Ruggedness of Visible-Residue Limits for Cleaning (Part II) - Pharmaceutical Technology

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Ruggedness of Visible-Residue Limits for Cleaning (Part II)
The author challenges current detection methodologies.


Pharmaceutical Technology
Volume 35, Issue 3, pp. 122-128

Results and discussion


Table VI: Visible-residue limit (VRL) determination.
The results of the VRL determinations for both the random and sequential presentations are shown in Table VI. The random coupon presentation provided comparable results to the sequential coupon presentation. For both the sequentially and the randomly presented coupons, the experimentally determined VRLs were lower than the previously determined VRLs for three of the compounds and higher for the fourth. The lower VRLs resulted from spotting lower concentrations than in the initial VRL determination. The initial determinations were deemed acceptable because they were sufficiently lower than the swab limit or ARL (2). The sample preparation used for the more recent VRL determinations resulted in lower overall VRLs and a more rugged data set (6).


Figure 2: Sequential coupon presentation.
Aside from the presentation of the coupons, the other significant difference was the number of blank coupons presented. The VRL determination using the random coupon presentation involved a greater number of blank coupons (i.e., nine) than did the sequential coupon presentation (i.e., four). It was felt that the additional blank coupons would increase the physical separation of the soiled coupons, limit direct side-by-side comparisons of the soiled coupons, and enable a more independent assessment of each of the individual soiled coupons.

The consistent results obtained using either method of coupon presentation answered a long-standing question. The sequential coupon presentation raised a concern that the decreasing residue concentrations and the close proximity of adjacent residues might lead observers to see residues where they might not ordinarily have identified a visible residue.

Because the two methods of coupon presentation result in the same VRL, which way should one present coupons for VRL determinations? The sequential coupon presentation offers marginal advantages in the following areas.

  • It provides ease of setup and recording. The random coupon presentation requires slightly more paperwork with its matrix approach.
  • It is easier to do one or more multiple compounds/residues at a time. The random approach is more suited to multiple determinations.
  • It makes more efficient use of coupons, because the random approach will use additional coupons to fill in the square matrix as necessary.

As noted above, the primary advantage of the random presentation was to increase the physical separation of the soiled coupons and limit direct side-by-side comparisons.

To ensure rugged, reproducible results, however, the observers must be thoroughly trained. It is always emphasized during training that the VRL is a physical property of the residue and that the ability to see every spotted residue is not an expectation. Observers are then more likely to report what they see rather than what they think they are expected to see. Therefore, the optimal coupon presentation depends on the level of training for the coupon preparation and the observers. For newly trained personnel, the random coupon presentation might be appropriate, and the sequential coupon presentation might be more appropriate for more experienced personnel.


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