A visible-residue limit (VRL) currently is used in a clinical pilot plant for the introduction of new compounds (4, 5) in cases for which the VRL is lower than the acceptable-residue limit (ARL). The ARL is the amount of a formulation component that can be carried over to the next formulation with no pharmacological or adulteration concerns. The initial use of an active pharmaceutical ingredient (API) in the facility is followed by cleaning and a visual inspection against the previously determined VRL. Visually clean equipment means the current cleaning procedure is effective and the new API is not a new worst case that would require cleaning validation.
The same scientific rationale supports the use of VRLs in a manufacturing facility. The main difference between pilot plant and commercial manufacturing facilities is equipment size. Acceptable viewing parameters for the larger manufacturing equipment, including distance, viewing angle, and light level, consistently detect VRLs for several marketed formulations (6).The implementation of VRLs in the pilot plant and their potential use in the manufacturing facility were additions to established cleaning programs. The cleaning programs in both the pilot plant and manufacturing facilities established validation based on swab sample data using high-performance liquid chromatography (HPLC) for analysis. Visual inspections were part of the validation, but were qualitative determinations only.
It should be possible to demonstrate the correlation between the quantitatively determined VRL of either the API or formulation on the manufacturing equipment and the analytically determined swab recovery data. The data from the two determinations should be mutually supportive as part of a cleaning process validation. Therefore, a retroactive analysis of the pilot-plant validation study compared the previously obtained swab results with the more recently generated VRLs for the subject compounds.
In addition, a current cleaning validation study conducted in a clinical packaging area included VRL as an integral part of the study. The study used documented worst-case formulations to soil the equipment, followed by cleaning according to a standard operating procedure. Visual inspection used experimentally determined VRLs. Swab samples for the appropriate compound confirmed the equipment's cleanliness. Testing for each formulation was repeated twice to validate the cleaning procedure. The final report includes a comparison between the VRLs and the swab sample results.
Although the cleaning validation passed testing (i.e., all swab results were lower than the ARL), the swab results for several metformin samples assayed higher than the experimentally determined VRL. An investigation reconciled the discrepancy.
The cleaning-validation study for the pilot plant selected worst-case formulations. One formulation was validated for a dry-granulation equipment train and another for the wet-granulation process. Each piece of cleaned equipment was visually inspected before swab testing and both formulations were tested three times for validation.
The compounds tested were simvastatin and rofecoxib (Whitehouse Station, NJ, Merck & Co., Inc.). Four observers viewed dried solution spots of known concentrations to determine the VRLs. The experimentally derived VRLs for the compounds were 0.485 and 0.871 μg/cm2 , respectively (4). For a swab area of 25 cm2 , the limits were 12.1 and 21.8 μg/swab. The VRLs for the base and neutral detergents used to clean the equipment were <0.37 and <0.56 μg/cm2 (<9.3 and <14 μg/swab).