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 the process. Current monitoring tools, such as thermocouples and Pirani gauge pressure sensors, have several limitations such as affecting product dynamics or imprecise end point determination. In this work, a monitoring tool based on infrared (IR) thermography is used for batch freeze-drying processes. Batches using three different vial sizes, with up to 157 vials, were studied, allowing to extend and better describe the representativeness of IR thermography for this application. The detailed axial temperature profiles obtained through IR imaging allowed not only a comprehensive non-invasive temperature monitoring of the product, but also tracking of the sublimation interface. IR temperature measurements and primary drying end point determination were compared to standard methods and thus verified. Parameters important for freeze drying design space calculation, namely the global heat coefficient (K_v) and cake resistance to vapor flow (R_p), were also accurately estimated with the proposed method

On-line monitoring of the freeze-drying process: A new image-based PAT.

In this work a Process Analytical Technology (PAT) for the on-line monitoring of a Vacuum Freeze-Drying (VFD) based on the information extracted from the infrared images of the process is presented and validated. An infrared camera, placed inside the drying chamber, provided information about the thermal evolution of the process over time; after images pretreatment and segmentation, temperature profiles were extracted and processed to obtain the variables of interest. Experiments were carried out according to factorial design on a set of different operating conditions, namely fluid temperature and chamber pressure, type of vials and solid percentage in the solution. Both sucrose and mannitol solutions, were studied. Together with the temperature in several positions along the product height, we were able to correctly estimate the ending time of the primary drying phase together with the sublimating interface position and the heat and mass transfer coefficients, Kv and Rp. Those two parameters have a dramatic importance since they can be used in a mathematical model of the process for on-line or off-line optimization of the process. Being based on a contactless technology, the PAT studied in this work does not present any issue regarding the sterility requirement of the process or the possible interference of the sensing element with the product dynamics

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 (Kv) and the mass (Rp) transfer coefficients were estimated: tests at 8, 13 and 26 Pa were carried out to assess the chamber pressure effect on Kv. The design space of the primary drying stage was calculated using these parameters and a well-established model-based approach. The results obtained using the proposed tools were compared to the ones in case Kv and Rp were estimated in a lab-scale unit through gravimetric tests and a thermocouple-based method, respectively. Results: The IR-based method allows a non-gravimetric estimation of the Kv values while with the micro freeze-dryer gravimetric tests require a very small number of vials. In both cases, the obtained values of Kv and Rp, as well as the resulting design spaces, were all in very good agreement with those obtained in a lab-scale unit through the gravimetric tests (Kv) and the thermocouple-based method (Rp). Conclusions: The proposed tools can be effectively used for design space calculation in substitution of other well-spread methods. Their advantages are mainly the less laborious Kv estimation process and, as far as the MicroFD® is concerned, the possibility of saving time and formulation material when evaluating Rp

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. Therefore, product quality in the final product has to be checked in a statistically significant number of samples, in particular in the stage of process development. Here, Fourier-Transform Near-Infrared Spectroscopy is proposed as a fast, non-destructive technique for an off-line Statistical Quality Control application. At first, results obtained in a batch where product features are satisfactory are used to identify a target quality threshold. Then, a statistical controller is developed in such a way that in a production run it is possible to quickly check if product quality exceeds the desired threshold or not. Two approaches based on multivariate analysis are presented: one employs the Hotelling T2 and Mahalanobis statistics to calculate control charts, the other is an application of Partial Least Squares for discriminant analysis (PLS-DA). Control charts and PLS-DA were trained with samples obtained in a run where sucrose solution was processed and validated in other runs where the final product was known to have the desired qualitative characteristics or not. Overall, out-of-specification samples can be predicted by control charts and PLS-DA with 99% and 98% accuracy respectively. PLS-DA was shown to be able to better identify samples correctly processed, while the control charts where more accurate to identify vials where something went wrong. Focusing on residual moisture of the final product, all samples where it was higher than the target value were always correctly identified

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

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 Gramnegative pathogenic bacteria. The aim of the present work was to study the efficacy of EOs against Staphylococcus epidermidis and Escherichia coli in long-time treatments. In a preliminary microdilution test, a MIC value was obtained for thyme EO against S. epidermidis and E. coli. After that, disk diffusion and disk volatilization tests were set up to study the influence of main cultural parameters on EO activity in liquid or vapor phase. Both bacteria were inhibited by thyme and oregano EOs when applied pure (100% v/v) or diluted (75% and 50% v/v): a higher inhibition was observed in a disk diffusion test in which the antimicrobial effect was due to both liquid and vapor phase components. Finally, a comparison with literature data was carried out even if it was not so easy because standard methods are usually modified and adapted to specific case study. For this reason, the results have to be interpreted in relation to the analytical method applied

Monitoring of a vial freeze-drying process with IR thermography.

This work presents a new device constituted by an IR camera placed inside the drying chamber to monitor the temperature of the vials without interferences. It is possible to estimate the ending point of the primary drying, the heat transfer coefficient to the product and the resistance of the dried product to vapor flux. Experiments were performed in a freeze-dryer using thermocouples and the IR camera. The measurements validate the IR camera as an effective technology for the process

Process Analytical Technology for monitoring pharmaceuticals freeze drying - A Comprehensive Review

The goal of this paper is to review the available process analytical technology tools for monitoring the batch freeze-drying process for pharmaceuticals. These systems aim evaluating in-line product temperature, sublimation flow rate, and values of some model parameters in such a way that it can be used for in-line or off-line process optimization. A detailed survey of the systems proposed in the literature is presented, grouping them on the basis of monitored variable, namely, product temperature, heat flux to the product, sublimation flux, and, finally, other variables. The advantages and drawbacks of the techniques are critically assessed, taking into account the possibility of using them not only at lab-scale but also at production scale, beside, obviously, the possibility of getting reliable measurements of the desired variables