Many recently approved parenteral drugs are based on biotechnological processes. In the past three years, more than 30% of the parenteral FDA approvals granted were for lyophilized substances, according to Vetter’s research. These drugs are extremely sensitive to external influences, such as oxygen, sunlight, and pH values, which, along with other factors, can degrade a substance and negatively affect its bioactivity. In the case of proteins and other recombinant substances, the simplest and safest way to maintain bioactivity is by using a liquid formulation. Water, however, is both a medium and a reaction partner that can cause hydrolysis or deamidation, a form of hydrolysis of proteins. In addition, water increases chemical and physical instability, thereby allowing reactions with other substances. Liquid formulation does not allow sufficient long-term stability for many drugs. It makes sense, therefore, to remove as much water as possible from the liquid formulation to stabilize the substances until they are administered. The substance can be reconstituted with a diluent just before being injected.
Freeze-drying in primary packages has become a standard drying method. In the lyophilization process, the dissolved substance is frozen. The water is sublimated in a vacuum, and any remaining water is removed by raising the temperature slowly. The active substance and various excipients form a solid cake with an amorphous or crystalline structure. Depending on the formulation, the product will remain stable in this form for two to three years and can be reconstituted shortly before application. Two different systems have become established for freeze-drying in primary packages: vials and dual-chamber systems.
Vials versus dual-chamber systems
Vials. With new drugs, the vial may be the best primary packaging system. The entire filling process and the system with all its components (i.e. stoppers, seals, and adapters) are less complex than dual-chamber systems and are therefore simpler to develop. On the other hand, administration of the drug is more complex because diluents must be added separately. To administer, the user meters the diluent from a second vial into a syringe and then adds the diluent to the lyophilized vial for reconstitution. Next, the reconstituted drug is withdrawn from the vial and, after changing the needle, administered to the patient. A volume of 1 mL of active substance typically requires an overfill of 20% or more to ensure that an accurate dose is pulled into the syringe (1). For larger volumes, a lower overfill percentage is needed.
| Figure 1. Dual-chamber systems contain lyophilized product and diluent in one system. The compound is lyophilized in-situ and mixed with the diluent just before administering.
Figures 1 and 2 are courtesy of Vetter Pharma International GmbH.
Dual-chamber systems. An alternative is the dual-chamber system, which contains the active substance and the diluent in two separate chambers that remain unmixed until shortly before administration. The drug compound is lyophilized directly in-situ in the front chamber. After lyophilization, the diluent is filled into the second chamber. For administration, a simple "twist and push" forces the diluent through a glass bypass into the front chamber, where it is mixed with the active substance. Dual-chamber systems reduce the overfill needed and increase precision in dosing because drug and diluent are premeasured. For example, in a dual-chamber lyophilization system (see Figure 1, Vetter Lyo-Ject syringe) in which the substance is lyophilized and reconstituted within the system, 1 mL of active substance requires an overfill of only 6%, and 5 mL requires just 3%, according to Vetter’s research. Dual-chamber systems also decrease risk of medication error by eliminating the use of multiple vials and needles.
While the first steps of the freeze-drying process, compounding and filtration, are the same for vials and dual-chamber systems, subsequent steps of the freeze-drying process differ somewhat.
|Figure 2. Automated loading of a freeze dryer.|
Freeze-drying in vials
When lyophilizing in a vial, a stopper with an opening is inserted but not sealed, which allows water vapor to escape during freeze-drying. The vial is placed in the freeze-dryer (see Figure 2). This step is followed by the freezing phase, which can last anywhere between two and five hours depending on the substance, the composition, and the amount of substance solution present. The setting plates are cooled to -50 °C or less. The temperature in the vials drops to the -40 °C to -50 °C range, and the water in the solution freezes. Primary drying under vacuum begins by generating pressure of 0.1 mbar or less and opening an access valve to the condenser, where the temperature ranges from -70 °C to -160 °C, so that the water sublimates. The procedure can last from five hours to five days. Lyoprotectors permit an amorphous or crystalline structure to form from the solidifying substance solution. In the secondary drying step, the temperature is raised, and the product is kept under vacuum to extract most of the remaining water, leaving a “lyo-cake” with a water content of 1–3 %. The freeze-dryer is partially depressurized to approximately 700 mbar using dried nitrogen. The inert gas protects the substance in the primary packaging from oxidation. Next, the setting plates automatically drop, thereby pressing the stoppers into the vials. Sealing the vial under a partial vacuum is advantageous because when reconstituting the drug, the solvent is drawn in rather than being injected with pressure. The vial is removed from the freeze-dryer and capped with a flanged cap.
Freeze-drying in a dual-chamber system
Freeze-drying in a dual-chamber system has some differences. The middle stopper is inserted prior to the filling of the solution, thereby keeping the two chambers separate and preventing the substance from carrying over into the other chamber. The first chamber is filled with solution, and the closure system is placed on the dual-chamber syringe, thereby leaving an opening much in the same way as with the vial. The dual-chamber lyophilization process, however, is run differently than in vials because the product is situated on the top of the stopper away from the shelf. The process is governed by convection and radiation rather than by direct conductive heat exchange. After lyophilization, the system is depressurized to atmospheric pressure to avoid shifting the middle stopper and sealed by pressing the closure down with the upper-setting plate. If a cartridge system uses a crimp closure, it cannot be sealed inside the lyophilizer, but must be flanged outside the freeze-dryer under special climatic conditions with humidity of less than 10%. After the first chamber is sealed, the second chamber is filled with diluent, and the end stopper is set in place. Other processes and secondary packaging can be performed.
1. R. Soikes, BioPharm Intl. Biopharmaceutical Trends Report Supplement, 24 (9), s14–s18 (2011).