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Pharmaceutical Technology TRENDS IN MANUFACTURING 2022 eBOOK 29 A threshold is the critical product temperature that is required before a collapse occurs, Rosen- baum explains. The second limit is the minimum controllable pressure of the plant. The course of the chamber pressure and the sublimation rate is de- pendent on the heat transfer coefficient of the vial and the product resistance, which determines the correlation between the controlled parameters and the product temperature. Changes in the design of the freeze-dryer as well as product deviations may alter the drying process and could lead to product loss, and irregularities in the shelf temperature or drying pressure can result in uncontrolled freeze- drying, he cautions. Best practice approaches Having a best-practice approach to the lyophilization of biologic drug product is a good way to optimize product stability during the lyophilization cycle. Ap- proaching the problem early on in the drug product's development cycle is one such best practice. To develop a robust lyophilization cycle, spe- cial attention should be given in the early stages of development to comprehensively understand a product's physical characteristics and thermal properties, says Bourassa. Bourassa explains that having a deep knowledge of the formulated prod- uct's thermal profile is essential prior to developing a lyophilization cycle. "The use of modulated differential scanning calo- rimetry (mDSC) and freeze-dry microscopy (FDM) identifies the physical characteristics of the formu- lated drug product, such as a product's freezing point, glass transition, eutectic temperature, and collapse temperature, to tailor a lyophilization cycle that will produce a stable pharmaceutical product," Bourassa states. LSNE's Process Development team, for instance, will use a "sample thief " to collect nu- merous samples during development lyophilization runs. This allows the team to assess moisture con- tent or residual solvents in real-time and ascertain an optimal secondary drying cycle and lyophiliza- tion process parameters, Bourassa explains. Bourassa stresses the importance of taking pro- active steps to ensure phase-appropriate develop- ment, which helps to speed up progress and mini- mize API or biologic drug substance loss. "If the clinical program is successful, clients may choose to spend additional time and money on expanded development. If time or budget is constrained, a lyophilization development program with fewer development runs for early clinical needs may be the best approach," he says. Bourassa adds that using a conservative lyophi- lization cycle and later optimizing once dose range studies are complete can save time and money in early clinical trials. "Progressing with an opti- mized cycle is vital as a company approaches Phase III/registration and process validation batchesby greatly reducing risk during manufacturing and saving costs over the life of the product," he states. A number of techniques exist that are new to the study of freeze-drying. For instance, modeling and simulation are advanced techniques that can provide a useful understanding of the process itself. "Integrating the known product characteristics into the simulation will shorten the necessary trial- and-error development runs," says Rosenbaum. "If the freeze-drying parameters are well defined, the whole process will achieve the best efficiency and robustness." Reference 1. EC, "EU Legislation to Control F-gases," ec.europa.eu, accessed Jan. 14, 2022. PT