Primary Drying Research Articles

Experimental study on improvement of freeze-drying process for porcine aorta

Freeze-drying is an effective method for preservation of aortas. In order to maintain the original properties of aortas, the sublimation drying process requires accurate monitoring. In this study, we used a contactless mass measurement device to monitor drying process, porcine aortic segments were divided into four series for freeze-drying, then relevant experiments and calculations were carried out to evaluate the quality of lyophilized samples. The study found that the sublimation process could not be accurately monitored by measured temperature, however, the real-time weighing could do it well, and was suitable to judge the endpoint of primary drying. Meanwhile, the change law of sublimation temperature was obtained by quasi-steady heat transfer equations. The removal ratio of free water during the primary drying greatly affected the properties of lyophilized samples, thorough sublimation had contributed to better performance of products, especially in mechanical properties. In addition, compared with annular aortic segments, the flaky samples had better heat transfer and performed better in histological scanning.

Development of freeze-drying cycle via design space approach: a case study on vaccines

Freeze-drying is a dehydration process that provides improved stability of vaccine formulations for shipment and storage. During the primary drying steps of the process, product temperature has to be maintained below a critical value to avoid visual defects of the product, leading to an increase of the sublimation time and thus of the operational costs. In this work, we used the design space approach together with experimental analysis for the development of the primary drying step of a vaccine model formulation. First, the formulation was characterized by determining the glass transition and the collapse temperatures. Successively, the dynamic design space of primary drying was calculated via mathematical modelling, and a proven acceptable range (PAR) was defined around the selected operating values. Finally, the cycle and the PAR were validated by performing a freeze-drying cycle at pilot scale and by evaluating the values of the product critical quality attributes (e.g. moisture content, visual aspect, reconstitution time).

Freeze concentration during freezing: How does the maximally freeze concentrated solution influence protein stability?

During freeze drying of biologics, a highly viscous freeze concentrate (FC) is formed upon the initial freezing due to the crystallisation of ice. Protein stability in this freeze concentrated phase is not yet well understood, but can decide upon the success of the lyophilisation itself. Protein stability may be high below the Tg' as it is typically the case during primary drying but decreases above Tg', e.g. during annealing or during aggressive freeze drying above Tg' in presence of a crystalline bulking agent or, beyond freeze drying, during storage of frozen bulk. Different FCs containing monoclonal antibody, sucrose, histidine or phosphate buffer and sodium chloride were prepared via partial freeze drying and analysed for protein aggregation. No solute crystallisation is visible and the systems are vitrifying during cooling. Increasing sugar or buffer concentration showed positive effects on either melting and aggregation temperature or on protein self-interaction as indicated by A2 values. Protein integrity in the FC was not affected by 1month storage at temperatures above Tg'. Thus, upconcentration of solutes during freezing does not negatively impact protein stability. Exceeding Tg' during freeze drying e.g. upon annealing or, intentionally or unintentionally, during primary drying does not lead to protein aggregation.

Quantitative investigation on the effects of ice crystal size on freeze-drying: The primary drying step

The size of ice crystals formed in the freezing process has a significant impact on the subsequent primary drying process. However, the effects have not been fully understood. The purpose of this study was to quantitatively investigate the effects of ice crystal size on water vapor concentration, temperature, and primary drying time. A mathematical model considering the effects of ice crystals size was proposed, and it was solved by Comsol Multiphysics. Results show that there is less water vapor in the products with larger ice crystals. Temperature is found to decrease initially, and larger ice crystals lead to a higher temperature in the dried zone while the lower temperature in the frozen zone. The primary drying process proceeds faster when the ice crystal size is large, and the decrement of primary drying time gets smaller when further increasing the size of ice crystals. This work could provide help for the optimization of freeze-drying.

Integrated use of mechanistic models and targeted experiments for development, scale-up and optimization of lyophilization cycles: A single vial approach for primary drying

Development of lyophilization cycles, tech transfer and scale-up of the cycles, particularly of the primary drying, are common and challenging tasks for engineers in pharmaceutical companies. In this manuscript we share our experience with the scale-up of a previously tested cycle from pilot scale to production scale and then with optimization of the primary drying. We describe a workflow for a straightforward sequential and unbiased calculation of the mathematical model adjustable parameters: heat transfer coefficients and average radii of the pores (mass transfer coefficients). The calibrated model for the pilot scale can be then used for simulations of different scenarios at this scale, and for scale-up of the cycle to production scale. In production scale it is recommended to run water sublimation studies, to determine the heat transfer coefficients at this scale. The average radii of pores determined at the pilot scale can be used at the production scale. The calibrated model for the production scale can then be used to arrive at an optimum and robust lyo cycle at production. The final example of the case study illustrates the use of the developed model and software for primary drying optimization (shortening) by initially running it at a higher temperature. In summary, it can be concluded that the developed mathematical models, targeted experiments, and proposed workflow can significantly accelerate development, tech transfer and optimization of the primary drying.

Freeze-drying in protective bags: Characterization of heat and mass transfer

During lyophilisation of highly potent Active Pharmaceutical Ingredients (APIs) potential contamination of the freeze-drier is an important safety issue. Since the stoppers are in semistoppered position during the lyophilization process, API may contaminate the chamber and cross-contamination may occur as well. In this study two protective bags, which enclose each tray and their influence on heat and mass transfer during freeze-drying were investigated. Sublimation tests were performed using either purified water or solutions containing trehalose as well as hydroxypropyl-β-cyclodextrin (HPbCD) as bulking agents. During sublimation tests with purified water both bags clearly influenced heat and mass transfer compared to unpacked reference vials. The bag, which was originally designed to be used for steam sterilization, had a massive impact on drying characteristics. The bag membrane becomes the rate limiting factor, generating a separate compartment within the bag. In this compartment vapor pressure is much higher compared to the chamber pressure during primary drying, leading to altered drying conditions. However, drying was still possible. The other bag, which was specifically designed for lyophilization, also had an impact on drying behavior which could be assigned to the foil between shelf and bottom of the vials. This was detectable as differences in Kv values. Membrane resistance, however, becomes negligible when 10% (w/w) trehalose or HPbCD solutions were dried using the later bag as containment. The data reported in this work demonstrate the relevance and value of sublimation tests to understand the lyophilization process, especially when new components are implemented. The data should be considered, when freeze-drying shall be performed using such bags.

Automatic control of a freeze-drying process: Detection of the end point of primary drying

In freeze-drying, the detection of the end of primary drying is a crucial aspect for both the process economics and product quality. Furthermore, the extreme process conditions (low temperature, high vacuum, and sterility) require monitoring devices with a high degree of assurance. In this paper, the most promising methodologies for the detection of the end point of primary drying were investigated and compared. These devices include thermocouples, comparative pressure measurement, condenser pressure, controlled leakage, vacuum shut-off valve, microbalance, mass spectrometers, moisture sensors, and pressure rise test. Furthermore, a multi-scale model of the process was used to describe the process dynamics during the last part of drying, showing that the time difference between the onset and offset points depends on the batch heterogeneity, as well as process conditions and batch size. Ultimately, an automatic stop criterion, named EPD, has been designed and experimentally tested in a wide range of process conditions, batch size, vial size, and drug products. In particular, the experimental validation involved some of the most used excipients as model products, i.e., mannitol, dextran, lactose, and sucrose. In all the runs, the EPD drying times reasonably agreed with the comparative pressure measurement, which was the most reliable way to detect the end of primary drying. Thus, EPD can effectively be used to optimize primary drying without risking the product collapse because of a premature increase in shelf temperature for secondary drying.

Heat flux sensor to create a design space for freeze-drying development

Freeze-drying methodology requires an in-depth understanding and characterization for optimal processing of biopharmaceuticals. Particularly the primary drying phase, the longest and most expensive stage of the process, is of interest for optimization. The currently used process analytical technology (PAT) tools give highly valuable insights but come with limitations. Our study describes, for the first time, the application of a heat flux sensor (HFS) to build a primary drying design space and predict the process evolution. First, the heat transfer coefficient (Kv) generated by HFS and by the most accurate, but time-consuming and invasive, gravimetric method were compared. Second, the applicability to generate a design space was tested and verified. Obtained results revealed a good agreement of the values generated from this new and fast HFS compared to the gravimetric determination. Additionally, residual moisture assessed by Karl-Fischer titration and frequency modulated spectroscopy (FMS) support the quality of the obtained predictions. Thus, the HFS approach can substantially accelerate evaluation, development and transfer of a freeze-drying cycle.

Monitoring of primary drying in the freeze-drying process using an open-ended coaxial microwave resonator

An open-ended coaxial microwave resonator was designed and applied for monitoring the primary drying stage in the freeze-drying process by microwave resonance spectroscopy. A stainless steel cylindrical resonator with an inner cavity and cylindrical core was designed to sense the electrical permittivity and permeability (i.e., dielectric property) in the space over the resonator. The obtained spectrum patterns and peak intensities in the frequency range of 2500–3000 MHz responded sensitively to different volumes of ice over the probe. Monitoring of freeze-drying of a dextrin solution and sliced apple was successfully achieved by tracking the peak shift and/or the intensity of selected peak frequencies. The end-point of drying estimated from the microwave resonator perfectly corresponded to the point estimated from the product temperature during drying. This sensing device can potentially be applied for in-line monitoring of the freeze-drying process without contact to product, especially in a freeze-drying process.

Effect of formulation and inhaler parameters on the dispersion of spray freeze dried voriconazole particles.

Spray freeze drying is a particle engineering technique that allows the production of porous particles of low density with excellent aerosol performance for inhalation. There are a number of operating parameters that can be manipulated in order to optimise the powder properties. In this study, a two-fluid nozzle was used to prepare spray freeze dried formulation of voriconazole, a triazole antifungal agent for the treatment of pulmonary aspergillosis. A full factorial design approach was adopted to explore the effects of drug concentration, atomisation gas flow rate and primary drying temperature. The aerosol performance of the spray freeze dried powder was evaluated using the next generation impactor (NGI) operated with different inhaler devices and flow rates. The results showed that the primary drying temperature played an important role in determining the aerosol properties of the powder. In general, the higher the primary drying temperature, the lower the emitted fraction (EF) and the higher the fine particle fraction (FPF). Formulations that contained the highest voriconazole concentration (80% w/w) and prepared at a high primary drying temperature (-10°C) exhibited the best aerosol performance under different experimental conditions. The high concentration of the hydrophobic voriconazole reduced surface energy and cohesion, hence better powder dispersibility. The powders produced with higher primary drying temperature had a smaller particle size after dispersion and improved aerosol property, possibly due to the faster sublimation rate in the freeze-drying step that led to the formation of less aggregating or more fragile particles. Moreover, Breezhaler®, which has a low intrinsic resistance, was able to generate the best aerosol performance of the spray freeze dried voriconazole powders in terms of FPF.

Kinetics of Drying and Heat Treatment During Production of Textile Composites Made of Chemical Threads

Drying and heat treatment of textile composites produced by impregnating fabric made of chemical threads with an aqueous styrene-acrylate emulsion were examined. An analysis of the drying kinetics established that the rates of primary and secondary drying depended on the concentration of the aqueous polymer-binder emulsion; the total drying time, on the type of fabric. Mathematical models for calculating the total drying time of the textile composites produced by impregnation with an aqueous styrene-acrylate emulsion at concentrations from 50 to 500 g/L were developed and validated experimentally.

Determination of ice interface temperature, sublimation rate and the dried product resistance, and its application in the assessment of microcollapse using through-vial impedance spectroscopy

Through-vial impedance spectroscopy (TVIS) is a new approach for characterizing product attributes during freeze-drying process development. In this study, a pair of copper foil electrodes was attached to the external surface of a Type I glass tubing vial, of nominal capacity 10 mL and containing 3.5 g of an aqueous solution of 5%w/v lactose, and the impedance spectrum of the vial and contents recorded during a lyophilization cycle. The cycle included a temperature ramp in the primary drying stage in order to induce a collapse event in the dry layer. Using the peak in the dielectric loss spectrum, associated with the dielectric relaxation of ice, methods were developed to predict the sublimation rate and the ice interface temperature at the sublimation front, from which the dry layer resistance was then calculated. A four-fold increase in sublimation rate and a reduction in the dry layer resistance wereobserved once the ice interface temperature reached −33 °C, which coincides with the onset of the glass transition (as determined by DSC) and the time point at which micro-collapse occurred (as evidenced by SEM images at the end of the cycle). This work suggests a prospective application of impedance measurements in driving process efficiencies by operating the dryer at the highest achievable temperature (i.e. the collapse temperature) whilst avoiding macro-collapse.

Use of Industrial Waste for the Optimization of Ceramic Construction Materials

The massive growth of the ceramic industry and the consequent demand for construction materials worldwide has motivated the search for alternative solutions aimed at reducing the use of mineral / natural resources as the main source of raw materials. One of the strategies frequently adopted by the scientific community is the reuse of industrial waste. It is beneficial not only to reduce the overexploitation of mineral resources but also to reduce the environmental, economic and social impacts resulting from their incorrect disposal/treatment and consequent deposition on land unsuitable or that purpose. Duetoconsiderationssuchasphysico-mechanical characteristics and the high production rate, two different types of industrial waste were selected for this work, ashes resulting from the burning of coal in thermoelectric power plant, commonly known as bottom ash (B), and the Marble Powder (MP). It was intended to test the technological feasibility of the manufacture of ceramic materials produced from clay mixtures containing these two residues. For this purpose, the fine fraction(<63μm)obtained from the sieving of the marbleresidue(MR)and slag(Bf)was used,aswellasacoarsergrainslagfractionrangingfrom63-125μm(Bg). The resulting test samples were subjected to a firing of 950 °C under an oxidizing atmosphere, following a primary drying process. Faced with the standard values, the new ceramic materials obtained from MP have seen their mechanical and porous characteristics decrease and increase, respectively. Atthesametime,althoughtheadditionofBinno way influenced the mechanical characteristics,a significant improvement the porous characteristic was observed. The incorporation of these residues produced a color very close to the original sample material.
 Keywords: industrial waste, ceramic, construction materials, bottom ash, Marble Powder

Primary Drying Optimization in Pharmaceutical Freeze-Drying: A Multivial Stochastic Modeling Framework

Primary drying is the most time-consuming and energy-intensive step in pharmaceutical freeze-drying. Minimizing the duration of this stage is of paramount importance to speed up process development...

Model-Based Optimisation and Control Strategy for the Primary Drying Phase of a Lyophilisation Process.

The standard operation of a batch freeze-dryer is protocol driven. All freeze-drying phases (i.e., freezing, primary and secondary drying) are programmed sequentially at fixed time points and within each phase critical process parameters (CPPs) are typically kept constant or linearly interpolated between two setpoints. This way of operating batch freeze-dryers is shown to be time consuming and inefficient. A model-based optimisation and real-time control strategy that includes model output uncertainty could help in accelerating the primary drying phase while controlling the risk of failure of the critical quality attributes (CQAs). In each iteration of the real-time control strategy, a design space is computed to select an optimal set of CPPs. The aim of the control strategy is to avoid product structure loss, which occurs when the sublimation interface temperature () exceeds the the collapse temperature () common during unexpected disturbances, while preventing the choked flow conditions leading to a loss of pressure control. The proposed methodology was experimentally verified when the chamber pressure and shelf fluid system were intentionally subjected to moderate process disturbances. Moreover, the end of the primary drying phase was predicted using both uncertainty analysis and a comparative pressure measurement technique. Both the prediction of and end of primary drying were in agreement with the experimental data. Hence, it was confirmed that the proposed real-time control strategy is capable of mitigating the effect of moderate disturbances during batch freeze-drying.

Freeze-Drying of Blueberries: Effects of Carbon Dioxide (CO2) Laser Perforation as Skin Pretreatment to Improve Mass Transfer, Primary Drying Time, and Quality.

Freeze-dried berry fruits are generally consumed as they are, whole and without peeling or cutting, as the conservation of their original shape and appearance is often desired for the final product. However, usually, berries are naturally wrapped by an outer skin that imparts a barrier to vapor flow during freeze-drying, causing berry busting. Photo-sequence, experimental, and theoretical methodologies were applied to evaluate the application of CO2 laser microperforations to blueberry skin. Under the same set of freeze-drying conditions, blueberries with and without perforations were processed. The results showed that the primary drying time was significantly reduced from 17 ± 0.9 h for nontreated berries to 13 ± 2.0 h when nine microperforations per berry fruit were made. Concomitantly, the quality was also significantly improved, as the percentage of nonbusted blueberries at the end of the process increased from an average of 47% to 86%. From a phenomenological perspective, the analysis of the mass transfer resistance of nontreated fruits, in agreement with reported studies, showed a Type II curvature, with a sharp decrease at low time, followed by a linear increase. In contrast, blueberries with nine perforations depicted a Type III regime, with a saturation curvature toward the time axis. It was demonstrated that CO2-laser microperforation has high potential as a skin pretreatment for the freeze-drying of blueberries.

Use of a temperature ramp approach (TRA) to design an optimum and robust freeze-drying process for pharmaceutical formulations.

Freeze-drying, until now, has been a process that was designed using a trial and error experimental approach. This approach is often material and time consuming, and the resulting freeze-drying processes are neither optimum nor robust. Accordingly, the objective of this study was to develop a simple-to-use and experimental-based approach to design an optimum and robust freeze-drying process for any given formulation. The temperature ramp approach (TRA) detailed in this study involves the implementation of a customized design of experiments (DoE) to perform few (three or four) experiments using a given drug formulation. The DoE results are analyzed to define optimum processing conditions (i.e., shelf temperature and chamber pressure) based on a predefined range of target product temperature for primary drying, which could be defined from formulation characterization at its frozen state. In this study, a successful freeze-drying process of two model formulations using the TRA was designed. Verification experiments at the optimum processing conditions showed excellent agreement in both product temperature and sublimation rate with the values obtained using the TRA. Thus, the TRA detailed in this study offers a significant advantage to reduce development time and material, and enhance the efficiency and robustness of the resulting freeze-drying process.

Using mathematical modeling to optimize secondary drying stage of lyophilization technology

During lyophilization frozen water and moisture associated with dissolved substances are removed, desorption occurs in the process of secondary drying. This stage is one of the main stages of the technological process in terms of duration comparable with primary freeze drying and is of paramount importance for the further storage of lyophilisates. Mathematical modeling of secondary drying and the use of these methods in calculating design space of the process are described in the presented article. The equations for calculating the rate of secondary drying, residual moisture, and other conditions on the basis of values of the temperature of the heat-transfer fluid and pressure in the freezedrying chamber are shown. Possibilities for determining design space boundaries on the basis of the composition of lyophilisate, required values of residual moisture and drying kinetics are demonstrated. The proposed mathematical model makes it possible to estimate the duration of the secondary drying process for various values of temperature and pressure in the chamber within the design space.

Excipients in freeze-dried biopharmaceuticals: Contributions toward formulation stability and lyophilisation cycle optimisation.

Biopharmaceuticals are one of the fastest growing areas within the pharmaceutical industry. As protein drugs require parenteral administration, they are commonly formulated as aqueous solutions. However, this is not always feasible due to their general instability. In such cases, lyophilised powders for injection are the dosage form of choice, for the preparation of stable products. Lyophilisation is known to be highly time and energy consuming, and hence it is an expensive technological process. Thus, the pharmaceutical industry is increasingly focused on its optimisation. Implementation of aggressive conditions, together with optimisation of formulation parameters, represent the contemporary approach to reduction of the primary drying time. As such, incorporation of drug-specific excipients can contribute significantly to the stability of a biologically active ingredient, and indirectly they can also affect the time needed for lyophilisation. The addition of the most relevant protein stabilisers, surfactants, buffers and bulking agents is therefore crucial. The main aim of the present review is to define the most important groups of biopharmaceutical excipients, based on their roles in formulations and the mechanism(s) through which they support the lyophilisation process, to provide products with the required protein efficiency and product characteristics. The scope of the article is to critically discuss the suitability of novel stabilizers, with higher critical temperatures and bulking agents in terms of implementation of aggressive primary drying. For better assignment of the topic-related challenges, the stabilities of biopharmaceutical drugs and the fundamentals of the lyophilisation process are also briefly described.

A new mathematical model for monitoring the temporal evolution of the ice crystal size distribution during freezing in pharmaceutical solutions

The freezing step plays a key role in the overall economy of the vacuum freeze-drying of pharmaceuticals, since the nucleation and crystal growth kinetics determine the number and size distribution of the crystals formed. In this work, a new mathematical model of the freezing step of a (bio)pharmaceutical solution is developed and validated. Both nucleation and crystal growth kinetics are modeled and included in a one-dimensional population balance (1D-PBM) that describes, given the product temperature measurement, the evolution of the pore size distribution during freezing. The developed model is coupled with the real-time measurements obtained from an infrared video camera. The ending time of the primary drying stage, and the maximum temperature inside the material, simulated through a simplified model of the process and the pore distribution forecast, resulted in good agreement with experimental values. The resulting Process Analytical Technology (PAT) has the potential to boost the development and optimization of a freeze-drying cycle and the implementation of a physically grounded Quality-by-Design approach in the manufacturing of pharmaceuticals. A more general mathematical model, including the aforementioned population balance, of a vial filled with a solution of sucrose was also developed and used to further validate the approach.