Rational approaches and transfer strategies for the scale-up of freeze-drying cycles

Transcription

1 Scientific article - eer reviewed RESS DEVELMET Stefan. Schneid Rational approaches and transfer strategies for the scale-up of freeze-drying cycles STEFA. SEID1,2*, EIG GIESELER1 *orresponding author University of Erlangen, Division of armaceutics, auerstr. 4, Erlangen, 91058, Germany Syntacoll Gmb, Donaustr. 24, Saal, Germany ABSTRAT: The rational development and optimization of freeze drying cycles in the laboratory should be based on knowledge of the critical formulation properties, such as the collapse temperature. nce a recipe has been finalized that ensures acceptable quality of the final product, the transfer to manufacturing scale can be initiated. When scaling a freeze drying cycle from the laboratory to pilot or production scale, identical product temperature profiles over time must be established to assure the same quality defined in the lab. To achieve this, several important factors have to be taken into consideration. The most important parameters such as nucleation behaviour, differences in heat and mass transfer, freeze dryer design and performance and their impact on product quality will be surveyed. Additionally, methods to evaluate and compensate differences between freeze dryers are presented. ITRDUTI Freeze drying is a widely used process for stabilization of labile active pharmaceutical ingredients by removal of the solvent (typically water) at low temperatures (1). The relatively long process time and high energy consumption during constant cooling and heating of the shelves and the condenser make lyophilization a very cost-intensive drying technology (2). In the last years, pharmaceutical manufacturers have broadened their efforts to optimize freeze drying recipes and thereby shorten the process time (3). The more aggressive processes applied lead in turn to greater susceptibility of the product to potential process deviations, for example of chamber pressure or shelf temperature, and inhomogeneities within the batch. The development of an appropriate freeze drying cycle is usually performed in laboratory scale freeze dryers (shelf area 0.1 to 0.5 m2) with only limited amounts of product and at most several hundred vials. Later in the development phase, the optimized recipe needs to be transferred to a production scale lyophilizer with 10 to 50 m2 shelf area and correspondingly a much larger number of vials. There are numerous factors that influence the product performance during the scale-up step, most importantly freeze dryer design features (e.g. shelf and spool piece construction) and environmental factors (e.g. particulate content). Thorough understanding of the process and the equipment capabilities as well as studies of the impact of unavoidable differences can significantly facilitate and expedite the scale-up step. This article surveys the most important parameters and offers a starting point for fast and reliable transfer of freeze drying processes. RESS DEVELMET: RITIAL FRMULATI TEMERATURE The commonly accepted rational approach for the design of freeze drying processes is the initial characterization of the critical formulation temperature by differential scanning calorimetry or freeze dry microscopy (4, 5). Freeze dry microscopy is more representative for the actual conditions encountered in freeze drying, as water is continuously removed by sublimation during the measurement, and the dried product is studied for indication of structural alterations (Figure 1). Based on the information obtained, a process can be developed which ensures that the product temperature consistently remains below the collapse temperature throughout primary drying (6). Thermal characterization by DS is also essential for optimal design of the freezing and annealing step. During primary drying, the development of the resistance of the dried cake layer also plays an important role, as this parameter is directly interrelated to product temperature (7). Another important factor is the nucleation temperature and the extent of supercooling of the solution. Figure 1. Freeze dry microscopy of a 50 mg/ml sucrose solution: collapse of the cake structure. chimica oggi/hemistry Today - vol 29 n 1 January/February

2 RESS DEVELMET SALE-U RIILES To ensure rapid and adequate transfer of freeze drying processes from one freeze dryer to another, especially on different scales, it is important to not just reproduce the shelf (inlet) temperature and chamber pressure over time profile (the only two parameters which can be directly controlled by an operator) and rely on similar product performance. It is crucial to determine the critical product attributes and the range within which an acceptable product is obtained ( roduct Design Space ) before the cycle, and to define critical process parameters to retain the critical product parameters within this range (8, 9). In practice, in order to keep the product temperature within the desired range, modifications of shelf temperature and chamber pressure are required. Additionally the primary drying time can be extended to account for the potentially higher degree of supercooling. It is also imperative to already consider equipment limitations in manufacturing scale lyophilizers during development of the process in small scale. Important aspects here are high mass flow rates in early primary drying which may exceed the heat removal capacity of the condenser, or rapid ramp rates of shelf temperature during freezing and primary drying. If the process that has been developed in the laboratory cannot be replicated in manufacturing, additional expensive development and optimization is required. DIFFEREES I FREEZE DRYER DESIG AD TRL Laboratory scale freeze dryers are used for lyophilization of small amounts of product, either for simple preparation of relatively robust materials (benchtop freeze dryers) or for cycle development and subsequent transfer to a larger scale. It is beneficial if the design of the freeze dryers employed on the various scales is similar. The relevant design features include 2-chamber vs. 1-chamber design, cooling and heating rates of the shelves, condenser temperature and radiation effects from chamber door and walls (10, 11). The maximum allowable heating and cooling rate of the shelves is often between 1 / min and 2.5 /min on small scale units, and commonly around 1 /min in larger scale. Recently, cooling of the heat transfer fluid with liquid nitrogen instead of using compressors has become more common which allows faster ramping and lower freezing temperatures in production. The condenser temperature is mostly controlled below -65 in small scale freeze dryers, but may reach up to -55 in older manufacturing scale dryers. If vastly different freeze dryer setups are applied on the different scales (e.g. freezing outside the lyophilizer or primary drying without proper temperature control in laboratory scale), a rational transfer to a larger scale is extremely difficult, and major additional experiments and optimization are required. It is critical for successful development and transfer of lyophilization processes to obtain as much information as possible about the construction and performance of the freeze dryers used on different scales. ne of the most valuable methods for simulation of various process conditions is the performance of sublimation tests in bottomless trays (12). For this purpose, stainless steel frames which are slightly smaller than the shelf are lined with a thin plastic foil and filled with water, e.g. with approximately 1 cm fill depth. The water is frozen on the shelves, and subsequently vacuum is applied. The shelf inlet temperature and chamber pressure are then varied to simulate a range of drying rates. Information about freeze dryer performance under different load conditions should be available prior to cycle development in small scale so that limitations concerning control of chamber pressure and condenser temperature at high sublimation rates can be considered. As freeze drying processes are time consuming and costly, it is not 44 chimica oggi/hemistry Today - vol 29 n 1 January/February 2011 possible to perform extensive robustness experiments in production units. The determination of an appropriate Design Space in the laboratory which allows adaptations during transfer enables rapid transfer of a lyophilization process and development of a thorough understanding of the process. If equivalent or similar equipment with proper instrumentation (e.g. rocess Analytical Technology) is used, it is possible to design an optimized cycle including determination of process robustness in the laboratory, saving time and money during the process scale-up. This also applies to process control, for example use of identical sensor types for pressure control (apacitance Manometer vs. irani vs. Thermocouple Vacuum Gauge) to ensure that the same effective chamber pressure is used in all freeze dryers. ere it is also important to attach the pressure sensor directly to the chamber with minimal extensions to avoid systematic errors of the measurements. Some major differences in freeze dryer construction cannot be avoided but can be compensated by process adaptations within the Design Space later on. If more severe adaptation is required, additional supportive tests can be conducted in laboratory scale. Another important factor is the vapour flow velocity in the spool piece connecting chamber and condenser. If the spool piece is designed inappropriately for the mass flow rate, or if very aggressive primary drying conditions are applied, the flow velocity can approach Mach 1 (choked flow) which leads to a loss of pressure control in the chamber (13). Some freeze dryer manufacturers have omitted the spool piece entirely in their freeze dryer design to avoid these problems. For operational qualification, it is further beneficial to evaluate the gradient between heat transfer fluid inside the shelf and the shelf surface as well as the distribution of shelf surface temperature throughout the freeze dryer. This can easily be done by attachment of adhesive thermocouples at points where the highest diversity is expected. The flow pattern of the heat transfer fluid through the shelves differs substantially between different freeze dryers, leading to differences in hot and cold spots or even divergence between the separate shelves (14). For versatile shelf temperature mapping, the simulation of various sublimation rates and ramp rates should be included in the experimental design instead of just testing the temperature distribution in a clean, dry and empty freeze dryer. heat TRASFER ASETS To supply the energy removed by sublimation, heat needs to be transferred to the product. In freeze drying, three mechanisms of heat transfer to the product are relevant: direct conduction at the points of contact between vial and shelf, gas conduction via the gas in the chamber and radiative exchange between surfaces (15, 16). The radiation is not only emitted between vial and shelf but also from chamber walls and door. The extent of radiation transmitted to the vials depends on the effective emissivity of the surface, a parameter between 0 and 1 that is defined by material characteristics. The emissivity is especially high for acrylic glass (0.95) which is frequently used in laboratory scale units. olished stainless steel shows lower emissivity than non-polished steel (about 0.4 vs. 0.6). The elevated emissivity of materials used in laboratory scale freeze dryers and the higher fraction of vials in edge position lead to higher batch heterogeneity in small scale. The increased heat transfer to edge vials results in higher product temperature and shorter drying time compared to centre-positioned vials. To quantify the difference in radiation effects between different freeze dryers, several approaches can be followed. First, the effective emissivity of chamber wall and door can be determined using an infrared thermometer which requires the input of the effective emissivity for remote measurement of surface temperatures. An adhesive thermocouple is attached to

3 RESS DEVELMET the surface in question, and the emissivity constant is varied until both temperature readings become identical (Figure 2). This value can be employed to estimate the reduction in radiative heat transfer to edge vials in manufacturing scale, and to estimate the direct consequences of radiative heat transfer (17). Secondly, the more versatile vial heat transfer coefficient can be measured through sublimation tests with pure water in vials. ere the vials are arranged in the desired array, filled with a defined amount of water, and weighed individually. After freezing inside the freeze dryer, vacuum is applied and the shelf temperature is increased to allow sublimation. nce 30 to 50 percent of the mass of ice have been removed, the experiment is terminated, the ice is thawed and the mass loss for each vial is determined. In combination with the product temperature at the vial bottom, the vial heat transfer coefficient can be calculated. If this procedure is repeated at various chamber pressures, it is possible to calculate a Kv over pressure curve and thereby delineate the contribution of pressure-dependent and pressure-independent factors to the overall heat transfer (18, 19). Further the effect of a change in chamber pressure on the heat transmitted to the product can be estimated. By comparing Kv values of vials in different positions on the shelf, potential hot spots and cold spots of the shelf can be detected, and the atypical radiation to the edge vials can be quantified. In recent studies (18), an elevation of percent for the vial heat transfer coefficient of vials in the outermost row of an array was found for a laboratory scale lyophilizer despite the use of dummy vials (Figure 3). EVIRMETAL FATRS Figure 2. Measurement of the effective emissivity of the shelf surface using an IR thermometer. ne of the main differences between cycle development in the laboratory and a manufacturing cycle is the particulate content during preparation of the solution, in primary packaging materials and most importantly in the surrounding air. Due to the much higher number of particles encountered in laboratory scale, heterogeneous nucleation occurs at substantially higher temperatures (e.g. -10 to -15 ) than in production scale (often below -25 ) where a practically particulate-free environment is mandatory (20). hemicals for Research & Development Since 1964 Many roducts Available in Bulk Quantities Selected Metal atalysts & Ligands for rganic Synthesis ew roducts F S F Rh S 3 (t-butyl) Me 3 (3)3 Fe (3)3 Me l -X/- oupling Me y y d Me l y2 3 y ( 611)2 y d l ther atalysts and Ligands 2 (3)2 l Ru l Visit F ewburyport, MA 01950, USA Tel: (978) Fax (978) info@strem.com (t-bu)2 F3 BF Strem hemicals, Inc. + Br F3 F Bischheim France Tel: (33) Fax: (33) info.europe@strem.com chimica oggi/hemistry Today - vol 29 n 1 January/February

4 RESS DEVELMET while the remaining ice crystals grow in size. This way the ice crystals become more homogeneous and better comparable to conditions with lower supercooling. There have also been investigations into technical solutions for controlled nucleation. The benefit of this method is the ability to initiate nucleation with very low supercooling in all vials. ractically this can be achieved by rapid changes of chamber pressure or using an ice fog technique (21). ucleation at defined target temperature leads to significant improvements in the homogeneity of primary drying temperature and product resistance. Recently the first commercial product for controlled nucleation has been introduced by raxair. LUSIS This article outlines a scientific approach for the scale-up of lyophilization cycles using a modern AT-based approach consistent with the FDA Quality by Design initiative. Strategies for development of freeze drying processes in the laboratory scale should already consider the critical product attributes and equipment specifications. The developed process can be adapted within the determined Design Space to account for inherent differences between freeze dryers and environmental factors. This allows rapid implementation of the process in large scale with only little additional optimization work. Figure 3. Example for Kv distribution in a sublimation test at 65 mtorr for 20 ml serum tubing vials; T signifies vials including thermocouples. Supercooling is defined as the difference between equilibrium freezing point of a solution and the effective nucleation temperature. A high extent of supercooling results in formation of a large number of small ice crystals that leave behind small pores during the drying step. In contrast, low supercooling leads to formation of a small number of ice crystals which grow during the solidification step and lead to larger pores in the dried product (21). As the identical freezing procedure (i.e. controlled cooling of the shelves in the freeze dryer) leads to various and inhomogeneous degrees of supercooling on different scales, the dried product matrix shows differences in pore size and distribution between products prepared in different freeze dryers and even within the same batch. This leads to an overall increase of product resistance in manufacturing scale, and consequently elevated product temperatures and even extended primary drying times. As nucleation is an inherently random process, the differences in supercooling are much higher in production scale, so some vials can nucleate not only at lower temperatures but with several hours delay, leading to variations in ice crystal size and thermal history. An easy way to estimate the amount of supercooling in different environments is attachment of a thin wire thermocouple on the outside of a vial on the solution level. This way the approximate temperature of the solution just before nucleation can be measured without directly influencing the nucleation behaviour by introduction of a temperature sensor. owever, the nucleation temperature of few monitored vials is not necessarily indicative for all vials as described above. The heterogeneity in ice crystal size within the frozen product can be to some extent mitigated by administration of a thermal treatment or annealing step (22). In this procedure, the product is first frozen and completely solidified. ext the shelf temperature is elevated above the critical formulation temperature of the maximally freeze-concentrated solute and kept there for typically 3-6 hours. During this time, the ice crystals can ripen, i.e. the number of ice crystals decreases 46 chimica oggi/hemistry Today - vol 29 n 1 January/February 2011 REFEREES AD TES M.J. ikal,.r. ostatino, Lyophilization of Biopharmaceuticals; Biotechnology: armaceutical Aspects, Volume II R.T. Borchard,.R. Middaught, series eds. AAS ress, Arlington, VA (2004). M.J. ikal, Encyclopedia of armaceutical Technology, pp (2002). J.J. Schwegman, L.M. ardwick et al., arm Dev Technol., 10(2), pp (2005). E. Meister,. Gieseler, J arm Sci., 98(9), pp (2009). J. Beirowski,. Gieseler, Eur arm Rev., (6), pp (2008). T. Kramer, D.M. Kremer et al., J arm Sci., 98(1), pp (2009). X.. Tang, M.J. ikal et al., AAS armscitech., 7(4), p. 93 (2006). US FDA: Guidance for industry: AT - A framework for innovative pharmaceutical development, manufacturing and quality assurance. armaceutical cgms (2004). S.. Tsinontides, S.D. Reynolds et al., Int J arm., 280(1-2), pp (2004). S. Tchessalov, roc. R Freeze Drying of armaceuticals and Biologicals, Garmisch-artenkirchen, Germany (2006). J.J. Schwegman, M.J. Akers et al., armaceutical Technology Lyophilization, pp (2004). S. Rambhatla, M.J. ikal et al., AAS armscitech., 7(2), p. 39 (2006). S.M. atel, roc. R Freeze-Drying of armaceuticals and Biologicals, Breckenridge, (2008). S. Tchessalov,. Warne, European armaceutical Review, (3), pp (2008). S. Rambhatla, M.J. ikal, AAS armscitech., 4(2), pp (2003). M. Brulls, A. Rasmuson, Int J arm., 246(1-2), pp (2002). W.y. Kuu, M.J. Akers et al., Int J arm., 302(1-2), pp (2005). S. Schneid, M.J. ikal et al., J arm Sci., 98(9), pp (2009). A. ottot, J. Andrieu et al., DA J arm Sci Technol., 59(2), pp (2005). J.A. Searles, T.W. Randolph et al., J arm Sci., 90(7), pp (2001). S. Rambhatla, M.J. ikal et al., AAS armscitech., 5(4), pp. 58 (2004). J.A. Searles, T.W. Randolph et al., J arm Sci., 90(7), pp (2001).

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