Evaluation of manometric temperature measurement, a process analytical technology tool for freeze-drying: Part II measurement of dry-layer resistance

Abstract

The purpose of this work was to study the factors that may cause systematic errors in the manometric temperature measurement (MTM) procedure used to determine product drylayer resistance to vapor flow. Product temperature and dry-layer resistance were obtained using MTM software installed on a laboratory freeze-dryer. The MTM resistance values were compared with the resistance values obtained using the "vial method." The product dry-layer resistances obtained by MTM, assuming fixed temperature difference (ΔT; 2°C), were lower than the actual values, especially when the product temperatures and sublimation rates were low, but with ΔT determined from the pressure rise data, more accurate results were obtained. MTM resistance values were generally lower than the values obtained with the vial method, particularly whenever freeze-drying was conducted under conditions that produced large variations in product temperature (ie, low shelf temperature, low chamber pressure, and without thermal shields). In an experiment designed to magnify temperature heterogeneity, MTM resistance values were much lower than the simple average of the product resistances. However, in experiments where product temperatures were homogenous, good agreement between MTM and "vial-method" resistances was obtained. The reason for the low MTM resistance problem is the fast vapor pressure rise from a few "warm" edge vials or vials with low resistance. With proper use of thermal shields, and the evaluation of ΔT from the data, MTM resistance data are accurate. Thus, the MTM method for determining drylayer resistance is a useful tool for freeze-drying process analytical technology.

Evaluation of manometric temperature measurement (MTM), a process analytical technology tool in freeze drying, part III: Heat and mass transfer measurement

“…The resistance for 5% sucrose is less than that for 5% glycine, andR ps of 5% glycine is less thanR ps of 5% mannitol (Table 1). 11 The trend in Figure 1 can also be explained as a direct result of the increase in dry layer resistance with increasing primary drying time. In summary, the MTM method gives accurate K v values whenever the MTM P ice andR ps values are accurate.…”

“…12 However, the MTM-determined resistance parameter,R ps , is typically below the actual value due to fast vapor pressure rise from warm vials at the edge of the vial array. 11 In Equation 9, the K v is inversely proportional toR ps . Therefore, the small R p value will cause a large K v value.…”

“…The MTM K v values were improved when higher chamber pressure, higher shelf temperature, or thermal shields were used because the MTM R ps values were improved when freeze-drying is performed under these conditions. 11 The accuracy of MTMR ps values is also product resistance sensitive, ie, the difference between MTMR ps and actual values tends to be smaller at higher R ps . This is likely the reason why high concentration of glycine and the higher resistance materials gave more accurate MTM K v values.…”

Advanced approach to build the design space for the primary drying of a pharmaceutical freeze‐drying process

“…• the TDLAS sensor, 24 • one of the algorithms using the pressure rise test, [29][30][31][32][33][34][35] • an equation involving product-specific surface area, 36 • the monitored product temperature profile, 37 • a special weighing device placed in the chamber to measure the sublimation flux (i.e., m) and product temperature in the weighed vials. [38][39][40] A detailed discussion and comparison of the methods available to determine model parameters is given in Ref.…”

In-Line Optimization and Control of an Industrial Freeze-Drying Process for Pharmaceuticals

“…Most of them use the pressure rise test (PRT) to monitor the process: the valve placed between the drying chamber and the condenser is periodically closed for a short time interval (typically 5-30 s), and the measured pressure rise is related to the temperature of the product by means of a mathematical model. Several algorithms were proposed to interpret the PRT, namely the Barometric Temperature Measurement, 17-20 the Manometric Temperature Measurement, [21][22][23][24] the Dynamic Pressure Rise, 25 the Pressure Rise Analysis, 26,27 and the Dynamic Parameters Estimation (DPE) 28,29 : the type and the details of the mathematical model, and the parameters that are estimated, are the main differences among the various algorithms.…”