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

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

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

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) [...