Application of Visible-Residue Limit for Cleaning Validation - Pharmaceutical Technology

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Application of Visible-Residue Limit for Cleaning Validation


Pharmaceutical Technology


A handheld light source (Sport Shot, model VEC1 24B, Vector Machinery, Ltd., Fort Lauderdale, FL) maximized viewing conditions. By moving the light source, an observer control control the lighting conditions to optimize the incident light angle and the effect of reflected light on the formulation residue and minimize the light reflection. A light meter was used to set and verify various light-intensity levels.

The viewing distances for this study were dependent on the size of the equipment. In the pilot plant, a comfortable viewing distance of 1 ft was achievable (6). In a manufacturing facility, equipment sizes are larger and viewing distances are greater. Rather than define viewing distances for each piece of equipment, viewing distances of 5, 10, 15, and 20 ft were chosen to complement previously established data (6).

The viewing angle also is restricted by the equipment size and configuration. Therefore, residues were viewed over a range of 12–90° angles. The minimum angle resulted from a combination of a comfortable viewing angle and the viewing distance. Data at intermediate viewing angles of 30° and 45° and a perpendicular viewing angle (90° to the observer) were evaluated.

To minimize the effect of observer subjectivity, four observers viewed all samples. Sample concentration levels were spotted above and below the previously determined VRL (6) to allow for increased distances and higher intensity light, respectively. Therefore, the targeted spotting levels for the formulations were at the API's ARL (typically 4 μg/cm2 , the previously determined VRL [6]) and at the ±25% VRL levels.

Experiment

Samples were prepared by dissolving or dispersing tablets with methanol in an appropriately sized volumetric flask to achieve the targeted API concentration. Concentrations were targeted so that similar volumes were dispensed to form the residue spots because the volume controls the spot size. The sample volume was varied for concentration differences, and a complementary volume of methanol was added to each sample to achieve a constant spot volume. Methanol evaporated rapidly under a stream of nitrogen and left no solvent residue.

Two samples were applied to each 3 x 6-in. coupon. The spots were dried under a stream of nitrogen to prevent the material from oxidizing. If these steps were not taken, then oxidation would chemically alter the material and potentially change its visual properties. The dried spots were measured to determine the amount per unit area (μg/cm2 ) of each spot (see Table I).

Observers viewed the spots against a stainless steel background to more closely simulate larger manufacturing equipment and the ambient light encountered during observation. Three pieces of 27 x 34 in.-stainless steel were placed perpendicular to one another, forming a three-sided corner. The coupons were positioned at several angles to the observer within the stainless steel field (see Appendix, Figure 6).


Figure 1: The effects of distance and spotlight intensity on residue detection were studied in trials with four observers. Because a portable light´s intensity is a function of the distance from a stainless steel coupon, observers adjusted the angle of the incident light to the coupons to enable the best lighting conditions.
The ambient fluorescent light source controlled the lower end of the light-intensity range. Ambient light positioned directly above the viewing surface affected residue detection, therefore indirect ambient light was used to minimize reflected-light effects. The observer held the portable light source to simulate viewing under manufacturing plant conditions. The light intensity of the portable light source on the coupons was a function of the distance from the coupon and decreased with distance (see Figure 1). Observers moved the portable light as far as an arm's length from their bodies and turned the light to adjust the angle of the incident light to the coupons. This procedure provided the best lighting conditions for each observer.


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