Before formal cleaning validation programs were instituted, visual inspection was the primary means of determining equipment
cleanliness. The use of visual inspection is still typically a component of a cleaning validation program and for routine
inspections of cleaning effectiveness, but the use of visual inspection as a sole criterion for equipment cleanliness has
not been successfully implemented as a valid approach for cleaning validation.
A validated cleaning program based on quantitative visual inspections in conjunction with swab testing is possible. Acceptable
visible-residue limits (VRLs) can be established in conjunction with and compared with swab results. Assuming the swab results
demonstrated a validated cleaning procedure, if the results are in agreement, then the VRLs may be used going forward. A similar
argument has been successfully used to defend the use of rinse sampling established in conjunction with swab results.
Mendenhall proposed the use of only visual examination to determine equipment cleanliness in 1989 (1). He concluded that
visible cleanliness criteria were more rigid than quantitative calculations and clearly adequate. LeBlanc also explored the
role of visual examination as the sole acceptance criterion for cleaning validation (2). Nonetheless, the US Food and Drug
Administration saw the use of a visually clean criterion limited to between lots of the same product (3). Recent work described
the implementation of VRLs for the introduction of new compounds into a pharmaceutical pilot plant with previously validated
cleaning procedures (4, 5). VRLs were established for all new compounds and compared with the acceptable-residual limit (ARL).
If the VRL was lower, then visual cleanliness was used to determine if the compound was a new worst-case requiring validation.
Additional work established VRLs and acceptable viewing parameters for several marketed formulations under the more challenging
viewing conditions associated with larger size manufacturing equipment (6). This work was conducted in an effort to determine
if VRLs and visual inspection only could be adopted as an adequate methodology in a multiproduct pharmaceutical manufacturing
plant with previously validated cleaning procedures.
Figure 1: A risk-analysis grid using visual-residue limits (VRLs) and acceptable-residue limits (ARLs) as criteria.
The advantages of a properly validated and maintained VRL program are numerous. Visual inspection tests all visible equipment
surfaces. Other than piping or tubing, most manufacturing equipment can be broken down such that the vast majority of surfaces
are visible. For complex equipment and modules that are inaccessible to swabbing, rinse-sample testing can supplement visual
inspections. VRL inspections reduce the personnel time needed to swab the manufacturing equipment. They eliminate ongoing
analytical resource needs beyond the initial validation. Method development and validation resources for new development compounds
are not required, which can be considerable. With the expanded use of VRL data in lieu of surface testing, the extent of testing
and documentation necessary for each assessment is reduced, as well as the costs for long-term storage of the documentation
and data. The advantage for the manufacturing area is the instant availability of visual-testing results, which minimizes
equipment downtime while waiting for analytical results and increases manufacturing productivity. Savings in manpower, analytical
instrumentation, and documentation free these resources for other tasks.
Implementing a VRL program includes the assumption of some degree of risk. Risks arise from the uncertainties of implementing
a new cleaning strategy and can be diminished by generating more data, spending more resources, and taking more time. A balance
of quality, time, and cost is necessary to manage risks associated with a VRL program. Risk management identifies the risks, analyzes the seriousness and probability of the risks, and plans appropriate responses to prevent or
mitigate the risks. Risk analysis includes the benefits of viewing risk objectively and realistically, prioritizing resources, and justifying decisions to
support prudent risk-taking.
Table I: Applications and risk assessment of visible-residue limits (VRLs).