Insights into Thermal Interactions in Frozen Pharmaceutical Vials: Effects on Ice Nucleation Times and Inhibition.

PURPOSE: This study investigates the thermal interactions between adjacent vials during freezing and assesses their impact on nucleation times. METHODS: Various loading configurations were analyzed to understand their impact on nucleation times. Configurations involving direct contact between vials and freeze-dryer shelves were studied, along with setups using empty vials between filled ones. Additionally, non-conventional loading configurations and glycol-filled vials were tested. The analysis includes 2R and 20R vials, which are commonly utilized in the freezing and lyophilization of drug products, along with two different fill depths, 1 and 1.4 cm. RESULTS: The investigation revealed that configurations with direct contact between vials and freeze-dryer shelves led to substantial thermal interactions, resulting in delayed nucleation in adjacent vials and affecting the temperature at which nucleation takes place in a complex way. In another setup, empty vials were placed between filled vials, significantly reducing thermal interactions. Further tests with non-conventional configurations and glycol-filled vials confirmed the presence of thermal interactions with a minimal inhibitory effect. CONCLUSIONS: These findings carry significant implications for the pharmaceutical industry, highlighting the role of thermal interactions among vials during freezing and their impact on the temperature at which ice nucleation occurs.

Nanoparticles obtained by confined impinging jet mixer: poly(lactide-co-glycolide) vs. Poly-ε-caprolactone.

This paper is focused on the production and characterization of polymeric nanoparticles obtained by nanoprecipitation. The method consisted of using a confined impinging jet mixer (CIJM), circumventing high-energy equipment. Differences between the use of poly-ε-caprolactone (PCL) and poly(lactide-co-glycolide) (PLGA) as concerns particle mean size, zeta potential, and broad-spectrum antibiotic florfenicol entrapment were investigated. Other analyzed variables were polymer concentration, solvent, and anti-solvent flow rates, and antibiotic initial concentration. To our knowledge, no data were found related to PLGA and PCL nanoparticles comparison using CIJM. Also, florfenicol encapsulation within PCL or PLGA nanoparticles by nanoprecipitation has not been reported yet. The complexity of the nanoprecipitation phenomena has been confirmed, with many relevant variables involved in particles formation. PLGA resulted in smaller and more stable nanoparticles with higher entrapping of florfenicol than PCL.

Cotton fabric functionalisation with menthol/PCL micro- and nano-capsules for comfort improvement.

OBJECTIVE: Cotton functionalisation with poly-ɛ-caprolactone (PCL) micro- and nano-capsules containing menthol was carried out with the aim of introducing a long-lasting refreshing sensation. MATERIALS AND METHODS: The preparation of the polymer micro- and nano-capsules was carried out by solvent displacement technique. A confined impinging jets mixer was used in order to ensure fast mixing and generate a homogeneous environment where PCL and menthol can self-assemble. RESULTS: The micro- and nano-capsules and the functionalised fabrics were characterised by means of DSC, FT-IR spectroscopy and SEM imaging. Micro- and nano-capsules of different size, from about 200 to about 1200 nm, were obtained varying menthol to PCL ratio (from 0.76 to 8), overall concentration and flow rate (i.e. mixing conditions). The inclusion of menthol was confirmed by DSC analysis. DISCUSSION AND CONCLUSION: A patch test was carried out by 10 volunteers. Micro-capsules were found to be effective in conferring the fabric a refreshing sensation without altering skin physiology.

Dynamic light scattering and X-ray photoelectron spectroscopy characterization of PEGylated polymer nanocarriers: internal structure and surface properties.

In this work, nanospheres and nanocapsules are precipitated in confined impinging jet mixers through solvent displacement and characterized. Acetone and water are used as the solvent and antisolvent, respectively, together with polymethoxypolyethylene glycol cyanoacrylate-co-hexadecylcyanoacrylate and Miglyol as the copolymer and oil, respectively. Characterization is performed with dynamic light scattering, with electrophoretic measurements, and for the first time with X-ray photoelectron spectroscopy. Results show that the presence of polyethylene glycol chains seems to be more pronounced on the surface of nanospheres than on that of nanocapsules. The thickness of the copolymer layer in nanocapsules ranges from 1 to 10 nm, depending on the value of the oil:copolymer mass ratio. Fast dilution is confirmed to have a positive effect in suppressing aggregation but can induce further copolymer precipitation.

Use of soft sensors to monitor a pharmaceuticals freeze-drying process in vials.

PURPOSE: This paper presents a soft sensor that can be effectively used for in-line monitoring of the primary drying step of a pharmaceuticals freeze-drying process in vials. METHODS: Process modeling and product temperature measurements are used to estimate the residual amount of ice in the vial and the heat transfer coefficient from the shelf to the product in the vial. The resistance of the dried cake to vapor flow is determined through the heat balance equation at the interface of sublimation. Mathematical simulation and experimental tests have been carried out to validate the estimations provided by the soft sensor. RESULTS: Accurate estimations of the dynamics of the product until the end of primary drying are obtained, as well as of the heat and mass transfer coefficients, even in the case of a highly non-uniform batch. The reduction in the number of variables directly estimated by the soft sensor allows increasing the robustness of the tool with respect to other sensors presented in the literature. CONCLUSIONS: The proposed soft sensor is thus effective for process monitoring and it allows using model-based tools for cycle development in lab-scale units, where thermocouples are usually available, and for process monitoring in industrial-scale freeze-dryers, in case wireless sensors are used.

NaTech triggered by lightning: Novel insights from past events in the process industry.

Lightning strikes, a prominent meteorological event, pose a significant risk of triggering technological disruptions within the process industry. To better understand this phenomenon, an analysis focused on past lightning-triggered events was carried out, examining open-source industrial-accident databases to compile a new NaTech-driven dataset of 689 records. First, an overall quantitative analysis revealed that over 80 % of these events involved incidents or loss of containment. Notably, 83.3 % of them occurred during the spring and summer, indicating a seasonal pattern. Based on the frequency of functional attributes, the chemical and petrochemical macro-sector was the most vulnerable, followed by storage and warehousing. About 40 % of all classifiable events happened on storage equipment, while 21 % happened on electric and electronic devices. Given the lack of valuable information for the principal source of data (NRC), the technological scenarios triggered were characterized using a refined subset of 127 observations, obtained considering the "other sources" of data. Fire scenarios predominated at 56 %; coincidentally, roughly 70 % of all scenarios involved hazardous substances classified as physical hazards. Estimated losses for the available information underscored the adverse consequences of lightning-triggered NaTech events, highlighting their major impact on both safety and the environment. An analysis of the event tree showed the logical path from the lightning strike to the final ignition scenarios (considering a subset of 107 records). This path accounted for 36 % of the classifiable records that directly affected the structure, while more than 50 % of them did not. Bayesian network structures made it possible to get conditional probabilities from the event tree and improved the model by adding attributes for vulnerable equipment and macro-sectors. In order to deal with the uncertain data, algorithms were used to generalize the models that were obtained from smaller subsets of data with more accurate information to the whole dataset. It provides an important additional view of unclassifiable data that otherwise remained in the dark. This novel insight contributes to increase the vulnerability awareness of industrial assets against lightning strikes.

Quality by design: optimization of a freeze-drying cycle via design space in case of heterogeneous drying behavior and influence of the freezing protocol.

PURPOSE: This paper shows how to optimize the primary drying phase, for both product quality and drying time, of a parenteral formulation via design space. METHODS: A non-steady state model, parameterized with experimentally determined heat and mass transfer coefficients, is used to define the design space when the heat transfer coefficient varies with the position of the vial in the array. The calculations recognize both equipment and product constraints, and also take into account model parameter uncertainty. RESULTS: Examples are given of cycles designed for the same formulation, but varying the freezing conditions and the freeze-dryer scale. These are then compared in terms of drying time. Furthermore, the impact of inter-vial variability on design space, and therefore on the optimized cycle, is addressed. With this regard, a simplified method is presented for the cycle design, which reduces the experimental effort required for the system qualification. CONCLUSIONS: The use of mathematical modeling is demonstrated to be very effective not only for cycle development, but also for solving problem of process transfer. This study showed that inter-vial variability remains significant when vials are loaded on plastic trays, and how inter-vial variability can be taken into account during process design.

Quality by design: scale-up of freeze-drying cycles in pharmaceutical industry.

This paper shows the application of mathematical modeling to scale-up a cycle developed with lab-scale equipment on two different production units. The above method is based on a simplified model of the process parameterized with experimentally determined heat and mass transfer coefficients. In this study, the overall heat transfer coefficient between product and shelf was determined by using the gravimetric procedure, while the dried product resistance to vapor flow was determined through the pressure rise test technique. Once model parameters were determined, the freeze-drying cycle of a parenteral product was developed via dynamic design space for a lab-scale unit. Then, mathematical modeling was used to scale-up the above cycle in the production equipment. In this way, appropriate values were determined for processing conditions, which allow the replication, in the industrial unit, of the product dynamics observed in the small scale freeze-dryer. This study also showed how inter-vial variability, as well as model parameter uncertainty, can be taken into account during scale-up calculations.

On the Use of Temperature Measurements as a Process Analytical Technology (PAT) for the Monitoring of a Pharmaceutical Freeze-Drying Process.

The measurement of product temperature is one of the methods that can be adopted, especially in the pharmaceutical industry, to monitor the freeze-drying process and to obtain the values of the process parameters required by mathematical models useful for in-line (or off-line) optimization. Either a contact or a contactless device and a simple algorithm based on a mathematical model of the process can be employed to obtain a PAT tool. This work deeply investigated the use of direct temperature measurement for process monitoring to determine not only the product temperature, but also the end of primary drying and the process parameters (heat and mass transfer coefficients), as well as evaluating the degree of uncertainty of the obtained results. Experiments were carried out with thin thermocouples in a lab-scale freeze-dryer using two different model products, sucrose and PVP solutions; they are representative of two types of commonly freeze-dried products, namely those whose structures are strongly nonuniform in the axial direction, showing a variable pore size with the cake depth and a crust (leading to a strongly nonlinear cake resistance), as well as those whose structures are uniform, with an open structure and, consequently, a cake resistance varying linearly with thickness. The results confirm that the model parameters in both cases can be estimated with an uncertainty that is in agreement with that obtained with other more invasive and expensive sensors. Finally, the strengths and weaknesses of the proposed approach coupled with the use of thermocouples was discussed, comparing with a case using a contactless device (infrared camera).

Freeze-Drying of Pharmaceuticals in Vials Nested in a Rack System-Part I: Freezing Behaviour.

The distribution of biopharmaceuticals often requires either ultra-cold conditions or lyophilisation. In both cases, the drug product is frozen and, thus, exposed to similar stress conditions, which can be detrimental to its quality. However, these stresses can be inhibited or mitigated by a suitable formulation and/or an appropriate freezing design. This paper addresses how the key freezing parameters, i.e., ice nucleation temperature and cooling rate, impact the freezing behaviour of a sucrose-based formulation. The analysis included two loading configurations, vials directly resting on the shelf and nested in a rack system. The loading configuration affected the product freezing rate and the ice nucleation temperature distribution, resulting in larger ice crystals in the case of vials nested in a rack system. SEM micrographs and specific surface area measurements confirmed the different product morphology. Eventually, the different product morphology impacted the bioactivity recovery of lactate dehydrogenase.

The Freeze-Drying of Pharmaceuticals in Vials Nested in a Rack System-Part II: Primary Drying Behaviour.

The freeze-drying of biopharmaceuticals is a common strategy to extend their shelf-life and facilitate the distribution of therapeutics. The drying phase is the most demanding one in terms of energy consumption and determines the overall process time. Our previous work showed how the loading configuration can impact freezing. This paper focuses on primary drying by comparing the thermal behaviour of vials loaded in direct contact with the shelf or nested in a rack system. The overall heat transfer coefficient from the apparatus to the product was evaluated at different chamber pressures (5-30 Pa) and shelf temperatures (from -10 °C to +30 °C), and in the case of various vial positions (central, semi-border, and border vials). Because of the suspended configuration, the heat transfer coefficient was less affected by chamber pressure in vials nested in a rack system. The two loading configurations displayed comparable heat transfer efficiency below 10 Pa. For higher chamber pressure, the heat transfer coefficients of nested vials were lower than those of vials in direct contact with the shelf. Nevertheless, the rack system was beneficial for reducing the inter-vial variability as it promoted higher uniformity in the heat transfer coefficients of central vials. Eventually, thermal image analyses highlighted limited temperature differences between the vials and the rack system.

Use of Microfluidic Capillary Electrophoresis for the Determination of Multi-Component Protein Adsorption Isotherms: Application to High-Throughput Analysis for Hydrophobic Interaction Chromatography.

Chromatography is a widely used separation process for purification of biopharmaceuticals that is able to obtain high purities and concentrations. The phenomena that occur during separation, mass transfer and adsorption are quite complex. To better understand these phenomena and their mechanisms, multi-component adsorption isotherms must be investigated. High-throughput methodologies are a very powerful tool to determine adsorption isotherms and they waste very small amounts of sample and chemicals, but the quantification of component concentrations is a real bottleneck in multi-component isotherm determination. The behavior of bovine serum albumin, Corynebacterium diphtheriae CRM197 protein and lysozyme, selected as model proteins in binary mixtures with hydrophobic resin, is investigated here. In this work we propose a new method for determining multi-component adsorption isotherms using high-throughput experiments with filter plates, by exploiting microfluidic capillary electrophoresis. The precision and accuracy of the microfluidic capillary electrophoresis platform were evaluated in order to assess the procedure; they were both found to be high and the procedure is thus reliable in determining adsorption isotherms for binary mixtures. Multi-component adsorption isotherms were determined with a totally high-throughput procedure that turned out to be a very fast and powerful tool. The same procedure can be applied to every kind of high-throughput screening.

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.

Supporting data and methods for the multi-scale modelling of freeze-drying of microparticles in packed-beds.

A multi-scale approach can be used to simulate the drying behavior of microparticles in packed-bed. Data outcomes from discrete element method (DEM) and computational fluid dynamics (CFD) simulations can be used to estimate some relevant product characteristics, such as the porosity, tortuosity, voids in the bed and permeability which are required by the multi scale model. Data from DEM simulations are presented, with a particular focus on the influence of the model parameters, packing characteristics and inhomogeneities (wall effect and particles segregation); computational costs and scala bility are also considered. Data on the properties of packings as modeled at the macroscale are presented with regard to the thermal conductivity of gases in the Knudsen regime and effective properties of packed-beds modeled as a pseudo-homogeneous medium. A mathematical model of the freeze-drying of single microparticles and its outcomes are first presented. Data outcomes from the mathematical model at the macroscale concerning the drying behavior of microparticles in a tray and in a vial are then presented and can be used for process design. Some further data, with detailed interpretation and discussion of the presented data, can be found in the related research data article, "A multi-scale computational framework for modelling the freeze-drying of microparticles in packed-beds" (Capozzi et al., 2019).

Bio-Functional Textiles: Combining Pharmaceutical Nanocarriers with Fibrous Materials for Innovative Dermatological Therapies.

In the field of pharmaceutical technology, significant attention has been paid on exploiting skin as a drug administration route. Considering the structural and chemical complexity of the skin barrier, many research works focused on developing an innovative way to enhance skin drug permeation. In this context, a new class of materials called bio-functional textiles has been developed. Such materials consist of the combination of advanced pharmaceutical carriers with textile materials. Therefore, they own the possibility of providing a wearable platform for continuous and controlled drug release. Notwithstanding the great potential of these materials, their large-scale application still faces some challenges. The present review provides a state-of-the-art perspective on the bio-functional textile technology analyzing the several issues involved. Firstly, the skin physiology, together with the dermatological delivery strategy, is keenly described in order to provide an overview of the problems tackled by bio-functional textiles technology. Secondly, an overview of the main dermatological nanocarriers is provided; thereafter the application of these nanomaterial to textiles is presented. Finally, the bio-functional textile technology is framed in the context of the different dermatological administration strategies; a comparative analysis that also considers how pharmaceutical regulation is conducted.

Strategies to control the particle size distribution of poly-epsilon-caprolactone nanoparticles for pharmaceutical applications.

In this work turbulent precipitation through solvent displacement for the production of poly-epsilon-caprolactone (PCL) nanoparticles is investigated; two different PCL molecular weights have been employed, using acetone and water as solvent and anti-solvent, respectively. The main important thermodynamic and kinetic parameters, such as solubility and interfacial tension of PCL in water-acetone mixtures, are determined and the effect of the process operating conditions on the final particle size distribution is also investigated. Particles produced under different conditions into a Confined Impinging Jets Reactor (CIJR) were characterized by Dynamic Light Scattering, Zeta potential measurements and Scanning Electronic Microscopy. Results clearly show the strong effect of mixing on the particle size distribution and how mixing must be controlled in order to obtain a product with particular characteristics. Eventually the measured thermodynamic and kinetic parameters are used to interpret the obtained experimental data.

The Effect of Human Error on the Temperature Monitoring and Control of Freeze Drying Processes by Means of Thermocouples.

Monitoring product temperature is mandatory in a freeze-drying process, in particular in the process development stage, as final product quality may be jeopardized when its temperature trespasses a threshold value, that is a characteristic of each product being freeze-dried. To this purpose thermocouples are usually inserted in some of the vials of the batch to track product dynamics. The position of the thermocouple inside the vials strongly affects the reading of the temperature evolution during the freeze-drying process and, thus, it is necessary to place them in the right position, in such a way that correct information about product temperature is obtained. In this work, at first, the probability of the operational error resulting into a wrong positioning of the thermocouple inside the vial has been estimated experimentally. Then, the effect of this error has been assessed in terms of risk of exceeding the limit temperature in the primary drying step. Both 4R and 10R vials have been considered, and the investigation evidenced that the probability of incorrect thermocouples placement can reach 30% for 10R vials, and about 32% for 4R vials. These probability values increase, respectively, to 47 and 39% when the trays containing the vials are shifted to their final position. Then, through IR thermal imaging it has been possible to evaluate the temperature gradients in a vial, pointing out that the temperature difference between the product at the center of the vial, where the thermocouple is supposed to be, and that of the wall, that is quite often measured by the thermocouples, can be about 1°C. Therefore, associated to each thermocouple reading there is a probability distribution of product temperature. These figures can be used to assess the risk of exceeding the limit temperature in a freeze-drying process and, thus, to quantify suitable safety margins when evaluating thermocouple readings to take into account the operational errors, given a risk tolerability criteria.

Computational Fluid Dynamics data for improving freeze-dryers design.

Computational Fluid Dynamics (CFD) can be used to simulate different parts of an industrial freeze-drying equipment and to properly design them; in particular data concerning the freeze-dryer chamber and the duct connecting the chamber with the condenser, with the valves and vanes eventually present are given here, and can be used to understand the behavior of the apparatus allowing an improved design. Pilot and large scale freeze-drying chambers have been considered; data of a detailed simulation of a complete pilot scale apparatus, including duct and condenser, are included. Data on conductance of an empty duct with different L/D ratio, on disk valves with different geometry, and on mushroom valve are presented. Velocity, pressure, temperature and composition fields are reported on selected planes for chambers and valves. Results of dynamic simulations are also presented, to evaluate possible performance of monitoring devices in the chamber. Some further data, with detailed interpretation and discussion of the presented data can be found in the related research article by Barresi et al. [1] and Marchisio et al. [2].

Use of computational fluid dynamics for improving freeze-dryers design and process understanding. Part 1: Modelling the lyophilisation chamber.

This manuscript shows how computational models, mainly based on Computational Fluid Dynamics (CFD), can be used to simulate different parts of an industrial freeze-drying equipment and to properly design them; in particular, the freeze-dryer chamber and the duct connecting the chamber with the condenser, with the valves and vanes eventually present are analysed in this work. In Part 1, it will be shown how CFD can be employed to improve specific designs, to perform geometry optimization, to evaluate different design choices and how it is useful to evaluate the effect on product drying and batch variance. Such an approach allows an in-depth process understanding and assessment of the critical aspects of lyophilisation. This can be done by running either steady-state or transient simulations with imposed sublimation rates or with multi-scale approaches. This methodology will be demonstrated on freeze-drying equipment of different sizes, investigating the influence of the equipment geometry and shelf inter-distance. The effect of valve type (butterfly and mushroom) and shape on duct conductance and critical flow conditions will be instead investigated in Part 2.

Use of computational fluid dynamics for improving freeze-dryers design and process understanding. Part 2: Condenser duct and valve modelling.

This manuscript shows how computational models, mainly based on Computational Fluid Dynamics (CFD), can be used to simulate different parts of an industrial freeze-drying equipment and to properly design them; in particular in this part the duct connecting the chamber with the condenser, with its valves, is considered, while the chamber design and its effect on drying kinetics have been investigated in Part 1. Such an approach allows a much deeper process understanding and assessment of the critical aspects of lyophilisation. This methodology will be demonstrated on freeze-drying equipment of different sizes, investigating influence of valve type (butterfly and mushroom) and shape on duct conductance and critical flow conditions. The role of the inlet and boundary conditions considered has been assessed, also by modelling the whole apparatus including chamber and condenser, and the influence of the duct diameter has been discussed; the results show a little dependence of the relationship between critical mass flux and chamber pressure on the duct size. Results concerning the fluid dynamics of a simple disk valve, a profiled butterfly valve and a mushroom valve installed in a medium size horizontal condenser are presented. Also in these cases the maximum allowable flow when sonic flow conditions are reached can be described by a correlation similar to that found valid for empty ducts; for the mushroom valve the parameters are dependent on the valve opening length. The possibility to use the equivalent length concept, and to extend the validity of the results obtained for empty ducts will be also discussed. Finally the presence of the inert gas modifies the conductance of the duct, reducing the maximum flow rate of water that can be removed through it before the flow is choked; this also requires a proper over-sizing of the duct (or duct-butterfly valve system).