Container closure systems (CSS) of pharmaceuticals affect their quality and safety. Changes in CCS post approval are common due to challenges such as glass delamination, vial breakage, innovations in CCS design etc. The frequency of CCS changes post approval has increased due to the supply challenges caused by the ongoing pandemic. There are guidances and best practices for assessing the risk to product quality on changing the CCS of pharmaceuticals. Unfortunately, these guidances may not be adequate for assessing the risk to process performance and product quality of  freeze-dried products. Freeze-drying involves heat and mass transfer phenomena which are highly affected by the characteristics of CCS. Thus, there is a need to develop  best practices and risk assessment tools for assessing the risk to process efficiency and product quality due to changing the CCS of freeze-dried products. To this end, we evaluated the feasibility of using the vial heat transfer coefficient as a measure of risk. More importantly, a systematic evaluation was conducted to determine the CCS variables, formulation characteristics, and freeze-drying process parameters with the highest risk of process failure due to changes in CCS without concomitant changes in the freeze-drying process. In addition, the impact of the vial position in the freeze-dryer on the potential risk to product quality was studied. The CCS variables that were evaluated were variation  in the glass vial dimensions and manufacturer. The formulation variables that were evaluated were the concentration of biologic drug substance in the formulation , total solid content, and fill height. Finally, the impact of the freezing (conventional freezing, annealing and controlled ice nucleation) and the primary drying parameters (shelf temperature and chamber pressure) on the extent of  potential risk to process and product failure was studied. For the CCS studied, our results revealed that changing the CCS of freeze-dried products without concomitant adjustments  in the freeze-drying process parameters may lead to a loss in process efficiency and product quality. The extent of risk was dependent on the formulation, the freeze-drying process parameters, and location of the product in the drying chamber.

Impact of product and process variables and location in the freeze-dryer on process efficiency and product quality when changing the container closure system of freeze-dried products

ACS Fall 2021

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