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Ruggedness of Visible-Residue Limits for Cleaning (Part II)
Visual inspection is always a component of a cleaning-validation program, and routine visual inspections for equipment cleanliness are a crucial part of day-to-day operations in a pharmaceutical facility (21 CFR 211.67 (b)-6). Visible-residue limits (VRLs) can be established for the active pharmaceutical ingredients (APIs), excipients, and detergents processed in the facility. The VRL of the API is generally the greatest concern because the API is the most potent component of the formulation. If the VRLs are lower than the health-based and adulteration-based acceptable residue limits (ARLs) as determined by the company, then the VRL is a viable approach to assess the equipment cleaning in the facility (1).
Sample preparation and viewing parameters for VRLs have been established for pilot-plant and commercial-manufacturing facilities in previous studies (1, 2). A solution or suspension of the API in methanol was applied at different concentrations to stainless-steel coupons, thus resulting in residues of uniform size. Studying viewing parameters, such as viewing distance, viewing angle, light intensity, residue composition, and observer subjectivity resulted in the optimal viewing conditions to detect visible residues. These viewing conditions in the pilot plant were set at 18 in., 30°, and > 200 lux, respectively. For commercial facilities with larger, fixed equipment, the viewing inspection parameters can be restricted. The limits for acceptable viewing conditions were determined to be ≤ 10 ft, ≥ 30°, and > 200 lux. A discussion of the applications of VRL use and the associated risks concluded that the potential for a cleaning failure was small when a well-controlled VRL program was employed (3–5).
The subjectivity of the observers and the appearance of the dried residues remained as 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 the VRLs of APIs in development at one site. In addition, a study of VRL determinations of five APIs at multiple sites helped to address the issues of observer subjectivity as well as residue sample preparation to better define the ruggedness of VRLs for cleaning (6).
The complete set of VRL data was examined for distribution and trends (6). The original VRL data set was compared with the subsequent data set and demonstrated improvements in the procedure and technique. Refining the testing range to lower concentrations improved the procedure. It resulted in more accurate VRLs and fewer in which the lowest spotted concentration was visible. The training of personnel in VRL appearance and detection both in the lab and in the field improved the technique of visual observation. The VRLs of the APIs, excipients, and formulations showed a correlation between the VRL of the API and its formulation. Appearance of the residues depends on the amount of API residue being spotted and the volume of spotting solvent, which translates to the concentration of the resulting residue. VRL residues can appear as a uniform residue at higher concentrations, or as a ring, which is typical of lower concentrations. Methanol is consistently used as the 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. 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.
Despite the extensive ruggedness data generated, the following questions about the constant parameters of the VRL studies
remain to be answered:
These issues will be the subject of future work and will require significant resources in time, material, and data to arrive at meaningful conclusions. The question explored in this study was the most straightforward: whether the presentation of the residues to the observers affects the VRL determination. The original study design anticipated that the lower concentration residues would not be visible. For a high percentage of samples, however, the VRL was determined to be less than the lowest residue concentration spotted on the coupons. The consistent ability of observers to see the lowest spotted residue prompted the question of whether they saw the residue because they knew there was a residue present. This was a legitimate concern when applied to clean equipment inspection, where the expectation is that there would be no residue present.
Results and discussion
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.
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.
The presentation order of the coupons appears to have no effect on the determination of VRLs. Both a sequential presentation from high to low concentration and a random presentation resulted in the same conclusions for VRL levels, thus confirming the ruggedness of the VRL determination.
Richard Forsyth is a senior consultant with Hyde Engineering + Consulting, 6260 Lookout Rd., Suite 120, Boulder, CO 80301, tel. 303.530.4526,
fax 303.581.0839, email@example.com
Submitted: Oct. 1, 2010. Accepted: Dec. 1, 2010.
1. R.J. Forsyth and V. Van Nostrand, Pharm. Technol. 28 (10), 58–72 (2004).
2. R.J. Forsyth and V. Van Nostrand, Pharm. Technol. 29 (10), 152–161 (2005).
3. R.J. Forsyth and V. Van Nostrand, Pharm. Technol. 29 (4), 134–140 (2005).
4. R.J. Forsyth, J.L. Hartman, and V. Van Nostrand, Pharm. Technol. 31 (4), 134–140 (2007).
5. R.J. Forsyth et al., Pharm. Technol. 30 (11), 90–100 (2006).
6. R.J. Forsyth, Pharm. Technol. 33 (3), 102–111 (2009).