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.Method
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 were selected.
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.