End Point Of Primary Drying Research Articles

Combining Mathematical Modeling and Thermal Infrared Data in the Freezing of Pharmaceutical Liquid Formulations

Infrared-based (IR) thermal imaging data was combined here with mathematical modeling to describe the freezing process of a pharmaceutical formulation being lyophilized using two different loading configurations; (i) vials in direct contact with the shelf and (ii) vials suspended over it. In all the experiments, the nucleation event was trigged at a specific time instant using the vacuum induced surface freezing (VISF) method. The IR thermal data was given as input to three different mathematical models for freezing and used to estimate the resulting cake’s pore size (dp) distribution. The resulting dp values were then compared to experimental data obtained through SEM images coupled with an image segmentation tool. The supersaturation model showed the best agreement between the estimated dp and experimental values, while minor discrepancies were shown by the other two models. Nonetheless, the outcomes of these last two models, given as inputs to a mathematical model for the primary drying phase, resulted in satisfactory predictions of the product temperature at the moving front, the product resistance to vapor flow, and the primary drying end point. It follows that the combination of the IR thermocamera and freezing modeling is a promising tool for the in-line monitoring and optimization of a freeze-drying cycle.

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. 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 (Kv) and cake resistance to vapor flow (Rp), were also accurately estimated with the proposed method.

Experimental study on improvement of freeze-drying process for porcine aorta

Freeze-drying is an effective method for preservation of aortas. In order to maintain the original properties of aortas, the sublimation drying process requires accurate monitoring. In this study, we used a contactless mass measurement device to monitor drying process, porcine aortic segments were divided into four series for freeze-drying, then relevant experiments and calculations were carried out to evaluate the quality of lyophilized samples. The study found that the sublimation process could not be accurately monitored by measured temperature, however, the real-time weighing could do it well, and was suitable to judge the endpoint of primary drying. Meanwhile, the change law of sublimation temperature was obtained by quasi-steady heat transfer equations. The removal ratio of free water during the primary drying greatly affected the properties of lyophilized samples, thorough sublimation had contributed to better performance of products, especially in mechanical properties. In addition, compared with annular aortic segments, the flaky samples had better heat transfer and performed better in histological scanning.

Automatic control of a freeze-drying process: Detection of the end point of primary drying

In freeze-drying, the detection of the end of primary drying is a crucial aspect for both the process economics and product quality. Furthermore, the extreme process conditions (low temperature, high vacuum, and sterility) require monitoring devices with a high degree of assurance. In this paper, the most promising methodologies for the detection of the end point of primary drying were investigated and compared. These devices include thermocouples, comparative pressure measurement, condenser pressure, controlled leakage, vacuum shut-off valve, microbalance, mass spectrometers, moisture sensors, and pressure rise test. Furthermore, a multi-scale model of the process was used to describe the process dynamics during the last part of drying, showing that the time difference between the onset and offset points depends on the batch heterogeneity, as well as process conditions and batch size. Ultimately, an automatic stop criterion, named EPD, has been designed and experimentally tested in a wide range of process conditions, batch size, vial size, and drug products. In particular, the experimental validation involved some of the most used excipients as model products, i.e., mannitol, dextran, lactose, and sucrose. In all the runs, the EPD drying times reasonably agreed with the comparative pressure measurement, which was the most reliable way to detect the end of primary drying. Thus, EPD can effectively be used to optimize primary drying without risking the product collapse because of a premature increase in shelf temperature for secondary drying.

Temperature Measurement by Sublimation Rate as a Process Analytical Technology Tool in Lyophilization

Product temperature (Tb) and drying time constitute critical material attributes and process parameters in the lyophilization process and especially during the primary drying stage. In the study, we performed a temperature measurement by the sublimation rate (TMbySR) to monitor the Tb value and determine the end point of primary drying. First, the water vapor transfer resistance coefficient through the main pipe from the chamber to the condenser (Cr) was estimated via the water sublimation test. The use of Cr value made it possible to obtain the time course of Tb from the measurement of pressure at the drying chamber and at the condenser. Second, a Flomoxef sodium bulk solution was lyophilized by using the TMbySR system. The outcome was satisfactory when compared with that obtained via conventional sensors. The same was applicable for the determination of the end point of primary drying. A laboratory-scale application of the TMbySR system was evidenced via the experiment using 220-, 440-, and 660-vial scales of lyophilization. The outcome was not dependent on the loading amount. Thus, the results confirmed that the TMbySR system is a promising tool in laboratory scale.

Thermal Imaging as a Noncontact Inline Process Analytical Tool for Product Temperature Monitoring during Continuous Freeze-Drying of Unit Doses.

Freeze-drying is a well-established technique to improve the stability of biopharmaceuticals which are unstable in aqueous solution. To obtain an elegant dried product appearance, the temperature at the moving sublimation interface Ti should be kept below the critical product temperature Ti,crit during primary drying. The static temperature sensors applied in batch freeze-drying provide unreliable Ti data due to their invasive character. In addition, these sensors are incompatible with the continuous freeze-drying concept based on spinning of the vials during freezing, leading to a thin product layer spread over the entire inner vial wall. During continuous freeze-drying, the sublimation front moves from the inner side of the vial toward the glass wall, offering the unique opportunity to monitor Ti via noncontact inline thermal imaging. Via Fourier's law of thermal conduction, the temperature gradient over the vial wall and ice layer was quantified, which allowed the exact measurement of Ti during the entire primary drying step. On the basis of the obtained thermal images, the infrared (IR) energy transfer was computed via the Stefan-Boltzmann law and the dried product mass transfer resistance ( Rp) profile was obtained. This procedure allows the determination of the optimal dynamic IR heater temperature profile for the continuous freeze-drying of any product. In addition, the end point of primary drying was detected via thermal imaging and confirmed by inline near-infrared (NIR) spectroscopy. Both applications show that thermal imaging is a suitable and promising process analytical tool for noninvasive temperature measurements during continuous freeze-drying, with the potential for inline process monitoring and control.

In-Situ Molecular Vapor Composition Measurements During Lyophilization.

Monitoring process conditions during lyophilization is essential to ensuring product quality for lyophilized pharmaceutical products. Residual gas analysis has been applied previously in lyophilization applications for leak detection, determination of endpoint in primary and secondary drying, monitoring sterilization processes, and measuring complex solvents. The purpose of this study is to investigate the temporal evolution of the process gas for various formulations during lyophilization to better understand the relative extraction rates of various molecular compounds over the course of primary drying. In this study, residual gas analysis is used to monitor molecular composition of gases in the product chamber during lyophilization of aqueous formulations typical for pharmaceuticals. Residual gas analysis is also used in the determination of the primary drying endpoint and compared to the results obtained using the comparative pressure measurement technique. The dynamics of solvent vapors, those species dissolved therein, and the ballast gas (the gas supplied to maintain a set-point pressure in the product chamber) are observed throughout the course of lyophilization. In addition to water vapor and nitrogen, the two most abundant gases for all considered aqueous formulations are oxygen and carbon dioxide. In particular, it is observed that the relative concentrations of carbon dioxide and oxygen vary depending on the formulation, an observation which stems from the varying solubility of these species. This result has implications on product shelf life and stability during the lyophilization process. Chamber process gas composition during lyophilization is quantified for several representative formulations using residual gas analysis. The advantages of the technique lie in its ability to measure the relative concentration of various species during the lyophilization process. This feature gives residual gas analysis utility in a host of applications from endpoint determination to quality assurance. In contrast to other methods, residual gas analysis is able to determine oxygen and water vapor content in the process gas. These compounds have been shown to directly influence product shelf life. With these results, residual gas analysis technique presents a potential new method for real-time lyophilization process control and improved understanding of formulation and processing effects for lyophilized pharmaceutical products.

Judgment about the Endpoint of Primary Drying for Freeze-dried Pig Aorta

How to process and preserve these biological material has always been a concerning problem. Vascular studying and evaluating the feasibility of preparing the vessel scaffold by freeze-drying technology is expected to provide high-qualified and reliable vascular graft for the clinical treatment of the related diseases. Judgment of the end of primary drying has always been a key point on the process of freeze-dried pig aorta, because it can directly affect the final quality of the dried sample if improper judgment has been used. In this study, different methods have been adopted to determine the endpoint of primary drying and then various methods of observation on the status of the aorta are used for contrast, including Micro-CT scanning, percentage of dehydration and calculation of the rehydrated rate and so on. From the results, differences are obvious. These experiments point out how to judge the endpoint of the pig aorta’s primary drying when they are freeze-dried by small laboratory equipments in which heat leakage and other external factors cannot be ignored.

An Integrated Process Analytical Technology (PAT) Approach to Monitoring the Effect of Supercooling on Lyophilization Product and Process Parameters of Model Monoclonal Antibody Formulations

The aim of the present study was to apply an integrated process analytical technology (PAT) approach to control and monitor the effect of the degree of supercooling on critical process and product parameters of a lyophilization cycle. Two concentrations of a mAb formulation were used as models for lyophilization. ControLyo™ technology was applied to control the onset of ice nucleation, whereas tunable diode laser absorption spectroscopy (TDLAS) was utilized as a noninvasive tool for the inline monitoring of the water vapor concentration and vapor flow velocity in the spool during primary drying. The instantaneous measurements were then used to determine the effect of the degree of supercooling on critical process and product parameters. Controlled nucleation resulted in uniform nucleation at lower degrees of supercooling for both formulations, higher sublimation rates, lower mass transfer resistance, lower product temperatures at the sublimation interface, and shorter primary drying times compared with the conventional shelf-ramped freezing. Controlled nucleation also resulted in lyophilized cakes with more elegant and porous structure with no visible collapse or shrinkage, lower specific surface area, and shorter reconstitution times compared with the uncontrolled nucleation. Uncontrolled nucleation however resulted in lyophilized cakes with relatively lower residual moisture contents compared with controlled nucleation. TDLAS proved to be an efficient tool to determine the endpoint of primary drying. There was good agreement between data obtained from TDLAS-based measurements and SMART™ technology. ControLyo™ technology and TDLAS showed great potential as PAT tools to achieve enhanced process monitoring and control during lyophilization cycles.

An impedance-based process analytical technology for monitoring the lyophilisation process

The aim of this work was to develop a minimally invasive, impedance spectroscopy method as a novel process analytical technology for monitoring the freeze drying process. This involved the application of planar electrodes, mounted externally to a conventional glass freeze-drying vial, coupled to a high-impedance analyser. The pseudo-relaxation process arising from the composite impedance of the glass wall and product interface was recorded over a frequency range 10(1)-10(6)Hz for a surrogate formulation comprising 2.5% sucrose. Features of the process (i.e. the peak amplitude, C"(peak) and characteristic peak frequency, fpeak) were monitored along with the product temperature data during the entire cycle. It was demonstrated that fpeak is strongly coupled to the temperature of the product (through the dependence of the product temperature on the electrical resistance of the product) whereas C"(peak) is dependent on the extent of ice sublimation and hence can be used to measure the rate of drying and end point of primary drying. This feature provides a distinct advantage over thermocouple measurements which are restricted to end point detection only. The potential to predict the end point of a cycle from C"(peak) vs. time profiles is highlighted in this work.

Implementation and evaluation of an optical fiber system as novel process monitoring tool during lyophilization

Lyophilization is an important and well-established pharmaceutical drying process. Product temperature is the most critical process parameter during lyophilization as it impacts both product quality and process efficiency. Traditionally, thermocouples (TCs) or resistance temperature detectors (RTDs) and recently, manometric temperatures measurements (MTMs) have been used to monitor the product temperature. But, all of these techniques have several drawbacks. The objective of this study was the implementation and evaluation of an optical fiber system as novel process monitoring tool during lyophilization. Therefore, temperature profiles of mannitol, sucrose, or trehalose were recorded with various prototypes of the optical fiber sensors (OFSs) and compared to data obtained with conventional TCs or Pirani/capacitance manometry with respect to the endpoint of primary drying. The OFS allowed easy handling and easy center bottom positioning. Data obtained with the OFS in contact with product were in good agreement with data obtained via TCs or Pirani/capacitance manometry. The OFSs showed significantly higher sensitivity, faster response, and better resolution compared to TCs. This allowed for the detection of additional excipient crystallization events. It was found that force effects on unshielded sensors enabled to detect glass transitions. Three-dimensional temperature profiles were obtained with an OFS helix configuration. The possible integration of a glass fiber with several OFSs in series into the shelf surface enables non-invasive, automatic loading compatible monitoring of the drying process. In conclusion, these advantages turn the novel optical fiber systems into a highly attractive process monitoring tool during lyophilization.

Determination of end point of primary drying in freeze-drying process control.

Freeze-drying is a relatively expensive process requiring long processing time, and hence one of the key objectives during freeze-drying process development is to minimize the primary drying time, which is the longest of the three steps in freeze-drying. However, increasing the shelf temperature into secondary drying before all of the ice is removed from the product will likely cause collapse or eutectic melt. Thus, from product quality as well as process economics standpoint, it is very critical to detect the end of primary drying. Experiments were conducted with 5% mannitol and 5% sucrose as model systems. The apparent end point of primary drying was determined by comparative pressure measurement (i.e., Pirani vs. MKS Baratron), dew point, Lyotrack (gas plasma spectroscopy), water concentration from tunable diode laser absorption spectroscopy, condenser pressure, pressure rise test (manometric temperature measurement or variations of this method), and product thermocouples. Vials were pulled out from the drying chamber using a sample thief during late primary and early secondary drying to determine percent residual moisture either gravimetrically or by Karl Fischer, and the cake structure was determined visually for melt-back, collapse, and retention of cake structure at the apparent end point of primary drying (i.e., onset, midpoint, and offset). By far, the Pirani is the best choice of the methods tested for evaluation of the end point of primary drying. Also, it is a batch technique, which is cheap, steam sterilizable, and easy to install without requiring any modification to the existing dryer.

Use of manometric temperature measurement (MTM) and SMART™ freeze dryer technology for development of an optimized freeze‐drying cycle

This report provides, for the first time, a summary of experiments using SMART Freeze Dryer technology during a 9 month testing period. A minimum ice sublimation area of about 300 cm(2) for the laboratory freeze dryer, with a chamber volume 107.5 L, was found consistent with data obtained during previous experiments with a smaller freeze dryer (52 L). Good reproducibility was found for cycle design with different type of excipients, formulations, and vials used. SMART primary drying end point estimates were accurate in the majority of the experiments, but showed an over prediction of primary cycle time when the product did not fully achieve steady state conditions before the first MTM measurement was performed. Product resistance data for 5% sucrose mixtures at varying fill depths were very reproducible. Product temperature determined by SMART was typically in good agreement with thermocouple data through about 50% of primary drying time, with significant deviations occurring near the end of primary drying, as expected, but showing a bias much earlier in primary drying for high solid content formulations (16.6% Pfizer product) and polyvinylpyrrolidone (40 kDa) likely due to water "re-adsorption" by the amorphous product during the MTM test.

Freeze-Drying Process Design by Manometric Temperature Measurement: Design of a Smart Freeze-Dryer

To develop a procedure based on manometric temperature measurement (MTM) and an expert system for good practices in freeze drying that will allow development of an optimized freeze-drying process during a single laboratory freeze-drying experiment. Freeze drying was performed with a FTS Dura-Stop/Dura-Top freeze dryer with the manometric temperature measurement software installed. Five percent solutions of glycine, sucrose, or mannitol with 2 ml to 4 ml fill in 5 ml vials were used, with all vials loaded on one shelf. Details of freezing, optimization of chamber pressure, target product temperature, and some aspects of secondary drying are determined by the expert system algorithms. MTM measurements were used to select the optimum shelf temperature, to determine drying end points, and to evaluate residual moisture content in real-time. MTM measurements were made at 1 hour or half-hour intervals during primary drying and secondary drying, with a data collection frequency of 4 points per second. The improved MTM equations were fit to pressure-time data generated by the MTM procedure using Microcal Origin software to obtain product temperature and dry layer resistance. Using heat and mass transfer theory, the MTM results were used to evaluate mass and heat transfer rates and to estimate the shelf temperature required to maintain the target product temperature. MTM product dry layer resistance is accurate until about two-thirds of total primary drying time is over, and the MTM product temperature is normally accurate almost to the end of primary drying provided that effective thermal shielding is used in the freeze-drying process. The primary drying times can be accurately estimated from mass transfer rates calculated very early in the run, and we find the target product temperature can be achieved and maintained with only a few adjustments of shelf temperature. The freeze-dryer overload conditions can be estimated by calculation of heat/mass flow at the target product temperature. It was found that the MTM results serve as an excellent indicator of the end point of primary drying. Further, we find that the rate of water desorption during secondary drying may be accurately measured by a variation of the basic MTM procedure. Thus, both the end point of secondary drying and real-time residual moisture may be obtained during secondary drying. Manometric temperature measurement and the expert system for good practices in freeze drying does allow development of an optimized freeze-drying process during a single laboratory freeze-drying experiment.

Continuous measurement of drying rate of crystalline and amorphous systems during freeze‐drying using an in situ microbalance technique

The use of a novel microbalance (Christ) technique to monitor continuously the weight loss of a vial standing on a shelf of a freeze‐dryer has been investigated. The drying rates of the following aqueous solutions were measured during the primary drying phase of a complete freeze‐drying cycle: sucrose (75mg/mL, 2.5‐mL fill volume), sucrose and phenylalanine (1:0.2 by weight, 75mg/mL, 2.5‐mL fill volume), and mannitol (75mg/mL, 2.5‐mL fill volume). The microbalance yields the cumulative water loss, mcu in grams, and the momentary drying rate, Δmcu/Δt in mg/10min, of the frozen cake. The momentary drying rate curves were especially useful for examining how Δmcu/Δt changes with time during primary drying. Initially, Δmcu/Δt rises to a sharp maximum and then decreases in a fashion depending on shelf temperature, chamber pressure, and the nature of the substance being dried. Different drying behavior was observed for the sucrose and sucrose/phenylalanine systems, which was attributed to the presence of crystalline phenylalanine in the amorphous sucrose. At low shelf‐temperature (−24°C) the crystalline mannitol showed lower Δmcu/Δt than with either sucrose or sucrose/phenylalanine. The balance could also detect differences in Δmcu/Δt when using different freezing protocols. ‘Slow’ and ‘moderate’ freezing protocols gave similar drying behavior, but ‘rapid’ freezing in liquid nitrogen produced greatly altered drying rate and internal cake morphology. The balance also could be used to detect the endpoint of primary drying. Different endpoint criteria and their influence on final dried cake properties were examined. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1345–1355, 2001