Glass transition temperature (Tg’) is one of the key parameters guiding choice of storage conditions for frozen bulk Drug Substance (FBDS). Storage temperature is a critical process parameter and it is well established that FBDS should be stored at temperatures below Tg’ to maintain their long term stability. While Modulated Differential Scanning Calorimetry (mDSC) is commonly used for determining Tg’, there are some inherent limitations to applying it for determining Tg’ in formulations with high crystallinity.
The development of Dynamic Mechanical Analyzer (DMA) represents a promising strategy for Tg’ determination and FBDS characterization. To that end, using internal protein assets, we successfully developed the thermal analysis DMA technique to characterize high crystalline formulations and compared it to mDSC. While mDSC exhibited convoluted phase transitions with transition peaks exceeding detection limits in some cases, DMA yielded accurate and reproducible transition temperatures, generated phase transitions that were easy to interpret, and provided a high level of sensitivity. The ability to implement this highly sensitive technique capable of accurately predicting the transition temperature and producing consistent, analyst-agnostic data would be valuable for elucidating Tg’ of formulations with high crystallinity and may serve as a tool orthogonal to mDSC.
In this study, we also developed strategies to reconcile DMA results with those of mDSC, since previous research showed the huge difference in Tg’ values obtained by these two techniques. Previous study proposed to use tan δ to estimate Tg’, but as our data showed that elastic modulus showed better consistency and provided more useful information. Because the definition of Tg’ determination with DMA varies with application, we propose to use elastic modulus for biopharma product to characterize the frozen FBDS.