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This article presents a new process analytical technology to monitor a vial freeze-drying process taking into account the batch nonuniformity. It is based on a soft sensor, using a mathematical model of the process, and on the temperature measurement obtained using a new wireless device. It allows estimating the residual ice content in the monitored vials until the end of the primary drying stage and the values of the heat (and mass transfer) coefficients. Experiments carried out with aqueous solutions containing various excipients (sucrose, mannitol, polyvinylpyrrolidone) or with a pharmaceutical formulations show the effectiveness of the proposed system. [ABSTRACT FROM AUTHOR]

The problem of process design for the freeze-drying of pharmaceutical products is here addressed. A comparative analysis between the various optimization tools so far proposed is given. The above analysis aims to give some guidelines to lyophilization professionals in the choice of the best design strategy compatible with their objectives and the technology available. In particular, this study examines the strengths and weaknesses of design space and of the different model-based control techniques so far proposed with a view to a better understanding of factors that still limit the use of these techniques at the manufacturing scale. With this regard, the above methods are compared in terms of robustness and scalability of the cycle, number and type of input parameters, management of product and equipment constraints, as well as batch unevenness. The first part of the study is carried out by means of mathematical simulations, as this approach makes it possible to better investigate the controller performance eliminating the uncertainty due to the experiment reproducibility. This study shows that although design space can provide a detailed view of the impact of processing conditions on product quality, its use for the cycle development can hardly lead to a real process optimization. By contrast, this objective can be achieved if model-based control is used. Experiments obtained for mannitol and sucrose-based formulations confirmed this result. [ABSTRACT FROM PUBLISHER]

This paper is focused on the secondary drying step of a freeze-drying process, where the bound water is desorbed from the (partially) dried product, with the goal to achieve the target value of residual moisture in the final product. Mathematical modeling is used to get a deep understanding of the process, i.e., to study the effect of the operating variables (mainly the temperature of the heating shelf and the duration of the operation) on the state of the product (temperature and residual moisture). An innovative tool is used to provide an effective support to get quality by design: it is based on the measurement of the desorption rate, through the test of pressure rise, and on a mathematical model of the process. It allows us to monitor in-line the process, as well as to determine the kinetic parameters of water desorption and their dependence on the operating conditions. The mathematical model of the process is used to calculate the design space of the secondary drying process, i.e., to identify those operating conditions that allow the fulfillment of product quality requirements, and then to minimize the duration of the secondary drying. The case study used to test the proposed methodology is the drying of 5% w/w aqueous solutions of sucrose: a linear dependence of the desorption rate on the residual moisture is evidenced by the experimental investigation, and the Arrhenius equation appears to adequately describe the dependence of the kinetic constant on the temperature, with a frequency factor equal to 277 s−1, and an activation energy equal to 37,714 J mol−1. The model is then used to calculate the design space, as well as to optimize the operating conditions; in case the target value of residual moisture is 2%, the duration of secondary drying can be decreased from 16 h in case of constant shelf temperature to 7.35 h in case the recipe is optimized. [ABSTRACT FROM AUTHOR]

This article is focused on the design of pharmaceutical freeze-drying recipes using in-line or off-line tools. In particular, the model predictive control system is here used to optimize the in-line process, and the design space is used for off-line optimization. Because both methods uses a mathematical model of the process, the problem of estimating the model parameters, including their uncertainty or variability in the lot of vials, is addressed. Then, the strengths and the weaknesses of the various methods are discussed, with particular emphasis on their robustness and their application in industrial-scale freeze dryers. In particular, the ability of the model predictive control tool to obtain the optimal recipe in only one run and its capacity to manage the system in case of an in-line modification of the product properties are shown. For this purpose, experimental results obtained for sucrose- and mannitol-based formulations are presented. [ABSTRACT FROM PUBLISHER]

This paper aims to extend the field of application of the pressure rise, test technique, from freeze drying of pharmaceutical or biological products in vials to freeze drying of liquids or foodstuff in trays. The proposed method, which is based on DPE+ algorithm, has been adapted to monitor the drying of liquids in trays and of individually quick frozen products. Examples of results obtained in a small-scale plant wherein such a method was used for monitoring the freeze drying of spinach samples and solutions of sucrose and lactose are presented. Since in bulk freeze drying the radiant energy coming from the upper shelf might be not negligible, the effectiveness of this method has been tested in the presence of different radiating contributions. A more sophisticated algorithm to interpret the pressure rise curve, which uses a mathematical model accounting for both conduction heat transfer from the bottom and radiant energy coming from the upper shelf and including heat accumulation into the dried layer, is proposed and experimentally tested. [ABSTRACT FROM AUTHOR]

This paper proposes a simple and effective methodology for the scale-up and process transfer of freeze-drying recipes. Process modeling allows the study of the silico product evolution in a given freeze-dryer, and calculation of the operating conditions that result in the same product dynamics in different equipment. Few experiments are necessary to determine model parameters and to characterize the two freeze-dryers. The problem of the batch non-uniformity and the effect of the parameters' uncertainty are also addressed. The effectiveness of this approach is demonstrated by means of various examples. [ABSTRACT FROM AUTHOR]

This article deals with the monitoring and control of the freeze drying of pharmaceuticals in vials taking into account batch heterogeneity. Firstly, the problem of nonuniformity of the batch is addressed: the vials in the chamber of the freeze dryer can, in fact, exhibit different time evolutions due not only to radiation from the wall of the chamber, but also to temperature gradients on the heating shelf, vapor fluid dynamics, and nonuniform inert distribution, as it has been evidenced by means of computational fluid dynamics simulations. Then, the effect of batch heterogeneity on the performance of the monitoring and control system is discussed and a new tool is presented, based on an advanced algorithm, the Dynamic Parameters Estimation, that estimates the state of the system (product temperature and residual ice content) by using the results of the pressure rise test, coupled with a controller (LyoDriver) that changes the shelf temperature in order to maintain product temperature below the maximum allowed value while minimizing the duration of primary drying. [ABSTRACT FROM AUTHOR]

In-line monitoring of the primary drying of the lyophilization process of a pharmaceutical product in vials is addressed in this article. A soft sensor (observer) based on the high gain concept is designed to this purpose. The proposed observer combines the physical measure of the frozen product temperature at the bottom of the vial with a simplified mathematical model of the process. This approach allows the continuous estimation of the entire temperature profile of the product and the monitoring of the state of progression of the primary drying phase. The main issues arising in the design of this observer are discussed. A detailed and experimentally validated mono-dimensional model is used as a source of measured data, in order to compare and validate by means of numerical simulations the results provided by the soft sensor. Finally, the performance of the high gain observer is compared with that of a Kalman filter-based observer previously proposed for the same process, evidencing the advantages of the high gain approach. [ABSTRACT FROM AUTHOR]

The aim of this article is to investigate the characteristics of a vial freeze-dried product as a function of the temperature at which the primary drying is carried out. The effect of the drying temperature and composition on the product appearance and final characteristics (apparent density and rehydratability) of pure substances (mannitol, sucrose, and dextran) has been studied: rehydratability is faster for the product freeze dried at lower temperature, when the structure of the product is more porous and softer; higher rehydration rates were also observed for samples obtained from lower initial concentration. In case of binary mixtures (mannitol and dextran, sucrose and dextran) the rehydratability gets worse when higher drying temperatures are used, whereas the relative composition has a smaller effect. Nevertheless, high drying temperatures are required to shorten the process, both in case of pure substances and in case of binary mixtures; thus, it is important to consider the process time-product quality relationship to choose the optimal drying temperature. Finally, we show that the freeze drying of mixtures can be easier and faster than that of one of the components alone; this is partly a consequence of the higher temperatures allowed, but it is evident that in some cases the drying kinetics can be higher even with the same process temperature. [ABSTRACT FROM AUTHOR]

This article deals with the control of a freeze-drying process in vials. Firstly, the results that can be obtained when the operation is carried out at constant chamber pressure and shelf temperature are predicted by means of mathematical simulations, using a previously validated detailed model, thus allowing off-line optimization of the process. Further improvements can be obtained if the shelf temperature is varied during the process in such a way that the product temperature is always maintained at the maximum allowable value. This strategy for the in-line control of the process allows to minimize the time required for the primary drying, besides satisfying the process constraints. The possibility of manipulating the chamber pressure for control purposes is also discussed. An alternative strategy based on a simple feedback controller, with proportional-integral action, is also investigated: it is able to control the product temperature at a predetermined value, giving stable and fast responses. The controller uses a soft sensor to get a reliable in-line estimate of the controlled variable; i.e., of the maximum temperature of the product. [ABSTRACT FROM AUTHOR]

The aim of this article is to develop an experiment and a procedure to investigate the restoration of water-damaged paper and archival materials using freeze drying in order to allow a reproducible test and comparison of the influence of different operating conditions on drying time and restored paper quality. Firstly, a reproducible method for the preparation of soaked samples simulating water-damaged paper has been developed. Then, the samples have been freeze-dried in a laboratory-scale apparatus that allowed monitoring the temperature as well as the weight of the samples. The technique of evaporative freezing, which reduces the drying time required, has been used in this case. An innovative procedure for the visualization of the progress of the drying process has been validated, thus allowing the validation of a simple phenomenological model of the time evolution of the ice core volume; in addition, data on the residual moisture of the dried paper sheets in different zones have been given. Finally, optimization of this particular drying process by using simple or more sophisticated approaches has been discussed. [ABSTRACT FROM AUTHOR]