Visible inspection is an essential component of a cleaning validation program and a requirement for compliance with good
manufacturing practice (GMP). The use of inspection as the sole means of determining equipment cleanliness for pharmaceutical
facilities was initially proposed by Mendenhall and Leblanc (1, 2). FDA's 1993 Guide to Inspection of Validation of Cleaning Processes, however, indicated that its use should be limited to batches of the same product, which has led to its limited exploitation
to date within the industry (3). Nevertheless, this topic continues to be a subject of discussion; for example, a risk-based
approach supported by visible residue limit (VRL) data has been proposed for R&D pilot plants, in conjunction with validated
cleaning procedures (4–9).
Potential benefits of the use of visual inspection alone include significant time savings compared with the commonly used
techniques of swab or rinse analysis, as well as the fact that visual inspection, in principle, has the capability of testing
100% of the equipment surface. The risks associated with factors that have been demonstrated to affect VRL measurements, however,
need to be managed. These factors include observer subjectivity, lighting level, distance, viewing angle, and inspection methodology
(4, 6, 8, 9).
Data published previously on VRLs have largely focused on evaluating limits on stainless-steel metal plates. For this study,
using a small number of active pharmaceutical ingredients (APIs), a range of plates was assessed of different surface types
typically found in API and drug-product manufacturing plants. In addition, the potential for variance in the VRL with metal-surface
roughness was investigated.
Surfaces examined comprised borosilicate clear glass (QVF), white polytetrafluoroethylene (PTFE), Pfaudler World Wide Glass
white (9125) and dark blue (9115) Glasteel, and stainless steel S316. Metal plates of different surface roughness were examined,
with the range selected to encompass actual measured values for items of equipment in the manufacturing facilities, typically
between 0.0 to 0.7 µm. Additionally, a 1.1-µm surface roughness was examined to determine the consequence of any deterioration
in condition of the metal. The surface roughness was measured using a Surtronic Duo instrument (Taylor Hobson), and the variation
in roughness across the plates was within 10% of the stated mean.
The method was designed to minimize variables of subjectivity, environment, and solvent effects, in accordance with the conclusions
reported in previous studies. The VRL evaluations were conducted under the controlled conditions of an analytical-science
laboratory, determined as representative of a typical manufacturing room, with ambient lighting of approximately 300 lux.
Solutions of APIs to be tested were prepared by dissolution in methanol, which was selected because the solvent leaves no
surface residue and dries to a more even coverage, with minimal sample rings. APIs known to be stable to aerial oxidation
The solutions were applied dropwise to 10 x 10 cm flat plates of the various materials of construction, with concentrations
set to ensure complete, even coverage of plates. A starting coverage of 10 µg/dm2 was used because it met the minimum requirements to enable useful application in actual plant equipment. Each plate was
left to dry naturally before visual examination. If the API was not visible, the loading operation was repeated to increase
the amount of material on the surface in a stepwise fashion until it could be visually detected on the plate. Four observers,
trained as cleaning inspectors, viewed each plate independently, from a distance of between 6 and 50 inches before comparing
findings. The observations were all conducted in the same location in the laboratory to minimize any variability due to lighting
conditions as well as to ensure that every possible viewing angle was assessed. Each examination was conducted first in ambient
laboratory lighting, followed with additional aid of a portable spotlight source. The angle and distance of the spotlight
and observer were varied each time to maximize the capability to view any contamination, taking into consideration surface
reflectivity. The clear glass plates were viewed from both upper and lower sides (i.e., looking directly onto and through
the glass) by means of one, independent person manipulating the plate with a second person performing the role of inspector.