Abstract
This study examines the factors that may cause systematic errors in the manometric temperature measurement (MTM) procedure used to evaluate product temperature during primary drying. MTM was conducted during primary drying using different vial loads, and the MTM product temperatures were compared with temperatures directly measured by thermocouples. To clarify the impact of freeze-drying load on MTM product temperatures, simulation of the MTM vapor pressure rise was performed, and the results were compared with the experimental results. The effect of product temperature heterogeneity in MTM product temperature determination was investigated by comparing the MTM product temperatures with directly measured thermocouple product temperatures in systems differing in temperature heterogeneity. Both the simulated and experimental results showed that at least 50 vials (5 mL) were needed to give sufficiently rapid pressure rise during the MTM data collection period (25 seconds) in the freeze dryer, to allow accurate determination of the product temperature. The product temperature is location dependent, with higher temperature for vials on the edge of the array and lower temperature for the vials in the center of the array. The product temperature heterogeneity is also dependent upon the freeze-drying conditions. In product temperature heterogeneous systems, MTM measures a temperature close to the coldest product temperature, even, if only a small fraction of the samples have the coldest product temperature. The MTM method is valid even at very low product temperature (−45°C).
Keywords: freeze-drying/lyophilization, manometric temperature measurement, process analytical technology for freeze drying, product temperature heterogeneity
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References
- 1.Pikal MJ. Lyophilization. In: Swarbrick J, Boylan J, editors. Encyclopedia of Pharmaceutical Technology. New York, NY: Marcel Dekker; 2001. pp. 1299–1326. [Google Scholar]
- 2.Carpenter JF, Pikal MJ, Chang BS, Randolph TW. Rational design of stable lyophilized protein formulations: some practical advice. Pharm Res. 1997;14:969–975. doi: 10.1023/A:1012180707283. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 4.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] [Google Scholar]
- 5.Pikal MJ. Freeze-drying of proteins: process, formulation, and stability. Washington, DC: American Chemical Society; 1994. pp. 120–133. [Google Scholar]
- 6.Roy ML, Pikal MJ. Process control in freeze-drying: determination of the end point of sublimation drying by an electronic moisture sensor. J Parenter Sci Technol. 1989;43:60–66. [PubMed] [Google Scholar]
- 7.Milton N, Pikal MJ, Roy ML, Nail SL. Evaluation of manometric temperature measurement as a method of monitoring product temperature during lyophilization. PDA J Pharm Sci Technol. 1997;51:7–16. [PubMed] [Google Scholar]
- 8.Pikal MJ. Freeze-drying of proteins. II. Formulation selection. BioPharm. 1990;3:26–30. [Google Scholar]
- 9.Pikal MJ, Shah S, Senior D, Lang JE. Physical chemistry of freeze-drying: measurement of sublimation rates for frozen aqueous solutions by a microbalance technique. J Pharm Sci. 1983;72:635–650. doi: 10.1002/jps.2600720614. [DOI] [PubMed] [Google Scholar]
- 10.Tang XC, Nail SL, Pikal MJ. Mass transfer in freeze-drying: Measurement of dry layer resistance by a non-steady state method (the MTM procedure). AAPS PharmSci (supplement). 1999;S-564 Abstract 3740.
- 11.Tang XC, Nail SL, Pikal MJ. Freeze-drying process design by manometric temperature measurement: design, of a smart freeze-dryer. Pharm Res. 2005;22:685–700. doi: 10.1007/s11095-005-2501-2. [DOI] [PubMed] [Google Scholar]
- 12.Tang X, Pikal MJ. Design of freeze-drying processes for pharmaceuticals: practical advice. Pharm Res. 2004;21:191–200. doi: 10.1023/B:PHAM.0000016234.73023.75. [DOI] [PubMed] [Google Scholar]