Management of risks

Proper risk management can mitigate or eliminate the probability and seriousness for a given risk. Ideally, all risk would be eliminated, but in reality risk is reduced to an acceptable level. Universal visual inspection complemented by swab testing minimizes the probability of soiled equipment being used for subsequent manufacturing.

The risk minimization of using visual inspection and VRLs is ensured by a 100% inspection of the equipment surface that verifies product residue has been removed to an acceptable level. Inspector training should include familiarity with all manufacturing equipment, including disassembly, cleaning, and the appearance of visible residues for each API and product. The inclusion of new equipment, APIs, or products would necessitate additional training. A well-trained inspection group significantly decreases the risk of soiled equipment passing inspection.

Standard operating procedures for equipment cleaning also should address the issue of recleaning visibly soiled equipment. Once a visible soil is identified, a documented follow-up procedure ensures the equipment is recleaned and an investigation is conducted to determine the root cause of the issue and possible need to revise the cleaning procedure. With proper procedures in place, risk for a visual inspection is comparable to risk for other inspection methods.

The ARL should be determined before the VRL is established. The VRL is established experimentally and compared with the ARL. Only VRLs below the ARL level justify the use of visual inspections as a surrogate to surface sampling. Experimental VRL levels should be verified by at least four inspectors to minimize subjectivity. This procedure should minimize the risk of a VRL resulting in residues above the ARL.

A regulatory question on the use of VRLs should be anticipated. A sound justification of the extent of VRL used backed up by solid VRL data will mitigate potential agency concerns. To further mitigate regulatory risks, the initial validation of a new cleaning procedure may incorporate both surface sampling and visual inspection. Once cleaning performance has been validated with quantitative surface residual data and correlated to VRL data, the regulatory risks with extended use of VRL data would be reduced. VRL data were generated for specific APIs, excipients, and formulations (4, 6). Of the 39 marketed formulations evaluated to date for VRL, 27 formulation VRLs were <1 µg/cm² ; 10 VRLs were 1–2 µg/cm² ; 1 VRL was 2–3 µg/cm² ; and only 1 VRL was 3–4 µg/cm² . The VRLs were generally well below a baseline ARL of 4 µg/cm² , further reducing the risk of carryover and mitigating potential regulatory concern.

Redundancy can add value to VRL determination and routine visual inspections with minimal additional resource requirements. Several personnel can check the equipment sequentially. Personnel cleaning the equipment, the inspector, and the subsequent formulator can all sign off that the equipment is clean. Two or more inspectors can perform the visual examination and document passing visual inspections. Other combinations of personnel are just as effective. In addition, the frequency of an ongoing monitoring program can be increased using visual inspections in place of swab testing.

Uses of VRLs by a pilot-plant facility

The use of VRLs has previously been described (4, 5) for the introduction of new compounds into a pilot plant. Before a new compound is manufactured in the pilot plant, a VRL is established for the API. After the initial batch is manufactured, the equipment is cleaned and visual inspection using the VRL confirms the current cleaning procedure is sufficient and that the new compound is not a new worst-case requiring further validation. This process has been successfully implemented without compromising product quality. This application, along with its risk mitigation, is shown in Table I.

VRLs also are used for periodic assessment of cleaning in the pilot plant. Monthly independent visual inspections using VRLs are conducted on several pieces of equipment to ensure that routine cleaning removes all product residues. These inspections are in addition to routine visual inspections for cleanliness conducted after each use by the manufacturing technician. Over the course of the year, these independent periodic inspections check all of the different types of equipment in the pilot plant to generate a comprehensive review of ongoing cleaning effectiveness in the pilot plant.