Abstract
The objective of this research was to assess the applicability of manometric temperature measurement (MTM) and SMART™ for cycle development and monitoring of critical product and process parameters in a mini-freeze dryer using a small set of seven vials. Freeze drying cycles were developed using SMART™ which automatically defines and adapts process parameters based on input data and MTM feedback information. The freeze drying behavior and product characteristics of an amorphous model system were studied at varying wall temperature control settings of the cylindrical wall surrounding the shelf in the mini-freeze dryer. Calculated product temperature profiles were similar for all different wall temperature settings during the MTM-SMART™ runs and in good agreement with the temperatures measured by thermocouples. Product resistance profiles showed uniformity in all of the runs conducted in the mini-freeze dryer, but absolute values were slightly lower compared to values determined by MTM in a LyoStar™ pilot-scale freeze dryer. The resulting cakes exhibited comparable residual moisture content and optical appearance to the products obtained in the larger freeze dryer. An increase in intra-vial heterogeneity was found for the pore morphology in the cycle with deactivated wall temperature control in the mini-freeze dryer. SMART™ cycle design and product attributes were reproducible and a minimum load of seven 10R vials was identified for more accurate MTM values. MTM-SMART™ runs suggested, that in case of the wall temperature following the product temperature of the center vial, product temperatures differ only slightly from those in the LyoStar™ freeze dryer.
Highlights
Germany. 2 Division of Pharmaceutics, Freeze Drying Focus Group, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91058, Erlangen, Germany. 3 CSL Behring GmbH, Emil-von-Behring-Straße 76, 35041, Marburg, Germany. 4 To whom correspondence should be addressed
A trend towards lower Tb-manometric temperature measurement (MTM) values compared to Tb-TC can be observed which is in agreement with the MTM bias towards the coldest vials of the batch described in the literature [11]
Due to the safety margin of 3°C the SMARTTM software used, Tb-TC values remained at least 1.5°C below the collapse temperature under applied conditions confirming the capability of MTM-SMARTTM to select appropriate process conditions for this excipient solution
Summary
Germany. 2 Division of Pharmaceutics, Freeze Drying Focus Group, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91058, Erlangen, Germany. 3 CSL Behring GmbH, Emil-von-Behring-Straße 76, 35041, Marburg, Germany. 4 To whom correspondence should be addressed. (e–mail: Abbreviations: Ap, Ice sublimation area; dm/dt, Sublimation rate; dQ/ dt, Heat flow into the product vial; Kv, Vial heat transfer coefficient; LC, LyoCapsuleTM; Ldry, Dry layer thickness; LS, LyoStarTM; MTM, Manometric temperature measurement; PAT, Process analytical technology; Pice, Vapor pressure of ice at sublimation interface; Rp, Dried product layer resistance; SEM, Scanning electron microscopy; Tb-MTM, Product temperature at vial bottom by MTM; Tb-TC, Product temperature at the vial bottom by TC; TC, Thermocouple; TDLAS, Tunable diode laser absorption spectroscopy; Tp-MTM, Product temperature at sublimation interface by MTM; Ts, Shelf temperature; Twall, Wall temperature in the LyoCapsuleTM; Veff, Effective chamber volume.Due to the increasing number and spectrum of (bio)pharmaceutical and diagnostic products, freeze drying is a method of increasing importance to ensure long-term stability of these sensitive active pharmaceutical ingredients [1,2,3,4]. The typically high value of biopharmaceuticals increases the need for indicative studies in small-scale freeze drying equipment to reduce the financial risk during development [5, 6]. Cycles developed in miniaturized equipment are typically difficult to scale-up owing to non-representative conditions. Innovative process analytical technology (PAT) tools enable precise monitoring and control of the freeze drying process with the objective of a reliable and reproducible cycle performance [7]. The non-invasive determination and comparison of critical product attributes offers clear benefits in terms of process transfer between different freeze dryers and successful scale-up to larger units [8, 9]. An example of a non-invasive PAT tool for realtime determination of key process and product parameters is manometric temperature measurement (MTM). The technology relies on quickly (i.e., less than a second)
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