The viewing angle of the observer to the residue was a critical factor for detecting formulation residue. Under ambient light
and at the minimum angle (~15°) (see Table II), the observers did not detect most VRLs at 15 ft and only detected a few at
20 ft. When the viewing angle increased to 30° (see Table IV), the observers detected more residue spots at 15 and 20 ft,
but not enough to make a significant difference compared with data at 15°. As the viewing angle increased to 45° and 90°,
the observers detected almost all VRLs at 15 ft (see Table IV) and most VRLs at 20 ft. The observers detected essentially
all ARLs at 20 ft and at >30° viewing angles. When the observer's position changed with respect to the stainless steel background,
observers detected all VRLs from 10 ft, at a 45° coupon angle, and with light intensities as low as 100 lx (see Appendix,
Figure 7).
Observer variability was a factor in determining the VRL (6) for API and formulation residues. For this study, each factor
examined had an effect on the observer's ability to detect the formulation residues. Observer detection was dependent on the
formulation residue level, observer viewing distance, light intensity, and viewing angle. Certain observers had trouble detecting
several formulation residues.
Observer variability increased with greater viewing distances, particularly for those beyond 10 ft (see Table II). This trend
also was true of the observer angle factor. At 15° and 30° viewing angles, observer variability was comparable with other
factors (see Table IV). At a viewing angle greater than 30°, the ability to detect residue increased significantly and observer
variability decreased accordingly (see Figures 3 and 4). Residue detection was comparable using the portable light source
and 400-lx ambient light (see Appendix, Figure 8) and was not a significant factor at decreasing light intensity levels until
100 lx, at which VRL detection was problematic (see Figure 5).
Conclusions
Using a visible-residue limit (VRL) to verify equipment cleanliness is a viable possibility in a manufacturing facility for
formulations with a VRL that is lower than the acceptable-residue limit (ARL). The ability to detect pharmaceutical compounds
down to their VRLs has been demonstrated using formulation residue level, observer viewing distance, light intensity, and
viewing angle as variables.
The factors that affect visible-residue detection can be determined and viewing of residues can be controlled. Under defined
viewing conditions, a trained observer can detect formulation residue. The observer should be within 10 ft of the equipment
surface to minimize the effect of the light intensity or the viewing angle. In addition, the observer should view the surface
from a >30° angle to minimize the risk of the residue blending in with the background. Finally, the ambient light level should
be at least 200 lx. Otherwise a portable light source can be used.
Acknowledgments
The authors thanks Michael McQuade, Tara Lukievics, and Joseph Schariter for their efforts as observers during these studies.
Richard Forsyth* is an associate director in Worldwide GMP Quality with Merck & Co., Inc., WP53C-307, West Point, PA 19486, tel. 215.652.
7462, fax 215.652.7106, richard_forsyth@merck.com
Vincent Van Nostrand is a research chemist in Pharmaceutical R&D with Merck & Co., Inc.
*To whom all correspondence should be addressed.
Submitted: June 14, 2005. Accepted: June 29, 2005.
References
1. Code of Federal Regulations, Title 21, Food and Drugs (General Services Administration, Washington, DC, Apr. 1, 1973, Part 211.67.b.6.
2. R.J. Forsyth and D. Haynes, "Cleaning Validation in a Pharmaceutical Research Facility," Pharm. Technol.
22 (9), 104–112 (1998).
3. US Food and Drug Administration, Guide to Inspection of Validation of Cleaning Processes (FDA, Rockville, MD, 1993).
4. D.A. LeBlanc, " 'Visually Clean' as a Sole Acceptance Criteria for Cleaning Validation Protocols," J. Pharm. Sci. Technol.
56 (1), 31–36 (2002).
5. D.W. Mendenhall, "Cleaning Validation," Drug Dev. Ind. Pharm . 15 (13), 2105–2114 (1989).
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