Risk-Management Assessment of Visible-Residue Limits in Cleaning Validation - Pharmaceutical Technology

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Risk-Management Assessment of Visible-Residue Limits in Cleaning Validation
A risk-management assessment of visible-residue limits (VRL) in cleaning validation of pharmaceutical formulations was conducted for both pharmaceutical pilot plant and manufacturing facilities. The authors discuss how potential risks were identified, analyzed for probability, considered for seriousness, and controlled through avoidance or mitigation. These opportunities for VRL implementation then were identified for both pilot plant and manufacturing settings.

Pharmaceutical Technology

The interval of use (manufacturing campaign) and the interval between end of use and cleaning are process parameters that must be validated. Theoretically, the more batches a piece of equipment processes, the greater the soil load, and the more difficult it is to clean. Hence, the need to challenge cleaning cycles after campaigns of different lengths. Nonetheless, some products' physical, chemical, and surface adhesion properties do not change over the campaign length. For manufacturing these products (dry processing), certain types of equipment do not allow residues to accumulate over time by design. This equipment is sloped for gravity removal of product, whereby the soil load (both the amount and nature of the soil) after one batch is comparable to the load after multiple batches within a campaign (i.e., "freely draining"). This can be verified by visual inspection on a routine basis. For stable products, manufactured in freely draining equipment, there should be low-to-no process risks with respect to extending a validated campaign length based on visual inspection. Routine inspections for visual cleanliness would mitigate any potential process risks with carryover of process residuals and confirm cleaning performance. This same rationale could be applied to extending validated times for the interval between the end of use and equipment cleaning.

Once a cleaning process is validated in a GMP manufacturing environment, the process should be monitored periodically to ensure consistent and robust performance. Independent visual inspections should be incorporated into the periodic assessment program to confirm that cleaning processes remain in a state of control. A second person should check for visual cleanliness, and the frequency of recleaning is an appropriate metric for assessing cleaning performance. This additional control helps to ensure robustness of the validated cleaning procedure. With an appropriate VRL program, visual inspection may be used rather than surface and rinsate testing to demonstrate continued consistent cleaning performance.


Visible-residue limits (VRL) have been evaluated for pilot plants and manufacturing facilities from a risk-assessment perspective. Opportunities for VRL implementation have been identified with the acceptable mitigation of the associated risks.


1. D.W. Mendenhall, "Cleaning Validation," Drug Development and Industrial Pharmacy 15 (13), 2105–2114 (1989).

2. D.A. LeBlanc, "'Visually Clean' as a Sole Acceptance Criteria for Cleaning Validation Protocols," PDA J. Pharm. Sci. and Technol. 56 (1), 31–36 (2002).

3. US Food and Drug Administration, Guide to Inspection of Validation of Cleaning Processes, (FDA, Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs, Rockville, MD, July 1993).

4. R.J. Forsyth, V. Van Nostrand, and G. Martin, "Visible Residue Limit for Cleaning Validation and Its Potential Application in a Pharmaceutical Research Facility," Pharm. Technol. 28 (10), 58–72 (2004).

5. R.J. Forsyth and V. Van Nostrand, "The Use of Visible Residue Limit for Introduction of New Compounds in a Pharmaceutical Research Facility," Pharm. Technol. 29 (4), 134–140 (2005).

6. R.J. Forsyth and V. Van Nostrand, "Application of Visible Residue Limit for Cleaning Validation in a Pharmaceutical Manufacturing Facility," Pharm. Technol. 29 (10), 152–161 (2005).

7. G.L. Fourman and M.V. Mullen, "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations," Pharm. Technol. 17 (4), 54–60 (1993).

8. K.M. Jenkins and A.J. Vanderwielen, "Cleaning Validation: An Overall Perspective," Pharm. Technol. 18 (4), 60–73 (1994).

9. R.J. Forsyth and D. Haynes, "Cleaning Validation in a Pharmaceutical Research Facility," Pharm. Technol. 22 (9), 104–112 (1998).


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