Use of Raman spectroscopy and PCA for quality evaluation and out-of-specification identification in biopharmaceutical products.

Over the past three decades, there was a remarkable growth in the approval of antibody-based biopharmaceutical products. These molecules are notably susceptible to the stresses occurring during drug manufacturing, often leading to structural alterations. A key concern is thus the ability to detect and comprehend these alterations caused by processes, such as aggregation, fragmentation, oxidation levels, as well as the change in protein concentration throughout the process steps, potentially resulting in out-of-spec products.

Experiment data: Human-in-the-loop decision support in process control rooms.

These datasets contain measures from multi-modal data sources. They include objective and subjective measures commonly used to determine cognitive states of workload, situational awareness, stress, and fatigue using data collection tools such as NASA-TLX, SART, eye tracking, EEG, Health Monitoring Watch, a survey to assess training, and a think-aloud situational awareness assessment following the SPAM methodology. Also, data from a simulation formaldehyde production plant based on the interaction of the participants in a controlled control room experimental setting is included.

New Trends in Freeze-Drying of Pharmaceutical Products.

Freeze-drying, also known as lyophilization, is a process that facilitates the removal of water through sublimation from a frozen product (primary drying) [...

A New Model-Based Approach for the Development of Freeze-Drying Cycles Using a Small-Scale Freeze-Dryer.

This paper presents a model-based approach for the design of the primary drying stage of a freeze-drying process using a small-scale freeze-dryer (MicroFD® by Millrock Technology Inc.). Gravimetric tests, coupled with a model of the heat transfer to the product in the vials that account also for the heat exchange between the edge vials and the central vials, are used to infer the heat transfer coefficient from the shelf to the product in the vial (K), that is expected to be (almost) the same in different freeze-dryers.

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.

Use of machine learning tools and NIR spectra to estimate residual moisture in freeze-dried products.

Residual Moisture (RM) in freeze-dried products is one of the most important critical quality attributes (CQAs) to monitor, since it affects the stability of the active pharmaceutical ingredient (API). The standard experimental method adopted for the measurements of RM is the Karl-Fischer (KF) titration, that is a destructive and time-consuming technique. Therefore, Near-Infrared (NIR) spectroscopy was widely investigated in the last decades as an alternative tool to quantify the RM.

Agar Plate Methods for Assessing the Antibacterial Activity of Thyme and Oregano Essential Oils against and .

The resistance to antimicrobials (AMR), especially antibiotics, represents a serious problem and, at the same time, a challenge. In the last decade, a growing interest in the use of essential oils (EOs) as antimicrobial substances was observed. Commercial thyme and oregano EOs are reported to be the main responsible of the oil antimicrobial efficacy against both Gram-positive and Gram-negative pathogenic bacteria.

Investigation of the Freezing Phenomenon in Vials Using an Infrared Camera.

The freezing phenomenon has a dramatic impact on the quality of freeze-dried products. Several freezing models applied to solutions in vials have been proposed to predict the resulting product morphology and describe heat transfer mechanisms. However, there is a lack of detailed experimental observations of the freezing phenomenon in vials in the literature.

Evaluation of the Robustness of A Novel NIR-based Technique to Measure the Residual Moisture In Freeze-dried Products.

(Bio)pharmaceutical products freeze-dried in vials must meet stringent quality specifications: among these, the residual moisture (RM) is crucial. The most common techniques adopted for measuring the RM are destructive, e.g.

Application of Near-Infrared Spectroscopy to statistical control in freeze-drying processes.

Batch freeze-drying of pharmaceutical products in vials may result in a high degree of intra-batch variability due to several reasons, e.g. non uniform heating rate in the drying chamber.

Micro Freeze-Dryer and Infrared-Based PAT: Novel Tools for Primary Drying Design Space Determination of Freeze-Drying Processes.

Purpose: 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.

Methods: 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 (K) and the mass (R) transfer coefficients were estimated: tests at 8, 13 and 26 Pa were carried out to assess the chamber pressure effect on K.

The Influence of Arginine and Counter-Ions: Antibody Stability during Freeze-Drying.

Amino acids, for example L-arginine, are used in lyophilisation as crystalline bulking, buffering, viscosity reducing or stabilising excipients. In this study, arginine was formulated with different counter ions (hydrochloride, citrate, lactobionate, phosphate, and succinate). A monoclonal antibody was investigated in sugar-free arginine formulations and mixtures with sucrose regarding cake appearance and protein aggregation and fragmentation.

Temperature/end point monitoring and modelling of a batch freeze-drying process using an infrared camera.

Temperature monitoring and accurate drying end time determination are crucial for final product quality in vacuum freeze-drying of pharmaceuticals. Whether crystalline or amorphous solutes are used in the formulation, product temperature during ice sublimation should be kept below a threshold limit to avoid damage to the product structure. Hence, there is a need to continuously monitor product temperature throughout this process.

Method development and analysis of the water content of the maximally freeze concentrated solution suitable for protein lyophilisation.

During freeze-drying of a liquid formulation, a freeze-concentrate is formed in the first phase, the freezing step. Understanding the composition of the maximally freeze concentrated solution can help to judge the process stability of biopharmaceuticals during lyophilisation. Our objective was to develop a suitable method to determine the water content of the maximally freeze concentrated solution using differential scanning calorimetry (DSC).

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.

Development of Freeze-Drying Cycles for Pharmaceutical Products Using a Micro Freeze-Dryer.

This article aims to investigate how a small-scale freeze-dryer can be used for process design. The system encompasses a temperature controlled metallic ring that surrounds a small batch of vials, in contact with the external vials through removable thermal conductors. The temperature of the ring can be modified to keep a constant difference with the temperature of one or more vials of the batch.

Monitoring of the freezing stage in a freeze-drying process using IR thermography.

This paper presents a new Process Analytical Technology based on the use of an infrared camera and a mathematical model to estimate the ice crystal size distribution obtained at the end of the freezing stage of a vial freeze-drying process. Both empirical laws and first-principle based equations, already presented in the Literature, may be used to this purpose, if the temperature gradient in the frozen product and the freezing front rate are obtained from the analysis of the thermal images. The resistance of the dried product to vapor flux may be then calculated from the distribution of the ice crystal diameters, thus enabling the use of a one-dimensional model for process simulation and optimization.

On the use of a micro freeze-dryer for the investigation of the primary drying stage of a freeze-drying process.

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.

Crystallizing amino acids as bulking agents in freeze-drying.

Bulking agents as mannitol (Man) and glycine (Gly) require high bulking agent to stabilizer ratios to ensure their crystallization during the freeze-drying process. The aim of this study was to investigate several amino acids (AA) as potential alternative bulking agents in low AA to sucrose (Suc) ratios. A fast freeze-drying process was performed above the collapse temperature (Tc) of the amorphous phase challenging the crystalline AA scaffold.

On the Use of Infrared Thermography for Monitoring a Vial Freeze-Drying Process.

Monitoring a vial freeze-drying process without interfering with product dynamics is a challenging issue. This article presents a novel device constituted by an infrared camera designed to be placed inside the drying chamber, able to monitor the temperature of the vials, very close to that of the product inside. By this way it is possible to estimate the ending point of the primary drying, the heat transfer coefficient to the product (K), and the resistance of the dried product to vapor flux (R).

Use of microreactors and freeze-drying in the manufacturing process of chitosan coated PCL nanoparticles.

This paper is focused on the synthesis of chitosan-coated polycaprolactone nanoparticles in microreactors and on the freeze-drying of the nanosuspension, to separate the particles from the liquid phase. Nanoparticles were produced in the confined impinging jets mixer (CIJM) and in the multi-inlet vortex mixer (MIVM), using the solvent displacement method, with acetone or tert-butanol (TBA) as polymer solvent. The study was initially carried out considering a feed flow rate of 80 ml min: using acetone, the mean particle size was lower (163 ± 7 nm) and the Zeta potential was higher (31.

On the effect of ultrasound-assisted atmospheric freeze-drying on the antioxidant properties of eggplant.

The low operating temperatures employed in atmospheric freeze-drying permits an effective drying of heat sensitive products, without any impairment of their quality attributes. When using power ultrasound, the drying rate can be increased, thus reducing the process duration. However, ultrasound can also affect the product quality.