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.
Validated cleaning procedures should include specific instructions for disassembly and assembling equipment. Visual inspection
and 100% access to all contact surfaces of the product will help mitigate the risks of undetected product carryover. Care
must be taken to ensure that all contact surfaces of equipment products are inspected with appropriate lighting and viewing
angles. For complex equipment, additional routine testing of rinse samples could be considered to supplement visual inspections.
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.