Title

Heat and mass transfer scale-up issues during freeze-drying

Date of Completion

January 2003

Keywords

Chemistry, Pharmaceutical

Degree

Ph.D.

Abstract

The overall objective of this research is to develop useful guidelines and algorithms to allow reliable scale-up of heat and mass transfer effects from laboratory to manufacturing scale lyophilizers. Scale up issues include variations in shelf surface temperature, heterogeneity in heat transfer rates with respect to position on the shelf, freezing variations between manufacturing and laboratory lyophilizers and variations that can occur due to differences in freeze dryer design. ^ Cake shrinkage during freeze-drying is related to the heat and mass transfer characteristics of the product and highlights the importance of product temperature control during drying. A combined experimental and theoretical approach was used to show that conditions of secondary drying impact cake shrinkage and that the product temperature should be maintained below the glass transition temperature throughout secondary drying. ^ Atypical radiation heat transfer experienced by edge vials due to their clear view of a warmer surface is responsible for their higher heat transfer rates and this atypical behavior poses a scale-up issue. Convection heat transfer was not responsible for this atypical behavior. Variation in the degree of supercooling between laboratory and manufacturing cycles may lead to significant variations in primary drying time. A correlation between product resistance during primary drying and the specific surface area of the product provided a quantitative prediction of the impact of freezing variations during scale up. Control of nucleation temperature within vials of the same batch was achieved by using an ice fog technique. ^ Data obtained from controlled sublimation tests on laboratory and manufacturing freeze dryers was used to estimate inter-vial variation in heat transfer rates based on design characteristics. Shelf non-uniformity, variable emissivities of representative surfaces, and the individual resistances offered by chamber, condenser and refrigeration system, are design parameters that were evaluated from sublimation tests. ^ Steady state heat and mass transfer theory was then used to combine data obtained for various scale-up issues in order to provide overall “rules and algorithms” for successful scale up from laboratory to manufacturing scale. ^

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