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.

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.

Table I: Applications and risk assessment of visible-residue limits (VRLs).