. Case in point: the recently developed mRNA-based vaccines, which require cold storage for stability. A product that has a properly developed formulation could achieve commercial success as a liquid, frozen or lyophilized presentation, depending on the long-term stability data during commercial development.
Why are bulking agents used in lyophilization?
A bulking agent such as sucrose, mannitol, glycine or trehalose is included in a formulation when the active ingredient is present at too low a concentration to result in a freeze-dried solid that occupies the same volume as the solution filled into the vial before freeze-drying. A bulking agent provides a scaffold that supports the other ingredients in the formulation. A bulking agent can also be used to increase the critical temperature for the formulation so that it can be processed at higher temperatures, resulting in a more efficient cycle. Formulations with low concentrations of solids may appear as a film at the bottom of the vial or may collapse due to a low critical product temperature. Both are examples of poor appearance that can lead to complaints when the product is on the market. Another reason for avoiding collapse is that collapsed solids require more time for reconstitution and may be less stable environments for active ingredients.
Crystallization of mannitol or glycine can result in breakage of vials during the process, so we study the dried solid to ensure that the molecules are completely crystalline. We test that by performing x-ray powder diffraction (XRPD) to determine if changes occur over the course of a stability study.
Baxter recently conducted experiments on the use of rubber stoppers with freeze-dried products. Why is continuing research so important?
There are several reasons why stopper selection for a product, particularly a lyophilized product, is important and warrants continued research. One critical consideration is the stopper’s permeability to moisture. If you have a product that is moisture-sensitive, then you do not want your stopper to transmit moisture during long-term storage.
Not all stopper formulations are the same. Some are more hydrophobic than others. Formulations that are hydrophobic will not hold onto moisture after washing and drying, but they will allow some water vapor to transfer from the environment through the stopper to the product, and that could decrease stability for moisture-sensitive drug products. Depending on the rubber formulation and the sterilization conditions, different stoppers can retain different levels of residual moisture. Therefore, the transfer of the residual moisture from the stopper to the cake during long-term stability studies needs to be investigated.
Baxter has its own Lyophilization Center of Excellence (LCOE), which is co-located at Baxter’s Bloomington, Indiana, facility. How does this help pharma and biotech companies to improve their development programs?
The lyophilization process developed at the LCOE uses a design space approach that ensures that the cycle developed in the laboratory will easily transfer to our full-scale production lyophilizers. The design space approach calculates the most efficient lyophilization cycle parameters while considering the freeze-dryer capabilities and the critical product attributes of the specific formulation. Additionally, it provides data to support investigations into potential process excursions.
By developing a lyophilization process on site, our scientists can develop formulations and lyophilization cycles and can assist in the technical transfer of the cycle from laboratory scale to our commercial filling lines and commercial lyophilizers. Having full-service development and tech transfer capabilities is very rare in the CMO/CDMO space.
Increasingly, customers prefer a “one-stop shop” for product development and scale-up activities. Having our R&D group on site at our BPS facility in Bloomington, Indiana, helps customers harmonize their external vendors to allow for a more streamlined development program, while ensuring that critical product development information doesn’t get lost during technical transfer activities.