Best Practices and Guidelines (2022) for Scale-up and Technology Transfer in Freeze Drying Based on Case Studies. Part 2: Past Practices, Current Best Practices, and Recommendations.

Scale-up and transfer of lyophilization processes remain very challenging tasks considering the technical challenges and the high cost of the process itself. The challenges in scale-up and transfer were discussed in the first part of this paper and include vial breakage during freezing at commercial scale, cake resistance differences between scales, impact of differences in refrigeration capacities, and geometry on the performance of dryers. The second part of this work discusses successful and unsuccessful practices in scale-up and transfer based on the experience of the authors. Regulatory aspects of scale-up and transfer of lyophilization processes were also outlined including a topic on the equivalency of dryers. Based on an analysis of challenges and a summary of best practices, recommendations on scale-up and transfer of lyophilization processes are given including projections on future directions in this area of the freeze drying field. Recommendations on the choice of residual vacuum in the vials were also provided for a wide range of vial capacities.

Best Practices and Guidelines (2022) for Scale-Up and Tech Transfer in Freeze-Drying Based on Case Studies. Part 1: Challenges during Scale Up and Transfer.

The freeze-drying process scale-up and transfer remain a complicated and non-uniform practice. We summarized inefficient and good practices in these papers and provided some practical advice. It was demonstrated that using the same process set points/times in laboratory and commercial scale dryers may lead to loss of product quality (collapse or vial breakage). The emerging modeling approach demonstrated practical advantages. However, the upfront generation of some input parameters (vial heat transfer coefficient, minimum controllable pressure, and maximum sublimation rate) is essential for model utilization. While the primary drying step can be transferred with a high degree of confidence (e.g., using modeling), and secondary drying is usually fairly straightforward, predicting potential changes in product behavior during freezing remains challenging.

Equipment Capability Measurement of Laboratory Freeze-Dryers: a Comparison of Two Methods.

The objective of this investigation was to evaluate two methods for measuring the maximum sublimation rate that a freeze-dryer will support-the minimum controllable pressure method and the choke point method. Both methods gave equivalent results, but the minimum controllable pressure method is preferred, since it is easier, faster, and less subjective. The ratio of chamber pressure to condenser pressure corresponding to the onset of choked flow was considerably higher in this investigation (up to about 20:1) than in previously published reports. This ratio was not affected by the location of the pressure gauge on the condenser; that is, on the foreline of the vacuum pump versus on the body of the condenser itself. The total water loss due to sublimation as measured by tunable diode laser absorption spectroscopy was consistently within 5% of gravimetrically determined weight loss, regardless of whether the measurement took place during choked versus non-choked process conditions.

Determining Maximum Sublimation Rate for a Production Lyophilizer: Computational Modeling and Comparison With Ice Slab Tests.

Equipment capability is an important factor in scale up and technology transfer for lyophilized pharmaceutical products. Experimental determination of equipment capability limits, such as the maximum sublimation rate at a given chamber pressure, is time-intensive for production lyophilizers. Here, we present computational fluid dynamics modeling of equipment capability and compare it with experimental data for minimum controllable pressure ice slab sublimation tests in a 23 m2 shelf area freeze dryer. It is found that the vapor flow in the production scale is characterized by turbulent effects at high sublimation rates. For the considered freeze dryer configuration, the onset of turbulence occurs at a sublimation rate of 17 kg/h and leads to an increase in the minimum controllable pressure by 3-4 mTorr for the flow rates up to 40 kg/h. Variations in the shelf and duct orientations as well as the valve stroke distance and their effect on the equipment limit and pressure uniformity are also discussed. The minimum controllable pressure measured experimentally agreed within 5% with computational fluid dynamics results. For high vapor sublimation rates at final stages of ice slab testing, the condenser load affects the product chamber pressure control. Estimate of condenser pressure changes because of ice accumulation has been included.

Freeze-Dryer Equipment Capability Limit: Comparison of Computational Modeling With Experiments at Laboratory Scale.

The equipment capability curve is one of the bounding elements of the freeze-drying design space, and understanding it is critical to process design, transfer, and scale-up. The second bounding element of the design space is the product temperature limit beyond which the product collapses. The high cost associated with freeze-drying any product renders it crucial to operate using the most efficient cycle within the limits of the equipment and the product. In this work, we present a computational model to generate the equipment capability curve for 2 laboratory scale freeze-dryers and compare the results to experimentally generated equipment capability curves. The average deviations of the modeling results from the experiments for the 2 lyophilizers modeled are -4.8% and -7.2%. In addition, we investigate the effect of various numerical and geometric parameters on the simulated equipment capability. Among the numerical parameters, the chamber wall thermal boundary conditions exert the largest influence with a maximum value of 12.3%. Among the geometric parameters, the inclusion of the isolation valve reduces the equipment capability by 23.7%. Larger isolation valves, required for controlled nucleation technology, choke the flow in the duct at lower sublimation rates, thereby lowering the equipment capability limit.