Continuous freeze-drying and its relevance to the pharma/biotech industry

The new paradigm of pharmaceutical industry is to move from batch to continuous processes in order to satisfy the stringent requirements of quality, safety and efficiency set by regulatory authorities and reduce production costs. In this perspective, freeze-drying needs to be completely rethought in order to be more integrated in the chain of production of drugs, more flexible to respond to variations in market needs and allowing the monitoring of product quality. The future of freeze-drying, as a downstream process, is therefore to move from batch to continuous. Over the past decades many ideas regarding continuous freeze-drying has been proposed, but none of them has been successfully applied. The objective of this work is to demonstrate the feasibility of an innovative concept to produce lyophilized unit-dose drugs using a continuous process. This novel strategy was demonstrated to improve both yield and vial-to-vial uniformity, giving all those advantages that are typical of continuous technology such as flexibility and elimination of process scale-up from laboratory to industrial scale. The feasibility of continuous freeze-drying has been studied simulating the process using a functional version of the continuous freeze-dryer. Heat transfer during freezing and primary drying was studied reproducing the same conditions occurring in the continuous process. Various process conditions and formulations were investigated in order to better understand the range of applicability of this new process. It has been demonstrated that the cycle duration of the continuous freeze-drying was comparable to that of a conventional batch process, and the aesthetic acceptability of the product was achieved. The continuous freeze-drying technology also impacted positively on inter- and intra-vial heterogeneity. As can be seen Figure 1, the continuous technology gave the most narrow distribution of residual moisture at the end of primary drying. Please click Additional Files below to see the full abstract

Economic analysis of a freeze-drying cycle

Freeze-drying has always been considered an extremely expensive procedure to dehydrate food or pharmaceutical products, and for this reason, it has been employed only if strictly necessary or when the high added value of the final product could justify the costs. However, little effort has been made to analyze the factors that make this technology so unaffordable. In this work, a model was proposed to calculate in detail the operational (OC) and capital costs (CC) of a freeze-drying cycle and an evaluation of the process bottlenecks was made. The main result is that the process itself, contrary to the classic belief, is not the most expensive part of freeze-drying, while the initial investment is the real limiting factor. Under this consideration, the optimization of a freeze-drying cycle should be formulated in order to fit more cycles in the lifespan of the apparatus, instead of merely reducing the power consumption of the machine

CFD modelling based X-ray microtomography reconstruction of lyophilized products

In this work, 3D non-destructive X-ray micro-CT tomography is used to analyze and reconstruct the internal structure of lyophilized samples, and CFD simulations for calculating their structural properties, i.e., porosity, pore diameter, tortuosity, and permeability

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Looking inside the ‘black box’: Freezing engineering to ensure the quality of freeze-dried biopharmaceuticals

The freezing step plays a central role in reaching the most stringent requirements of quality, homogeneity and standardization of freeze-dried products. In this paper, a systematic procedure has been proposed to obtain a quantitative estimation of the pore-size variability of lyophilized products resulting from uncontrollable variations of the nucleation temperature. This procedure consisted in collecting the nucleation temperature from a statistically significant number of samples and correlating each nucleation temperature to the corresponding product morphology, using a mathematical model, to obtain a statistical description of the lyophilized product structure. This approach can also be used to obtain an estimation of the variability of the mass transfer resistance to vapor flow and, finally, of the drying time. Two different freezing configurations, i.e., conventional and suspended-vial freezing, have been used as case studies since they can produce significantly different freezing rates

Powder spreading and spreadability in the additive manufacturing of metallic materials: a critical review

3noreservedembargoed_20240701Capozzi, Luigi C.; Sivo, Antonio; Bassini, EmilioCapozzi, Luigi C.; Sivo, Antonio; Bassini, Emili

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). Keywords: Freeze-drying, Packed-bed, Lyophilization, DEM, CFD, Spray-freeze dryin

A multi-scale computational framework for modeling the freeze-drying of microparticles in packed-beds

This work investigates the behavior during freeze-drying of packing structures formed by spray-frozen microparticles. A multi-scale approach is used to study spray freeze-drying, and in particular, mass transfer during primary drying and its duration. The procedure starts with the generation of realistic packings of microparticles using DEM, and CFD simulations are used to determine some relevant characteristics at pore scale, i.e., porosity, tortuosity, the average size of the particle-to-particle voids, and permeability. Finally, these parameters are used to describe mass transfer within the packed-bed. This procedure is used to describe some actual case studies and evaluate drying time and mass transfer resistance within the packing. We also investigated the role of packing structure on freeze-drying by generating packings from monodisperse and Gaussian-polydisperse microparticles, demonstrating that polydispersity increased the mass transfer resistance, and, finally, drying time