Application of Visible-Residue Limit for Cleaning Validation - Pharmaceutical Technology

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Application of Visible-Residue Limit for Cleaning Validation


Pharmaceutical Technology



Figure 2: Observers viewed formulation stainless steel coupons from various distances and angles.
The observers for this study were familiar with the appearance of API and formulation residues and all had 20/20 eyesight with or without corrective lenses. Observers stood perpendicular to the stainless steel background (see Figure 2, Appendix, Figure 7). The observers viewed the coupons separately and under the least favorable conditions first (i.e., at the minimum viewing angle, from the greatest distance, under the lowest light). The viewing distance, angle, and the light intensity were measured for each observation. As a final variable, the position of the observer relative to the stainless steel background was varied to ascertain the effects of the reflected ambient light and the stainless steel background (see Appendix, Figure 7).

Results and discussion

VRLs were evaluated for several marketed and late-development formulations on the basis their respective APIs' concentration. Each visible limit was designated as the lowest concentration at which all observers positively identified residue. The actual amount of material spotted in μg/cm2 was based on previous VRL work conducted in a pilot-plant environment (6). The ability to detect visible residue changed compared with the previous study as a result of the wider range of parameters (i.e., light intensity range, viewing distance, and viewing angle). In addition, a sample at the ARL was spotted to address greater distances coupled with lower light intensities. Each observer viewed the spots and indicated whether they saw any residue.

Stainless steel was chosen as a representative surface for the study. The use of a VRL criteria as a result of this study is limited to the stainless steel surfaces of manufacturing equipment.


Table I: Formulation residue concentrations.*
Using methanol as the spotting solvent improved the experimental results. The sample spot size and the resulting concentration levels were much tighter than in previous studies, in which various solvents were used (6). The application and drying of the spots were more controlled and more efficient. Despite the additional control, the residue spot sizes and control of the resulting spot concentrations still varied (see Table I). No noticeable effects of the solvent on the resulting residue appearance were observed.


Table II: Effect of viewing distance on visible-residue detection.*
As expected, the overall ability to visually detect formulation residue decreased with increased viewing distance (see Table II). At 400 lx and at the minimum viewing angle (15), observers detected the previously determined ARL and VRL for all tested formulations from 5 ft. Several VRLs were not detected from 10 ft. From 15 ft, the observers could not see most VRLs and could not consistently detect any VRLs from 20 ft. With regard to the ARLs, the observers saw most formulation residues under these viewing conditions from 10 and 15 ft. From 20 ft, the observers saw less than half of the formulation ARLs.


Table III: Effect of light intensity on visible-residue detection.*
The ability to detect residue also diminished with decreased ambient light (see Table III). With 200-lx ambient light, VRLs were consistently detected from 15 ft and a 45 viewing angle. At 100-lx ambient light, some VRLs were not detected at 15 ft and 45. VRLs were consistently detected from 10 ft at 100 lx, however.

The ambient light source controlled light intensity at the lower end of the viewing range. The portable light source controlled the light intensity at the upper end of the viewing range. The observer moved and adjusted the portable light source to optimize individual viewing conditions within the constraints encountered for various pieces of manufacturing equipment. Therefore, the maximum intensity of the portable light source decreased with distance.


Table IV: Effect of viewing angle on visible-residue detection.
In general, the spotlight did not increase the observer's ability to detect formulation residue. The intensity of the spotlight overwhelmed the residue, and the reflecting light from the spotlight hindered the observer's ability to detect the residue. Several instances occurred in which the spotlight enabled the observer to see a previously undetected spot. Nonetheless, there were more cases in which the observer did not detect a residue with the spotlight but did detect the same residue under ambient light. In practice, the effective use of a portable light source depends on the observer and the situation.


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