Search tips
Search criteria 


Logo of aapspharmspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
AAPS PharmSciTech. 2006 June; 7(2): E61–E70.
Published online 2006 April 21. doi:  10.1208/pt070239
PMCID: PMC2750289

Heat and mass transfer scale-up issues during freeze-drying, III: Control and characterization of dryer differences via operational qualification tests


The objective of this research was to estimate differences in heat and mass transfer between freeze dryers due to inherent design characteristics using data obtained from sublimation tests. This study also aimed to provide guidelines for convenient scale-up of the freeze-drying process. Data obtained from sublimation tests performed on laboratory-scale, pilot, and production freeze dryers were used to evaluate various heat and mass transfer parameters: nonuniformity in shelf surface temperatures, resistance of pipe, refrigeration system, and condenser. Emissivity measurements of relevant surfaces such as the chamber wall and the freeze dryer door were taken to evaluate the impact of atypical radiation heat transfer during scale-up. “Hot” and “cold” spots were identified on the shelf surface of different freeze dryers, and the impact of variation in shelf surface temperatures on the primary drying time and the product temperature during primary drying was studied. Calculations performed using emissivity measurements on different freeze dryers suggest that a front vial in the laboratory lyophilizer received 1.8 times more heat than a front vial in a manufacturing freeze dryer operating at a shelf temperature of −25°C and a chamber pressure of 150 mTorr during primary drying. Therefore, front vials in the laboratory are much more atypical than front vials in manufacturing. Steady-state heat and mass transfer equations were used to study a combination of different scaleup issues pertinent during lyophilization cycles commonly used for the freeze-drying of pharmaceuticals.

Keywords: Operational qualification, freeze-drying, scale-up

Full Text

The Full Text of this article is available as a PDF (294K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Rambhatla S, Pikal MJ. Heat and mass transfer issues in freeze-drying process development. In: Borchardt RT, Middaugh CR, editors. Biotechnology: Pharmaceutical Aspects. Vol 2. Lyophilization of Biopharmaceuticals. Arlington, VA: AAPS Press; 2006. pp. 75–109.
2. Pikal MJ. Use of laboratory data in freeze drying process design: heat and mass transfer coefficients and the computer simulation of freeze drying. J Parenter Sci Technol. 1985;39:115–139. [PubMed]
3. Pikal MJ, Roy ML, Shah S. Mass and heat transfer in vial freeze-drying of pharmaceuticals: role of the vial. J Pharm Sci. 1984;73:1224–1237. doi: 10.1002/jps.2600730910. [PubMed] [Cross Ref]
4. Incropera FP, Dewitt DP. Introduction to Heat Transfer. New York, NY: John Wiley & Sons; 1990.
5. Kobayashi M. Development of new refrigeration system and optimum geometry of the vapor condenser for pharmaceutical freeze dryers. In: Toei R, Mujumdar A, eds. Proceedings of the 4th International Drying Symposium; July 9–12, 1984; Kyoto, Japan; 2:464–471.
6. Liapis AI, Pikal MJ, Bruttini R. Research and development needs and opportunities in freeze drying. Drying Technol. 1996;14:1265–1300. doi: 10.1080/07373939608917146. [Cross Ref]
7. Rambhatla S, Pikal MJ. Heat and mass transfer scale up issues during freeze drying, I: atypical radiation and the edge-vial effect. AAPS PharmSciTech. 2003;4:e14–e14. doi: 10.1208/pt040214. [PMC free article] [PubMed] [Cross Ref]
8. Rambhatla S, Ramot R, Bhugra C, Pikal MJ. Heat and mass transfer scale up issues during freeze drying, II: control and characterization of the degree of supercooling. AAPS PharmSciTech. 2006;5:e58–e58. [PMC free article] [PubMed]

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists