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Figure 3: Effect of spin speed and brake settings on the detection rate of the machine. A setting of 1600 x 7 represents spin
speed of 1600 rpm and brake setting of 7. Performance improves as spin speed is increased and inspection is performed quickly
after stopping the vial.
Role of product properties. In addition to the machine settings, the product properties can have a significant impact on the performance of the AVI system.
Solution properties such as density, viscosity, and surface tension govern the movement of the foreign particle in the flow-field
generated by spinning the the vial. The speed at which meniscus recovers, as well as the time it takes for the foreign particle
to descend and stop after the application of brakes, is dependent on these solution properties. Figure 4 shows deterioration
in performance of the AVI system as the product viscosity is increased. As solution becomes viscous, the particle motion relative
to the solution is arrested and it becomes difficult for the machine to detect. Detection rates can improve by increasing
the spin speed and brake settings as shown in the figure by the three traces of color (blue, red, and green). The Figure 4
inset shows a closeup of the data set for 2.3 cP. It was observed that the two formulations with same viscosity but different
density and surface tensions (Formulation A is represented in yellow and has a density of 1.046 g/mL and surface tension of
48 mN/m2; Formulation B is represented in red and has density of 1.033 g/mL and surface tension of 61 mN/m2 at room temperature)
exhibit slightly different detection rates (about 7% variation). This finding demonstrates that variation in physical properties
other than viscosity can effect the way the particles are suspended and move during inspection, thereby affecting their detection
rates. However, as the spin speed was increased, the overall performance improved and the differences between the detections
rates for the two formulations was reduced.
Figure 4: Product properties can have a significant impact on machine performance. Detection rates (average of 100 μm and
400 μm particles) are reduced at higher viscosity and improve with increased speed and brake settings. Solutions with similar
viscosity can also exhibit differences in detection rates based due to differences in density and surface tension. A setting
of 1600 x 7 represents spin speed of 1600 rpm and brake setting of 7. Yellow fill color represents Formulation A while red
represents Formulation B.
In addition to the physical properties discussed above, other inherent properties of the protein solution could affect the
ability of the machine to differentiate between and true and false rejects. If the protein has a propensity to form or trap
particulates, such protein particles can be perceived by the AVI system as rejects. In such cases, kinetics of particulate
formation should be characterized to assess the feasibility of using automated inspection. The liquid formulation may also
have propensity to form micro air bubbles which can be perceived by the inspection system as foreign particulates. Beccause
air bubbles have a tendency to rise to the meniscus, inspection view height can be carefully selected to avoid any interference
with the bubbles. Some AIMs use a pre-spin to facilitate removal of air bubbles before the inspection spin. Such AVI process
issues could be very product specific and may cause costly delays during performance qualification. Selection of an appropriate
mimic solution for development runs is therefore critical to identify and trouble-shoot such problems early during product
development.
Figure 5: Contour plots representing the machine performance over a wide range of spin and brake settings for solutions of
different viscosities. The black area represents the operational parameter range that was not studied.
A design of experiments can be conducted to characterize the performance of the AVI system over a wide range of operational
parameters. A design space can then be created over the range that gives acceptable performance. Such design space characterization
offers the assurance of a consistent and robust process. Figure 5 shows results of a DOE study conducted over a wide range
of spin speed and brake settings for a fill volume of 1.7 ml in a 3cc vial using Formulation B. The contour colors represent
detection rates measured by the automated inspection system for solutions of different viscosities. As discussed above the
performance clearly deteriorates with increase in solution viscosity. While higher spin speed and higher brake settings results
in improved detection rates, other operational issues can come into play under such conditions. For example, very high spin
speed may cause the vials to shoot out of the spindles making the process operationally unfriendly. Very high brake settings
(inspecting very close to the termination of vial rotation) may not provide adequate time for the meniscus to recover. The
meniscus, in turn, puts a shadow on the sensor and can be wrongly classified as a defect. All these operational issues should
be carefully characterized to create a design space that offers acceptable performance during commercial manufacturing.
Figure 6: Comparison of detection rates for vials of different sizes and fill volumes. Smaller fill volumes are consistently
more challenging for automated inspection.
Role of fill configuration. In addition to machine settings and formulation properties, fill configuration of the final drug product presentation (i.e.,
size and shape of container and liquid fill volume) plays a significant role in determining the performance of an automated
inspection system. The radius of the container has a direct impact on the shape of the vortex formed when the vial is spun
and the recovery of the meniscus when brakes are applied. Syringe barrels usually have smaller radii than vials and pose a
bigger challenge for inspection. Higher spin speeds are needed for syringes to obtain performance comparable with vials. The
height of liquid level plays an equally important role as well. For a given vial size, as fill volume is reduced, the liquid
level is lowered and the size of the inspection window (i.e., distance between base and meniscus level) shrinks. Figure 6
demonstrates that the automated machine's performance was consistently better for larger fill volumes for each of the three
vial sizes. Inspecting very close to the meniscus level may result in false rejects due to the meniscus shadow being perceived
by the sensor as foreign particle. Careful selection of inspection view height is critical to minimizing such false rejects
while maximizing the size of the inspection window.
