The instrument control software offers the users a limited number of choices. The manual "Control" screen allows the operator
to activate certain functions such as the titration-cell wash routine, open and close the titration-cell cap, move the robot
arm grippers, control the balance door, and operate the decapping station gripper. The operator thus has sufficient control
to handle routine maintenance such as cleaning the titration cell and removing sample tubes that were left in the system after
a critical error or an emergency stop. Advanced functions such as control of the robot-arm movements are disabled for safety
reasons and can only be accessed through a password-protected administrator login.
The "Run Standards" screen allows the operator to perform titer determination using sodium tartrate. The raw data (volume
of titrant dispensed) is obtained from the titrator, the sample mass is obtained from the balance and the titer (mg H2O/mL KF reagent) is calculated and stored by the Focus software. Here, a minimum of three replicates are required. The average
value is used for all subsequent sample moisture determination.
The "Run Sample" screen allow users to enter the total number of samples to be analyzed and the number of titrations to be
performed before the titration cell is washed. These two user-input parameters are the only ones that directly affect system
operation. No product-specific methods exist. All samples are handled and analyzed in the same manner. After each moisture
determination, the result is sent to the computer and immediately printed on the attached line printer. To simplify system
validation, the authors decided not to include the optional 21 CFR Part 11: Electronic Records, Electronic Signature feature, but this functionality could be added in a future software revision
if needed.
The "Mock Run" screen is identical to the "Run Sample" screen, with exception that no titration is performed. This mode is
used for system demonstration and training purposes.
System testing
The system was subjected to comprehensive tests, including hardware error checking and recovery. No major difficulties were
encountered. Operational testing was simplified by the limited number of user input parameters. This section presents the
results from the most relevant studies: the moisture determination of active hygroscopic freeze-dried product from a fully
loaded sample rack.
Figure 3: The effect of queue time on sample moisture. The squares and dashed line represent Sample Set 1. The circles and
solid line represent Sample Set 2. (IMAGE IS COURTESY OF PHILIPPE LAM)
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For these studies, the sample queue times (i.e., the time the samples were on the rack awaiting analysis) were recorded. Figure
3 summarizes the results for two sets of samples consisting of two batches of active material lyophilized in 50-cm3 vials. For the second set, analysis was paused after 4.5 h and resumed 17 h later to increase the queue time.
The data show that, for this product, the sample moisture increases in a linear way as a function of queue time. The increase
suggests that the samples absorb environmental moisture, most likely from diffusion though the centrifuge tube wall or the
cap closure seal. The absolute overhead moisture present in a 15-mL sample tube under typical laboratory ambient conditions
of 21 °C and 50 ± 15% relative humidity is approximately 1.4 × 10-4 mg, an insignificant amount. The moisture-ingress rates for the two sets of samples are 0.018 wt%/h and 0.0095 wt %/h, respectively.
This behavior is expected and results from the sample-preparation method selected. Although this small amount of moisture
ingress seems to be a shortfall, in practice, analysts prepare 10–20 samples at a time, and samples are added only after most
of the initial samples have been tested. Hence, the queue time is typically only a few hours. This minor limitation was deemed
an acceptable tradeoff for the convenience afforded by an automated system.
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