When considering whether to use a dual-chamber system for a lyophilized drug, it is important to understand the necessary development process.
As global demand for injectable systems grows, so too does the demand for innovative delivery options beyond the traditional system of syringe and vial. For lyophilized forms, dual-chamber systems offer advantages. The prefilled dual-chamber system or cartridge is self-contained, holding both the lyophilized product and diluent in separate chambers. As such, there are fewer reconstitution steps. And there is reduced overfill, which results in API savings. The predefined dosing also means greater safety for the patient and caregiver as well as ease of self-administration.
When considering whether to use a dual-chamber system, it is important to understand the necessary development process, which is summarized in Figure 1. The following sections describe five steps that can help determine whether lyophilization in a dual-chamber system is a viable option for an injectable drug.
Step 1: Lyo cycle feasibility studies
Step one of the process involves lyophilization cycle feasibility studies, which include freeze-drying microscope and differential scanning calorimetry studies. Dual chamber trials based on existing vial lyophilization development are performed. Cycle options to test the viability of a product in a dual chamber and concentration and fill volume studies for multi-dose products are also performed.
Step 2: Process characterization studies
In step two, process characterization studies that help assess the current upstream process and any studies needed for the development in a dual-chamber system are completed. Compounding/mixing studies to determine mixing parameters and excipient matrix and tracer studies with minimum and maximum compounding volumes are undertaken. Filtration studies are used to determine the necessary filter sizes and flush volumes. Finally, pumping and dosing studies are undertaken to develop pump settings and filling needle movement for precise dosing.
Step 3: Design of experiment (DOE) cycle development and robustness runs
Step three includes design of experiment (DOE) cycle development and robustness runs to test the limits of the design space for both primary and secondary drying. The DOE approach is used with different temperature and pressure combinations. Target cycle parameters are selected to determine robustness for scale-up. Visual lyo cake appearance, product critical quality attributes (CQAs), residual moisture, and reconstitution times are analyzed.
Step 4: Siliconization/functionality testing
Step four involves siliconization and functionality testing. Different levels of silicone used to lubricate the dual-chamber system are tested for their impact on the drug product and the delivery device, such as the break-loose and gliding forces and the lowest and highest silicone spray rates achieved with different silicone emulsion concentrations. Samples of the formulation are filled into the dual-chamber system and tested for silicone level. Stability testing is also undertaken for the drug product-the same CQAs as in the lyo cycle development are assessed, and this completes the functionality testing step.
Step 5: Engineering runs for commercial scale-up
The final step entails engineering runs for scale-up to commercial production to ensure the process is scalable. Here, there are two stages. The first is non-GMP commercial scale-up consisting of general feasibility at production scale, fill volumes, product concentration testing, product temperature mapping, and sample analysis. The second step is lyo-cycle adaptation and testing including trials performed under “seeded run conditions” (i.e., several different test samples of the product are positioned in lyophilization storage units) and testing of multiple concentrations.
Process qualification/validation in the form of robustness runs to challenge the design space and extremes in temperature and pressure are undertaken. The minimum requirement is usually analysis of samples from two runs: high energy/high pressure and low energy/low pressure. Process qualification is performed at nominal conditions and a bracketing approach is used to cover several lyophilizers, product strengths, and minimum and maximum loads.
The steps outlined are essential in a typical product development approach used to assess if the dual-chamber system is suitable for delivering a specific drug formulation. If the lyophilization feasibility studies show that the dual-chamber system is a viable option for the drug product, characterization studies are required to optimize the process and develop a robust lyophilization cycle. Siliconization and functionality testing are important for determining the optimal silicone level and assessing its impact on the drug product and dual-chamber system. Finally, engineering runs are carried out to enable a scalable process.
About the Author
Joerg Zimmermann is vice-president, Vetter Development Service, Vetter Pharma-Fertigung GmbH & Co. KG. Vetter is the originator of dual-chamber technology.