Proteins tend to be more stable at lower temperatures especially when stored frozen below the glass transition temperature of the formulation. Therefore, long term storage and transportation of drug substance for monoclonal antibody therapeutics is often conducted in the frozen state at below -40°C. However, limited information is available on the impact of the freezing and thawing rates on protein aggregation as the freezing and thawing rates are typically not well controlled and are hard to measure. A wide range of approaches to freezing are used in the field with various freezing platforms and containers. This study examines measures the impact of freezing and thawing rates on protein aggregation during freezing and thawing of drug substance for long term storage. A scale down model was developed to mimic the conditions in bulk drug substance bags and the freeze and thaw rates were controlled over a wide range relevant to the manufacturing scale utilizing the same model. Protein aggregation was characterized both in terms of soluble aggregates and particulates. The impact of other parameters such as the protein concentration, buffering species in the formulation, and formulation pH on protein aggregation and its interaction with the freeze and thaw rates was also examined. Several different mAbs were included in the study in order to probe protein specific effects on protein aggregation during freeze and thaw. The results of the study were leveraged to develop a best recommended practice for freezing and thawing of mAbs in the absence of any previous freeze/thaw stability data at the bulk scale.

Impact of freezing and thawing rates on protein aggregation for drug substance long term storage

255th National Meeting (2018)

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