The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Michael J. Pikal - One of the best experts on this subject based on the ideXlab platform.
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applications of the tunable diode laser absorption spectroscopy in process estimation of Primary Drying heterogeneity and product temperature during lyophilization
Journal of Pharmaceutical Sciences, 2019Co-Authors: Puneet Sharma, William J Kessler, Robin H Bogner, Meena Thakur, Michael J. PikalAbstract:The aim of this research was to evaluate the impact of variability in ice sublimation rate (dm/dt) measurement and vial heat transfer coefficient (Kv) on product temperature prediction during the Primary Drying phase of lyophilization. The mathematical model used for Primary Drying uses dm/dt and Kv as inputs to predict product temperature. A second-generation tunable diode laser absorption spectroscopy (TDLAS)-based sensor was used to measure dm/dt. In addition, a new approach to calculate Drying heterogeneity in a batch during Primary Drying is described. The TDLAS dm/dt measurements were found to be within 5%-10% of gravimetric measurement for laboratory- and pilot-scale lyophilizers. Intersupplier variability in Kv was high for the same "type" of vials, which can lead to erroneous product temperature prediction if "one value" of vial heat transfer coefficient is used for "all vial types" from different suppliers. Studies conducted in both a laboratory- and a pilot-scale lyophilizer showed TDLAS product temperature to be within ±1°C of average thermocouple temperature during Primary Drying. Using TDLAS data and calculations to estimate Drying heterogeneity (number of vials undergoing Primary Drying), good agreement was obtained between theoretical and experimental results, demonstrating usefulness of the new approach.
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choked flow and importance of mach i in freeze Drying process design
Chemical Engineering Science, 2010Co-Authors: Sajal M. Patel, Swetaprovo Chaudhuri, Michael J. PikalAbstract:Abstract Occasionally the freeze Drying cycle conditions are developed on a small scale dryer that result in a water vapor flux during Primary Drying that the full-scale equipment cannot handle, resulting in loss of the ability to control chamber pressure. A Primary cause of loss of pressure control is a phenomenon commonly described as “choked flow”, where the required mass transfer through the duct connecting the Drying and condenser chamber cannot be maintained at the control pressure. Water vapor flow rate increases as the condenser pressure decreases, but it can continue to do so only until the velocity of water vapor reaches speed of sound (i.e., Mach I) at the duct exit. The flow is then said to be choked, and any further increase in water vapor flow rate results in an increase in chamber pressure (i.e., loss in chamber pressure control). Sublimation tests were carried out in Lyostar II freeze-dryer (SP Industries, NY) to predict the occurrence of choked flow. A capacitance manometer was installed in the “condenser chamber” and differential pressure ( P c − P cd ) was measured as a function of sublimation rate ( P c =chamber pressure and P cd =condenser pressure). Water vapor flow rate was measured by Tunable Diode Laser Absorption Spectroscopy (TDLAS) methodology, with a check by gravimetric data. Flow of water vapor in the duct connecting chamber and the condenser was modeled using computational fluid dynamics software (Fluent 6.3). The critical pressure ratio ( K ⁎= P c / P cd ) has been identified as an important variable that determines the onset of choked flow during Primary Drying. This ratio can be calculated given the mass flux. For our freeze-dryer, K * greater than 2.5 (for P c without interrupting the process. Also, TDLAS is a useful tool for determination of sublimation rate even at very high mass flux.
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determination of end point of Primary Drying in freeze Drying process control
Aaps Pharmscitech, 2010Co-Authors: Sajal M. Patel, Takayuki Doen, Michael J. PikalAbstract:Freeze-Drying is a relatively expensive process requiring long processing time, and hence one of the key objectives during freeze-Drying process development is to minimize the Primary Drying time, which is the longest of the three steps in freeze-Drying. However, increasing the shelf temperature into secondary Drying before all of the ice is removed from the product will likely cause collapse or eutectic melt. Thus, from product quality as well as process economics standpoint, it is very critical to detect the end of Primary Drying. Experiments were conducted with 5% mannitol and 5% sucrose as model systems. The apparent end point of Primary Drying was determined by comparative pressure measurement (i.e., Pirani vs. MKS Baratron), dew point, Lyotrack (gas plasma spectroscopy), water concentration from tunable diode laser absorption spectroscopy, condenser pressure, pressure rise test (manometric temperature measurement or variations of this method), and product thermocouples. Vials were pulled out from the Drying chamber using a sample thief during late Primary and early secondary Drying to determine percent residual moisture either gravimetrically or by Karl Fischer, and the cake structure was determined visually for melt-back, collapse, and retention of cake structure at the apparent end point of Primary Drying (i.e., onset, midpoint, and offset). By far, the Pirani is the best choice of the methods tested for evaluation of the end point of Primary Drying. Also, it is a batch technique, which is cheap, steam sterilizable, and easy to install without requiring any modification to the existing dryer.
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non invasive product temperature determination during Primary Drying using tunable diode laser absorption spectroscopy
Journal of Pharmaceutical Sciences, 2009Co-Authors: Stefan C. Schneid, Henning Gieseler, William J Kessler, Michael J. PikalAbstract:ABSTRACT The goal of this work was to demonstrate the application of Tunable Diode Laser Absorption Spectroscopy (TDLAS) as a non-invasive method to determine the average product temperature of the batch during Primary Drying. The TDLAS sensor continuously measures the water vapor concentration and the vapor flow velocity in the spool connecting the freeze-dryer chamber and condenser. Vapor concentration and velocity data were then used to determine the average sublimation rate (g/s) which was subsequently integrated to evaluate the amount of water removed from the product. Position dependent vial heat transfer coefficients (K v ) were evaluated using the TDLAS sensor data for 20mL vials during sublimation tests with pure water. TDLAS K v data showed good agreement to K v data obtained by the traditional gravimetric procedure. K v for edge vials was found to be about 20–30% higher than that of center vials. A weighted Kv was then used to predict a representative average product temperature from TDLAS data in partial and full load freeze Drying runs with 5%, 7.5%, or 10% (w/w) sucrose, mannitol, and glycine solutions. TDLAS product temperatures for all freeze-Drying runs were within 1–2°C of "center vial'' steady state thermocouple data. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3406–3418, 2009
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a procedure to optimize scale up for the Primary Drying phase of lyophilization
Journal of Pharmaceutical Sciences, 2009Co-Authors: D M Kremer, Michael J. Pikal, W J Petre, Evgenyi Shalaev, Larry A Gatlin, T KramerAbstract:Abstract This article describes a procedure to facilitate scale-up for the Primary Drying phase of lyophilization using a combination of empirical testing and numerical modeling. Freeze dry microscopy is used to determine the temperature at which lyophile collapse occurs. A laboratory scale freeze-dryer equipped with manometric temperature measurement is utilized to characterize the formulation-dependent mass transfer resistance of the lyophile and develop an optimized laboratory scale Primary Drying phase of the freeze-Drying cycle. Characterization of heat transfer at both lab and pilot scales has been ascertained from data collected during a lyophilization cycle involving surrogate material. Using the empirically derived mass transfer resistance and heat transfer data, a semi-empirical computational heat and mass transfer model originally developed by Mascarenhas et al. (Mascarenhas et al., 1997, Comput Methods Appl Mech Eng 148: 105–124) is demonstrated to provide predictive Primary Drying data at both the laboratory and pilot scale. Excellent agreement in both the sublimation interface temperature profiles and the time for completion of Primary Drying is obtained between the experimental cycles and the numerical model at both the laboratory and pilot scales. Further, the computational model predicts the optimum operational settings of the pilot scale lyophilizer, thus the procedure discussed here offers the potential to both reduce the time necessary to develop commercial freeze-Drying cycles by eliminating experimentation and to minimize consumption of valuable pharmacologically active materials during process development.
Thomas Beer - One of the best experts on this subject based on the ideXlab platform.
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model based optimization of the Primary Drying phase of oral lyophilizates
International journal of pharmaceutics: X, 2020Co-Authors: Brecht Vanbillemont, Thomas BeerAbstract:Oral lyophilizates also called orally disintegrating tablets (ODTs) are a patient friendly and convenient dosage form. They are manufactured by dosing a suspension in blister cups and subsequently freeze-Drying these blisters to achieve porous tablets that disintegrate quickly (< 10 s) when placed upon the tongue. This paper proposes a mechanistic model of the Primary Drying phase of these oral lyophilizates processed in cold-form blisters. A heat transfer coefficient (K v ) and dried layer resistance (R p ) are regressed and applied in a dynamic optimization of the Primary Drying phase. The optimization exercise showed the possibility of ultra-short sublimation times for polyvinyl acetate (PVA) based formulations with a Primary Drying time of 3.68 h for a 500 mg acetaminophen tablet.
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4d micro computed x ray tomography as a tool to determine critical process and product information of spin freeze dried unit doses
Pharmaceutics, 2020Co-Authors: Brecht Vanbillemont, Joris Lammens, Chris Vervaet, Wannes Goethals, Matthieu Boone, Thomas BeerAbstract:Maintaining chemical and physical stability of the product during freeze-Drying is important but challenging. In addition, freeze-Drying is typically associated with long process times. Therefore, mechanistic models have been developed to maximize Drying efficiency without altering the chemical or physical stability of the product. Dried product mass transfer resistance ( R p ) is a critical input for these mechanistic models. Currently available techniques to determine R p only provide an estimation of the mean R p and do not allow measuring and determining essential local (i.e., intra-vial) R p differences. In this study, we present an analytical method, based on four-dimensional micro-computed tomography (4D- μ CT), which enables the possibility to determine intra-vial R p differences. Subsequently, these obtained R p values are used in a mechanistic model to predict the Drying time distribution of a spin-frozen vial. Finally, this predicted Primary Drying time distribution is experimentally verified via thermal imaging during Drying. It was further found during this study that 4D- μ CT uniquely allows measuring and determining other essential freeze-Drying process parameters such as the moving direction(s) of the sublimation front and frozen product layer thickness, which allows gaining accurate process knowledge. To conclude, the study reveals that the variation in the end of Primary Drying time of a single vial could be predicted accurately using 4D- μ CT as similar results were found during the verification using thermal imaging.
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dual chamber cartridges in a continuous pharmaceutical freeze Drying concept determination of the optimal dynamic infrared heater temperature during Primary Drying
International Journal of Pharmaceutics, 2019Co-Authors: Laurens De Meyer, Pieter Jan Van Bockstal, Joris Lammens, Brecht Vanbillemont, Jos Corver, Chris Vervaet, Wolfgang Friess, Thomas BeerAbstract:Abstract The applicability of DCCs in a continuous freeze-Drying concept based on spin freezing and infrared heating was evaluated. Maximum applicable filling volume was evaluated. Secondly the mechanistic model for the determination of the optimal dynamic infrared heater temperature during Primary Drying of regular vials during continuous freeze-Drying was adapted and validated for DCCs. Finally, since spin frozen DCCs may be more prone to choked flow due to the small neck opening and the large product surface area, it was evaluated if the choked flow constraints in the model could be increased to improve the efficiency of the Drying process. The experiments revealed that the maximum allowable filling volume for spin freezing at the current experimental setup was 0.8 ml which is 80% of the maximum filling volume. Applying the mechanistic model for the determination of the optimal dynamic infrared heater temperature during Primary Drying of the studied DCCs and experimentally verifying this determined infrared heater temperature trajectory resulted in an elegant freeze-dried product without visual signs of collapse. The experimentally determined Primary Drying time agreed with the one calculated based on the mechanistic model. Choked flow did not occur during the continuous freeze-Drying of DCCs containing 3% sucrose or 3% mannitol.
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Developing a framework to model the Primary Drying step of a continuous freeze-Drying process based on infrared radiation.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2018Co-Authors: Pieter Jan Van Bockstal, Laurens De Meyer, Jos Corver, Krist V. Gernaey, Ingmar Nopens, Séverine Mortier, Thomas BeerAbstract:The continuous freeze-Drying concept based on spinning the vials during freezing and on non-contact energy transfer via infrared (IR) radiation during Drying, improves process efficiency and product quality (uniformity) compared to conventional batch freeze-Drying. Automated control of this process requires the fundamental mechanistic modelling of each individual process step. Therefore, a framework is presented for the modelling and control of the continuous Primary Drying step based on non-contact IR radiation. The IR radiation emitted by the radiator filaments passes through various materials before finally reaching the spin frozen vial. The energy transfer was computed by combining physical laws with Monte Carlo simulations and was verified with experimental data. The influence of the transmission properties of various materials on the emitted IR radiation profile was evaluated. These results assist in the selection of proper materials which could serve as IR window in the continuous freeze-Drying prototype. The modelling framework presented in this paper fits the model-based design approach used for the development of this prototype and shows the potential benefits of this design strategy by establishing the desired engineering parameters and by enabling the engineer to assess mechanical tolerances and material options.
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Global Sensitivity Analysis as Good Modelling Practices tool for the identification of the most influential process parameters of the Primary Drying step during freeze-Drying
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2018Co-Authors: Pieter Jan Van Bockstal, Severine Therese F C Mortier, Jos Corver, Krist V. Gernaey, Ingmar Nopens, Thomas BeerAbstract:Pharmaceutical batch freeze-Drying is commonly used to improve the stability of biological therapeutics. The Primary Drying step is regulated by the dynamic settings of the adaptable process variables, shelf temperature Ts and chamber pressure Pc. Mechanistic modelling of the Primary Drying step leads to the optimal dynamic combination of these adaptable process variables in function of time. According to Good Modelling Practices, a Global Sensitivity Analysis (GSA) is essential for appropriate model building. In this study, both a regression-based and variance-based GSA were conducted on a validated mechanistic Primary Drying model to estimate the impact of several model input parameters on two output variables, the product temperature at the sublimation front Ti and the sublimation rate ṁsub. Ts was identified as most influential parameter on both Ti and ṁsub, followed by Pc and the dried product mass transfer resistance αRp for Ti and ṁsub, respectively. The GSA findings were experimentally validated for ṁsub via a Design of Experiments (DoE) approach. The results indicated that GSA is a very useful tool for the evaluation of the impact of different process variables on the model outcome, leading to essential process knowledge, without the need for time-consuming experiments (e.g., DoE).
Davide Fissore - One of the best experts on this subject based on the ideXlab platform.
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micro freeze dryer and infrared based pat novel tools for Primary Drying design space determination of freeze Drying processes
Pharmaceutical Research, 2021Co-Authors: Maite Harguindeguy, Davide FissoreAbstract:Present (i) an infrared (IR)-based Process Analytical Technology (PAT) installed in a lab-scale freeze-dryer and (ii) a micro freeze-dryer (MicroFD®) as effective tools for freeze-Drying design space calculation of the Primary Drying stage. The case studies investigated are the freeze-Drying of a crystalline (5% mannitol) and of an amorphous (5% sucrose) solution processed in 6R vials. The heat (Kv) and the mass (Rp) transfer coefficients were estimated: tests at 8, 13 and 26 Pa were carried out to assess the chamber pressure effect on Kv. The design space of the Primary Drying stage was calculated using these parameters and a well-established model-based approach. The results obtained using the proposed tools were compared to the ones in case Kv and Rp were estimated in a lab-scale unit through gravimetric tests and a thermocouple-based method, respectively. The IR-based method allows a non-gravimetric estimation of the Kv values while with the micro freeze-dryer gravimetric tests require a very small number of vials. In both cases, the obtained values of Kv and Rp, as well as the resulting design spaces, were all in very good agreement with those obtained in a lab-scale unit through the gravimetric tests (Kv) and the thermocouple-based method (Rp). The proposed tools can be effectively used for design space calculation in substitution of other well-spread methods. Their advantages are mainly the less laborious Kv estimation process and, as far as the MicroFD® is concerned, the possibility of saving time and formulation material when evaluating Rp.
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On the use of a micro freeze-dryer for the investigation of the Primary Drying stage of a freeze-Drying process.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2019Co-Authors: Davide Fissore, Giuseppe Gallo, Angelo Emiliano Ruggiero, Taylor N. ThompsonAbstract:Abstract This paper deals with the use of a small-scale freeze-dryer, where very few vials are loaded (e.g. 19, each 10 mL, or 7, each 20 mL), for freeze-Drying cycle investigation. The system has a metallic ring surrounding the batch of vials, in contact with the external ones, and its temperature is manipulated independently from that of the shelf on the basis of the temperature of the product measured by thermocouples in some vials of the batch. The experimental study was carried out using two sucrose solutions (5% and 10% w/w), aiming to verify the homogeneity of the batch. Both product temperature and the weight loss after 6 h from the onset of the Primary Drying stage were selected as key parameters. Experiments were carried out according to a 2 N design of experiments, with two values of chamber pressure (60 and 90 mTorr) and two values of shelf temperature (−20 and 0 °C). Satisfactory results may be obtained by selecting a ring temperature 5 °C lower than that of the monitored samples in case of both products investigated. Besides, the system appears to be useful for the estimation of the coefficient of heat transfer to the product (Kv) and of the resistance of the dried cake to vapour flux (Rp), thus enabling the use of mathematical modelling for process design and optimization.
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computer aided framework for the design of freeze Drying cycles optimization of the operating conditions of the Primary Drying stage
Processes, 2015Co-Authors: Davide Fissore, Roberto PisanoAbstract:This paper deals with the freeze-Drying process and, in particular, with the optimization of the operating conditions of the Primary Drying stage. When designing a freeze-Drying cycle, process control aims at obtaining the values of the operating conditions (temperature of the heating fluid and pressure in the Drying chamber) resulting in a product temperature lower than the limit value of the product, and in the shortest Drying time. This is particularly challenging, mainly due to the intrinsic nonlinearity of the system. In this framework, deep process knowledge is required for deriving a suitable process dynamic model that can be used to calculate the design space for the Primary Drying stage. The design space can then be used to properly design (and optimize) the process, preserving product quality. The case of a product whose dried layer resistance, one of the key model parameters, is affected by the operating conditions is addressed in this paper, and a simple and effective method to calculate the design space in this case is presented and discussed.
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advanced approach to build the design space for the Primary Drying of a pharmaceutical freeze Drying process
Journal of Pharmaceutical Sciences, 2011Co-Authors: Davide Fissore, Roberto Pisano, Antonello BarresiAbstract:ABSTRACT This paper deals with the design space of a pharmaceutical freeze‐Drying process. Mathematical modeling is used to investigate the effect of the operating conditions [shelf temperature (Tshelf) and chamber pressure (Pc)] on product temperature (that has to remain below a limit value) and sublimation flux (that has to be lower than a level that would cause choked flow). The algorithm takes into account the variation of the design space with time due to the increase in the dried layer thickness. Besides Tshelf and Pc, the dried layer thickness is used as the third coordinate of the diagram, thus resulting in just one graph that can be used to build recipes with variable operating conditions, as well as to analyze the effect of process failures. Such results are compared with those obtained when the variation of the design space with time is not accounted for; in this case, the design space comprises those operating conditions that fulfill the operation constraints throughout Primary Drying, thus giving a much more conservative recipe when designing the process or potentially misleading results when analyzing process failures. Finally, the proposed method has been used to design, and experimentally validate, a recipe for a pharmaceutical formulation. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4922–4933, 2011
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freeze Drying cycle optimization using model predictive control techniques
Industrial & Engineering Chemistry Research, 2011Co-Authors: Roberto Pisano, Davide Fissore, Antonello BarresiAbstract:The problem of process control in the field of pharmaceutical freeze Drying is discussed, and a model predictive control (MPC) system is proposed to control, and optimize, in-line the Primary Drying step, beside preserving product quality. The controller can provide the optimal recipe for a given product, taking into account process constraints and modeling errors. Two control algorithms are proposed: the former manipulates both the chamber pressure and the temperature of the technical fluid, while the latter manipulates only the temperature of the fluid. The optimal formulation of the algorithms and the tuning of controller parameters are discussed by means of mathematical simulations.
Pieter Jan Van Bockstal - One of the best experts on this subject based on the ideXlab platform.
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A Primary Drying model-based comparison of conventional batch freeze-Drying to continuous spin-freeze-Drying for unit doses
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2020Co-Authors: Laurens Leys, Pieter Jan Van Bockstal, Joris Lammens, Brecht Vanbillemont, Jos Corver, Chris Vervaet, G. Nuytten, T. De BeerAbstract:Abstract An innovative continuous spin-freeze-Drying technology for unit doses was recently developed. For this technology, a mechanistic Primary Drying model was developed allowing the calculation of the optimal dynamic Drying trajectory for spin-frozen formulations. In this work, a model-based and experimentally verified comparison was made between conventional batch freeze-Drying and spin-freeze-Drying by analyzing the outputs (i.e., Primary Drying endpoint, optimal shelf temperature/power heater and product temperature profile) of both Primary Drying models. Input parameters such as dried product layer resistance ( R p ) and heat input parameters ( K v , P tot ) were experimentally determined for both freeze-Drying methods and compared. In addition, optimal dynamic process parameters were calculated for 3 model formulations by using both mechanistic models. Finally, model predictions were validated by measuring the product temperature and Primary Drying endpoint. It was observed that, when considering the same layer thickness, R p was generally lower for continuous spin-frozen formulations compared to vials frozen in a conventional batch freeze-dryer. This observation contributes to the short Primary Drying times of spin-frozen formulations. In addition, as spin-freezing drastically increases the surface area of the product and lowers the dried layer thickness, Drying times can be reduced even further while an excellent cake structure and appearance can still be obtained. The Primary Drying model for spin-frozen formulations proved to be equally accurate for the prediction of the Primary Drying endpoint and product temperature compared to the batch freeze-Drying model.
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dual chamber cartridges in a continuous pharmaceutical freeze Drying concept determination of the optimal dynamic infrared heater temperature during Primary Drying
International Journal of Pharmaceutics, 2019Co-Authors: Laurens De Meyer, Pieter Jan Van Bockstal, Joris Lammens, Brecht Vanbillemont, Jos Corver, Chris Vervaet, Wolfgang Friess, Thomas BeerAbstract:Abstract The applicability of DCCs in a continuous freeze-Drying concept based on spin freezing and infrared heating was evaluated. Maximum applicable filling volume was evaluated. Secondly the mechanistic model for the determination of the optimal dynamic infrared heater temperature during Primary Drying of regular vials during continuous freeze-Drying was adapted and validated for DCCs. Finally, since spin frozen DCCs may be more prone to choked flow due to the small neck opening and the large product surface area, it was evaluated if the choked flow constraints in the model could be increased to improve the efficiency of the Drying process. The experiments revealed that the maximum allowable filling volume for spin freezing at the current experimental setup was 0.8 ml which is 80% of the maximum filling volume. Applying the mechanistic model for the determination of the optimal dynamic infrared heater temperature during Primary Drying of the studied DCCs and experimentally verifying this determined infrared heater temperature trajectory resulted in an elegant freeze-dried product without visual signs of collapse. The experimentally determined Primary Drying time agreed with the one calculated based on the mechanistic model. Choked flow did not occur during the continuous freeze-Drying of DCCs containing 3% sucrose or 3% mannitol.
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Developing a framework to model the Primary Drying step of a continuous freeze-Drying process based on infrared radiation.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2018Co-Authors: Pieter Jan Van Bockstal, Laurens De Meyer, Jos Corver, Krist V. Gernaey, Ingmar Nopens, Séverine Mortier, Thomas BeerAbstract:The continuous freeze-Drying concept based on spinning the vials during freezing and on non-contact energy transfer via infrared (IR) radiation during Drying, improves process efficiency and product quality (uniformity) compared to conventional batch freeze-Drying. Automated control of this process requires the fundamental mechanistic modelling of each individual process step. Therefore, a framework is presented for the modelling and control of the continuous Primary Drying step based on non-contact IR radiation. The IR radiation emitted by the radiator filaments passes through various materials before finally reaching the spin frozen vial. The energy transfer was computed by combining physical laws with Monte Carlo simulations and was verified with experimental data. The influence of the transmission properties of various materials on the emitted IR radiation profile was evaluated. These results assist in the selection of proper materials which could serve as IR window in the continuous freeze-Drying prototype. The modelling framework presented in this paper fits the model-based design approach used for the development of this prototype and shows the potential benefits of this design strategy by establishing the desired engineering parameters and by enabling the engineer to assess mechanical tolerances and material options.
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Global Sensitivity Analysis as Good Modelling Practices tool for the identification of the most influential process parameters of the Primary Drying step during freeze-Drying
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2018Co-Authors: Pieter Jan Van Bockstal, Severine Therese F C Mortier, Jos Corver, Krist V. Gernaey, Ingmar Nopens, Thomas BeerAbstract:Pharmaceutical batch freeze-Drying is commonly used to improve the stability of biological therapeutics. The Primary Drying step is regulated by the dynamic settings of the adaptable process variables, shelf temperature Ts and chamber pressure Pc. Mechanistic modelling of the Primary Drying step leads to the optimal dynamic combination of these adaptable process variables in function of time. According to Good Modelling Practices, a Global Sensitivity Analysis (GSA) is essential for appropriate model building. In this study, both a regression-based and variance-based GSA were conducted on a validated mechanistic Primary Drying model to estimate the impact of several model input parameters on two output variables, the product temperature at the sublimation front Ti and the sublimation rate ṁsub. Ts was identified as most influential parameter on both Ti and ṁsub, followed by Pc and the dried product mass transfer resistance αRp for Ti and ṁsub, respectively. The GSA findings were experimentally validated for ṁsub via a Design of Experiments (DoE) approach. The results indicated that GSA is a very useful tool for the evaluation of the impact of different process variables on the model outcome, leading to essential process knowledge, without the need for time-consuming experiments (e.g., DoE).
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Mechanistic modelling of infrared mediated energy transfer during the Primary Drying step of a continuous freeze-Drying process
European Journal of Pharmaceutics and Biopharmaceutics, 2017Co-Authors: Pieter Jan Van Bockstal, Laurens De Meyer, Severine Therese F C Mortier, Jos Corver, Chris Vervaet, Ingmar Nopens, Thomas BeerAbstract:Conventional pharmaceutical freeze-Drying is an inefficient and expensive batch-wise process, associated with several disadvantages leading to an uncontrolled end product variability. The proposed continuous alternative, based on spinning the vials during freezing and on optimal energy supply during Drying, strongly increases process efficiency and improves product quality (uniformity). The heat transfer during continuous Drying of the spin frozen vials is provided via non-contact infrared (IR) radiation. The energy transfer to the spin frozen vials should be optimised to maximise the Drying efficiency while avoiding cake collapse. Therefore, a mechanistic model was developed which allows computing the optimal, dynamic IR heater temperature in function of the Primary Drying progress and which, hence, also allows predicting the Primary Drying endpoint based on the applied dynamic IR heater temperature. The model was validated by Drying spin frozen vials containing the model formulation (3.9 mL in 10R vials) according to the computed IR heater temperature profile. In total, 6 validation experiments were conducted. The Primary Drying endpoint was experimentally determined via in-line near-infrared (NIR) spectroscopy and compared with the endpoint predicted by the model (50 min). The mean ratio of the experimental Drying time to the predicted value was 0.91, indicating a good agreement between the model predictions and the experimental data. The end product had an elegant product appearance (visual inspection) and an acceptable residual moisture content (Karl Fischer).
Jos Corver - One of the best experts on this subject based on the ideXlab platform.
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A Primary Drying model-based comparison of conventional batch freeze-Drying to continuous spin-freeze-Drying for unit doses
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2020Co-Authors: Laurens Leys, Pieter Jan Van Bockstal, Joris Lammens, Brecht Vanbillemont, Jos Corver, Chris Vervaet, G. Nuytten, T. De BeerAbstract:Abstract An innovative continuous spin-freeze-Drying technology for unit doses was recently developed. For this technology, a mechanistic Primary Drying model was developed allowing the calculation of the optimal dynamic Drying trajectory for spin-frozen formulations. In this work, a model-based and experimentally verified comparison was made between conventional batch freeze-Drying and spin-freeze-Drying by analyzing the outputs (i.e., Primary Drying endpoint, optimal shelf temperature/power heater and product temperature profile) of both Primary Drying models. Input parameters such as dried product layer resistance ( R p ) and heat input parameters ( K v , P tot ) were experimentally determined for both freeze-Drying methods and compared. In addition, optimal dynamic process parameters were calculated for 3 model formulations by using both mechanistic models. Finally, model predictions were validated by measuring the product temperature and Primary Drying endpoint. It was observed that, when considering the same layer thickness, R p was generally lower for continuous spin-frozen formulations compared to vials frozen in a conventional batch freeze-dryer. This observation contributes to the short Primary Drying times of spin-frozen formulations. In addition, as spin-freezing drastically increases the surface area of the product and lowers the dried layer thickness, Drying times can be reduced even further while an excellent cake structure and appearance can still be obtained. The Primary Drying model for spin-frozen formulations proved to be equally accurate for the prediction of the Primary Drying endpoint and product temperature compared to the batch freeze-Drying model.
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dual chamber cartridges in a continuous pharmaceutical freeze Drying concept determination of the optimal dynamic infrared heater temperature during Primary Drying
International Journal of Pharmaceutics, 2019Co-Authors: Laurens De Meyer, Pieter Jan Van Bockstal, Joris Lammens, Brecht Vanbillemont, Jos Corver, Chris Vervaet, Wolfgang Friess, Thomas BeerAbstract:Abstract The applicability of DCCs in a continuous freeze-Drying concept based on spin freezing and infrared heating was evaluated. Maximum applicable filling volume was evaluated. Secondly the mechanistic model for the determination of the optimal dynamic infrared heater temperature during Primary Drying of regular vials during continuous freeze-Drying was adapted and validated for DCCs. Finally, since spin frozen DCCs may be more prone to choked flow due to the small neck opening and the large product surface area, it was evaluated if the choked flow constraints in the model could be increased to improve the efficiency of the Drying process. The experiments revealed that the maximum allowable filling volume for spin freezing at the current experimental setup was 0.8 ml which is 80% of the maximum filling volume. Applying the mechanistic model for the determination of the optimal dynamic infrared heater temperature during Primary Drying of the studied DCCs and experimentally verifying this determined infrared heater temperature trajectory resulted in an elegant freeze-dried product without visual signs of collapse. The experimentally determined Primary Drying time agreed with the one calculated based on the mechanistic model. Choked flow did not occur during the continuous freeze-Drying of DCCs containing 3% sucrose or 3% mannitol.
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Developing a framework to model the Primary Drying step of a continuous freeze-Drying process based on infrared radiation.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2018Co-Authors: Pieter Jan Van Bockstal, Laurens De Meyer, Jos Corver, Krist V. Gernaey, Ingmar Nopens, Séverine Mortier, Thomas BeerAbstract:The continuous freeze-Drying concept based on spinning the vials during freezing and on non-contact energy transfer via infrared (IR) radiation during Drying, improves process efficiency and product quality (uniformity) compared to conventional batch freeze-Drying. Automated control of this process requires the fundamental mechanistic modelling of each individual process step. Therefore, a framework is presented for the modelling and control of the continuous Primary Drying step based on non-contact IR radiation. The IR radiation emitted by the radiator filaments passes through various materials before finally reaching the spin frozen vial. The energy transfer was computed by combining physical laws with Monte Carlo simulations and was verified with experimental data. The influence of the transmission properties of various materials on the emitted IR radiation profile was evaluated. These results assist in the selection of proper materials which could serve as IR window in the continuous freeze-Drying prototype. The modelling framework presented in this paper fits the model-based design approach used for the development of this prototype and shows the potential benefits of this design strategy by establishing the desired engineering parameters and by enabling the engineer to assess mechanical tolerances and material options.
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Global Sensitivity Analysis as Good Modelling Practices tool for the identification of the most influential process parameters of the Primary Drying step during freeze-Drying
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2018Co-Authors: Pieter Jan Van Bockstal, Severine Therese F C Mortier, Jos Corver, Krist V. Gernaey, Ingmar Nopens, Thomas BeerAbstract:Pharmaceutical batch freeze-Drying is commonly used to improve the stability of biological therapeutics. The Primary Drying step is regulated by the dynamic settings of the adaptable process variables, shelf temperature Ts and chamber pressure Pc. Mechanistic modelling of the Primary Drying step leads to the optimal dynamic combination of these adaptable process variables in function of time. According to Good Modelling Practices, a Global Sensitivity Analysis (GSA) is essential for appropriate model building. In this study, both a regression-based and variance-based GSA were conducted on a validated mechanistic Primary Drying model to estimate the impact of several model input parameters on two output variables, the product temperature at the sublimation front Ti and the sublimation rate ṁsub. Ts was identified as most influential parameter on both Ti and ṁsub, followed by Pc and the dried product mass transfer resistance αRp for Ti and ṁsub, respectively. The GSA findings were experimentally validated for ṁsub via a Design of Experiments (DoE) approach. The results indicated that GSA is a very useful tool for the evaluation of the impact of different process variables on the model outcome, leading to essential process knowledge, without the need for time-consuming experiments (e.g., DoE).
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modelling the Primary Drying step for the determination of the optimal dynamic heating pad temperature in a continuous pharmaceutical freeze Drying process for unit doses
International Journal of Pharmaceutics, 2017Co-Authors: Laurens De Meyer, Joris Lammens, Severine Therese F C Mortier, Brecht Vanbillemont, Pieterjan Van Bockstal, Jos Corver, Chris Vervaet, Ingmar Nopens, Thomas BeerAbstract:Abstract In the pharmaceutical industry, traditional freeze-Drying of unit doses is a batch-wise process associated with many disadvantages. To overcome these disadvantages and to guarantee a uniform product quality and high process efficiency, a continuous freeze-Drying process is developed and evaluated. The main differences between the proposed continuous freeze-Drying process and traditional freeze-Drying can be found firstly in the freezing step during which the vials are rotated around their longitudinal axis (spin freezing), and secondly in the Drying step during which the energy for sublimation and desorption is provided through the vial wall by conduction via an electrical heating pad. To obtain a more efficient Drying process, the energy transfer has to be optimised without exceeding the product and process limits (e.g. cake collapse, choked flow). Therefore, a mechanistic model describing Primary Drying during continuous lyophilisation of unit doses based on conduction via heating pads was developed allowing the prediction of the optimal dynamic power input and temperature output of the electric heating pads. The model was verified by experimentally testing the optimal dynamic Primary Drying conditions calculated for a model formulation. The Primary Drying endpoint of the model formulation was determined via in-line NIR spectroscopy. This endpoint was then compared with the predicted model based endpoint. The mean ratio between the experimental and model based predicted Drying time for six verification runs was 1.05 ± 0.07, indicating a good accordance between the model and the experimental data.