How Vial Geometry Variability Influences Heat Transfer and Product Temperature During Freeze-Drying

Abstract

Vial design features can play a significant role in heat transfer between the shelf and the product and, consequently, in the final quality of the freeze-dried product. Our objective was to investigate the impact of the variability of some geometrical dimensions of a set of tubing vials commonly used for pharmaceuticals production on the distribution of the vial heat transfer coefficients (K) and its potential consequence on product temperature. Sublimation tests were carried out using pure water and 8 combinations of chamber pressure (4-50 Pa) and shelf temperature (-40°C and 0°C) in 2 freeze-dryers. K values were individually determined for 100 vials located in the center of the shelf. Vial bottom curvature depth and contact area between the vial and the shelf were carefully measured for 120 vials and these data were used to calculate K distribution due to variability in vial geometry. At low pressures commonly used for sensitive products (below 10 Pa), the vial-shelf contact area appeared crucial for explaining K heterogeneity and was found to generate, in our study, a product temperature distribution of approximately 2°C during sublimation. Our approach provides quantitative guidelines for defining vial geometry tolerance specifications and product temperature safety margins.

3D mathematical modelling to understand atypical heat transfer observed in vial freeze-drying

“…The sublimation heat flow was experimentally determined by following the method previously described by Scutellà et al [9]. A number of 540 vials in hexagonal arrangement were loaded on the middle shelf of the freeze-dryer pre-cooled at -50 °C using a bottomless tray.…”

“…After a freezing step of 2 hours, the pressure was decreased and the shelf temperature was increased at a rate of 1 °C/min to the set point. Six sublimation tests in total were carried out: four at the shelf temperature of 0 °C and chamber pressures of 4,6,9,15 Pa and two at the shelf temperature of -40 °C and chamber pressures of 4 and 6 Pa. The cycle was allowed to run long enough to sublimate up to 20-25 % of the initial mass of water.…”

“…The vial bottom was designed to have an area in contact with the shelf and a cylindrical concavity. The thickness of this concavity δ was considered equal to the mean bottom curvature depth calculated by Scutellà et al [9] (0.12 mm).…”

“…In the present work, the coefficient was determined considering experimental data of sublimation tests presented by Scutellà et al [9] (where = 2 /Ʌ , with 2 equal to 0.67). The determined value and other relevant parameters for heat transfer modelling are reported in Table 2.…”

“…vaccines, proteins, peptides), which are usually processed in small containers (vials) loaded on the shelf of the equipment. During the primary drying step, the total heat transfer towards the sublimation interface is mainly dependent on the operating parameters (shelf temperature, chamber pressure, step duration), but also on the vial geometry and on the position of the vial on the shelf [6][7][8][9]. Vials located at the periphery of the shelf (named edge vials) receive an additional heat flow and present a product temperature up to 4 °C higher compared to vials located in the centre of the shelf (named central vials) and surrounded only by other vials at the same conditions [6][7][8]10].…”