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Table II: Comparison of visible-residue limit (VRL) data.
Initial versus later VRL determination. Of the original 59 VRLs established (1), the average VRL in this experiment was 1.6 μg/cm2. Three of the four observers agreed on most residue levels, but one observer differed, which resulted in slightly higher
VRLs. Of the original set of VRLs, 78% were <2 μg/cm2, but 14% were >4 μg/cm2 (see Table II and Figure 1).
Figure 1: Visible-residue limit (VRL) distribution. (ALL FIGURES ARE COURTESY OF THE AUTHOR.)
Additional VRL determinations increased the experience level, widened the observer pool, and refined the experimental technique.
Instead of a small, dedicated group of observers, 20–30 scientists worked on the development compound to establish VRLs. The
most significant difference in subsequent VRL determinations, however, was the standardization of the residue-spot preparations
using lower spotted residue levels, which resulted in lower VRLs.
Table III: Current visible-residue limit (VRL) data.
Interestingly, variability among the observers decreased even as the observer pool increased. Three major factors led to greater
consistency: the initiation of a VRL training program for observers, equipment cleaners, and inspectors; overall increased
experience level of the observers; and a more consistent residue-spot preparation technique. Of the additional VRLs established,
the average VRL dropped to 0.9 μg/cm2 and 89% of determinations were <2 μg/cm2. Ninety-six percent of the total determinations were <3 μg/cm2, and only 2% were >4 μg/cm2 (see Table II). A t-test comparison of the original and additional VRL data in Figure 1 showed that the data distributions were not equivalent.
The additional VRL data with a lower average were statistically different when compared with the original VRL data, which
confirmed the effects of experience and technique refinement. The overall average VRL was ultimately <1.1 μg/cm2 for the 253 VRLs (see Table III) because 63% of the VRLs determined were less than the lowest level tested.
Richard J. Forsyth is an associate director of worldwide GMP quality with Merck & Co., Inc, WP53C-307, West Point, PA. 19486, tel. 215.652.7462, fax 215.652.7106.
Articles by Richard J. Forsyth
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