The storage of drug substance at subzero temperatures mitigates potential risks associated with liquid storage, such as degradation and shipping stress, making it the best solution for long-term storage. However, slower (generally uncontrolled) rates of freezing and thawing of drug substance in conventional large storage containers (>2L) can lead to greater cryoconcentration (exclusion of solute molecules) resulting in zones of higher protein and excipient concentrations and changes to the desired formulation pH and excipient concentration. These conditions can negatively impact product quality, thus changing the target product profile. Freeze/thaw studies can provide valuable knowledge on the molecule even when performed from an early formulation image. This study attempts to provide guidance and strategy for planning of drug substance freeze and thaw studies in early development using a scale-down model, evaluating the impact of the (1) freeze/thaw rate, (2) mode of freezing, (3) drug substance container, (4) drug substance concentration, and (5) formulation on the drug substance product quality. Data presented in this study showed no impact on drug substance product quality after undergoing the typical one freeze/thaw cycle process for the variables evaluated. These findings suggest that a qualified scale-down model is not required for early phases of process development and that existing small-scale models can be used for drug substance storage development studies. Based on our experience, a workflow is suggested with minimal experimental design to reduce the material requirement by >70% at early stages of product development to reduce constraints.
Keywords: developability; excipients; monoclonal antibody; protein aggregation; protein formulation.
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