Risk-Management Assessment of Visible-Residue Limits in Cleaning Validation

A risk-management assessment of visible-residue limits (VRL) in cleaning validation of pharmaceutical formulations was conducted for both pharmaceutical pilot plant and manufacturing facilities. The authors discuss how potential risks were identified, analyzed for probability, considered for seriousness, and controlled through avoidance or mitigation. These opportunities for VRL implementation then were identified for both pilot plant and manufacturing settings.
Sep 02, 2006
Volume 30, Issue 9

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.

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

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