Richard J. Forsyth

Richard J. Forsyth is an associate director of worldwide GMP quality with Merck & Co., Inc, WP53C-307, West Point, PA. 19486, tel. 215.652.7462, fax 215.652.7106.

The author challenges current detection methodologies.

The author discusses how the use of a visible residue limit has made the 10-ppm cleaning limit obsolete in many applications.

The author tests the ruggedness of VRL viewing conditions and defines optimal viewing conditions.

Regulatory agencies expect companies to establish and monitor clean equipment- and dirty equipment-hold times for manufacturing equipment as part of their cleaning validation program.

The material of construction is a factor in the recovery of residue in cleaning validation. An analysis of existing recovery data showed that recovery factors for drug products on various materials of construction may be categorized into several groupings.

An adulteration limit of 100 ?g/25cm? (4 ?g/cm?) was proposed for pilot-plant facilities. The dynamic changes in equipment, formulation, and residue determination made implementation of a constantly changing, calculated adulteration limit impractical. A single adulteration limit was simpler to communicate and document, making compliance achievable. The limit would be used only after it was determined to be lower than a health-based evaluation and a visual-cleanliness assessment.

The correlation between swab assay results and visible-residue limits (VRLs) for cleaning validation was examined. Previously completed validation studies were reviewed to compare swab results with recently determined VRLs. A current cleaning validation study evaluated both swab testing and VRL. Unexpected swab results led to an investigation, which showed the value of establishing the VRL in conjunction with swab recoveries for cleaning validation programs.

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.

Formulation residue, observer viewing distance, light intensity, viewing angle, observer viewing position, and observer-to-observer variability affect the ability to confirm the cleanliness of manufacturing equipment.