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.

Linear vs nonlinear ultrasonic testing of kissing bonds in adhesive joints.

Kissing bonds in adhesive joints are precursors to damage and failure in materials and components used in safety-critical industries. They are zero-volume, low-contrast contact defects widely regarded as "invisible" in conventional ultrasonic testing. In this study, the recognition of the kissing bonds is examined in automotive industry-relevant aluminum lap-joints with standard bonding procedures using epoxy- and silicone-based adhesives. The protocol to simulate kissing bonds comprised customary surface contaminants PTFE oil and PTFE spray. Preliminary destructive tests revealed brittle fracture of the bonds with typical single-peak stress-strain curves indicating ultimate strength reduction due to adding contaminants. The curves are analyzed by using nonlinear stress-strain relation with the higher-order terms containing the higher-order nonlinearity parameters. It is shown that the lower-strength bonds manifest a high nonlinearity while the high-strength contacts are candidates for a low nonlinearity. Based on that, the nonlinear approach is set side by side with linear ultrasonic testing for experimental locating of the kissing bonds fabricated in the adhesive lap-joints. The sensitivity of the linear ultrasound is shown to be adequate to detect only a substantial bonding force reduction caused by the irregular interface defects in adhesives, while a minor contact softening due to kissing bonds remains undistinguishable. On the contrary, the probing of the kissing bonds vibration with nonlinear laser vibrometry reveals dramatic growth of the higher harmonic amplitudes and thus validates highly-sensitive detectabilty of these troublesome defects.

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.

Mirror movements and the role of handedness: isometric grip forces changes.

Co-activation of both hemispheres seems to play a critical role in the generation of mirror movements, involuntary muscle contractions opposite to voluntary movements of one hand. The relationship between handedness und mirror movements is unclear. We measured repetitive grip force changes performed at slow and fast frequencies with the active hand and recorded mirror activity in the opposite inactive hand in 17 healthy left-handed (LH) and 17 right-handed (RH) participants. Data suggest significant differences between RH and LH with respect to the temporo-spatial characteristics of mirror activity, but not in general mirror movement strength. Mirror activity correlation was more pronounced when the non-dominant hand was active in RH, while LH did not show such an asymmetry. We suggest that the dependence of mirror activity on the active hand in right-handers but not in left-handers reflects the more general finding of stronger manual asymmetry in brain activation as well as in functional performance in right-handers.

Optokinetic stimulation in microgravity: torsional eye movements and subjective visual vertical.

INTRODUCTION: Microgravity provides unique sensory inputs to the vestibular and oculomotor systems. We sought to determine the effects of long-term spaceflight on sensing of spatial orientation. METHODS: Two cosmonauts participated in experiments on human vestibulo-visual interactions during a long-term mission (178 d) in the MIR station in 1995. During circular optokinetic stimulation (OKS) the tonic torsional eye position (torsional beating field, TBF) and the subjective visual vertical (SVV) were recorded on several days of the space mission as well as pre- and post-flight. A reference data set was obtained from healthy subjects on Earth, in whom the TBF was measured in upright and in prone positions. RESULTS: Neither cosmonaut showed changes in the SVV or the TBF values during the first days in microgravity. On flight day 149, cosmonaut A showed an increase of both values, which continued to rise by 4- and 10-fold until the end of the flight (TBF: 8.1 degrees; SVV: 216.8 degrees). This cosmonaut reported that the increase was accompanied by a loss of spatial orientation. In contrast, cosmonaut B's values remained at pre-flight levels (TBF: 1.6 degrees; SVV: 4.4 degrees). Post-flight values of the TBF did not significantly differ from pre-flight values for either cosmonaut. Subjects showed an increase of the TBF by more than a factor of 2 in prone position (range -7.7 degrees to +10.2 degrees) compared with upright position (range -3.7 degrees to +3.4 degrees). CONCLUSIONS: Pre-flight, post-flight and during the first part of the flight, both cosmonauts exhibited values similar to those of normal subjects in an upright position. The increased TBF values of cosmonaut A from flight day 110 on were within the range of the normal subjects in prone (face-down) position, when the gravity vector cannot be used to stabilize the TBF against the rotating stimulus (the axis of rotation is parallel to the gravity vector). The increasing deviations of cosmonaut A's SVV values in-flight suggest the presence of an internal body reference system, which weakened throughout the flight and thus lost its stabilizing effect.