Ruggedness of Visible Residue Limits for Cleaning Validation

The author tests the ruggedness of VRL viewing conditions and defines optimal viewing conditions.
Mar 02, 2009
Volume 33, Issue 3

Visual inspection is always used in cleaning validation programs and for routine inspections of cleaning effectiveness, but its use as a sole criterion for equipment cleanliness has not been implemented successfully as a valid cleaning validation approach. Visible residue limits (VRLs), however, can be established for processed active pharmaceutical ingredients (APIs), excipients, and detergents. VRLs for APIs are generally of greatest concern because the API is the most potent component of a drug's formulation. If the VRL is lower than the health-based and adulteration-based acceptable residue limit (ARL) as determined by the company, then the VRL is a viable approach to assessing equipment cleaning within a facility (1).

Sample preparation and viewing parameters for VRL use have been established for both pilot-and commercial-manufacturing facilities (1, 2). A solution or suspension of API applied at different concentrations to stainless-steel coupons results in residues of uniform size. Examination of these viewing parameters consisted of viewing distance, viewing angle, light intensity, residue composition, and observer subjectivity. These paremeters provided optimal viewing conditions to detect visible residues. Viewing conditions in the pilot plant were set at 18 in., 30°, and >200 lux. For commercial facilities with larger, fixed equipment, the viewing inspection parameters were more restricted. Optimal viewing conditions were set at <10 ft, >30°, and >200 lux. A discussion of VRL applications and associated risks concluded that the potential for cleaning failure was small under a well-controlled VRL program (3–5).

The subjectivity of observers and the appearance of dried residues were potential limitations to a VRL program. The original VRL work used a small group of four to six observers (1, 2). For subsequent work, a larger pool of observers determined VRLs of APIs in development at one site. In addition, a study of VRL determinations for five APIs at multiple sites helped address the issue of observer subjectivity and further defined the ruggedness of residue sample preparation.

The complete set of VRL data was examined for distribution and trends. Original VRL data were compared with the subsequent data set to assess improvements in process and technique. VRLs of the APIs, excipients, and formulations were also compared to determine whether a correlation exists between the VRL of a formulation and its components. Theoretically, the VRL of the formulation should be the same as the lowest component VRL. Analysis of VRL data showed differences between the early data and later VRL determinations. VRL data of the APIs, excipients, and formulations also proved to be worthwhile for future considerations and VRL policy definition.

VRL residues appear as a ring or as uniform residue. The appearance depends on the amount of API residue being spotted and the volume of spotting solvent, which translates to the concentration of the resulting residue. Other physical parameters include drying the solvent, and any physical or chemical interaction between the solvent and the residue. Methanol is consistently used as a spotting solvent because its low surface tension allows it to spread to a uniform spot size and its high volatility allows it to dry quickly.

The API, however, is consistently different, making control difficult. The amount of residue around the VRL is extremely low with an API, though, so it is more likely to fall out of the solution last. As methanol and other solvents dry, the perimeter of the wetted area is the last place to dry, which favors the ring-type residue appearance.

Experience gained through ongoing equipment inspections and direct soiling of manufacturing equipment with test soils confirmed that potential residue on cleaned equipment would be similar in appearance to the experimental VRL residues. Varying the application volumes and concentrations of the residue spots addressed the issue of residue appearance.

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