A Single Adulteration Limit for Cleaning Validation in a Pharmaceutical Pilot-Plant Environment - Pharmaceutical Technology

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A Single Adulteration Limit for Cleaning Validation in a Pharmaceutical Pilot-Plant Environment

Pharmaceutical Technology

Visible residue limits

The determination and use of VRLs demonstrated that the vast majority of formulations and APIs had VRLs lower than 100 μg/25 cm2 swab (4 μg/cm2 ) (14, 15). Of the 54 formulations evaluated to date, all were well below 100 μg/25 cm2 swab. Of the 102 APIs, excipients, and detergents evaluated, only five excipients and one API had VRLs greater than 100 μg/25 cm2 swab. Limited applications of VRLs have saved resources without sacrificing quality (16, 17).

Swab area. An often cited adulteration limit was 10 ppm or 100 μg/swab, using a swab area of 25 cm2 for cleaning validation. This amount was a feasible limit. The swab area was not as important as the scientifically justified limit but was a practical compromise to obtain a representative residue sample against the occasional need to swab smaller pieces of equipment.


The factors that affect the adulteration calculation made it an impractical situation for a pilot-plant application. A constantly changing adulteration limit caused documentation problems and made compliance difficult to enact and enforce.

An alternative single adulteration limit was proposed for compounds with ADIs >100 μg/day. An adulteration limit of 100 μg/25 cm2 swab (4 μg/cm2 ) was satisfactory as long as the equipment was visually clean. This limit ensured that there were no toxicity cross-contamination problems and that the equipment was visually clean. A single, scientifically determined adulteration limit is logical, practical, achievable, and verifiable, making it a justifiable adulteration limit for a pilot-plant facility.

Richard J. Forsyth* is an associate director in global clinical GMP quality with Merck & Co., Inc., WP53C-307, West Point, PA 19486, tel. 215.652.7462, fax 215.652.7106,
Alain Leblanc is a facility manager at Merck Frosst Canada's Center for Therapeutic Research. Mark Voaden is head of service for validation and compliance for facilities with Merck, Sharp & Dohme in the United Kingdom.

*To whom all correspondence should be addressed.

Submitted: June 20, 2006. Accepted: Aug. 24, 2006.

Keywords: adulteration limit, cleaning validation, compliance, pilot plant.


1. US Food and Drug Administration, Guide to Inspection of Validation of Cleaning Processes, (Rockville, MD, Office of Regulatory Affairs, 1993).

2. Food, Drug and Cosmetics Act, Chapter V, Section 501(a)(1), 1938.

3. FDA, CDER Human Drug CGMP Notes, 9 (2) (Rockville, MD, Division of Manufacturing and Product Quality, Office of Compliance, Center for Drug Evaluation and Research, 2001).

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

5. A.O. Zeller, "Cleaning Validation and Residue Limits: A Contribution to Current Discussions," Pharm. Technol. 17 (10), 70–80 (1993).

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


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