Is visually clean = clean?!

One of the common misconceptions about cleaning that visually clean surfaces are by default clean. While any equipment need to be visibly clean to be considered clean, this condition is not by itself a sufficient evidence of reduction of product residues to safe limits. Visible residue limit studies provide guidance for manufacturers on the minimum visible surface concentration of a specific product on a particular material of construction. Once this visually detectable threshold is established, it can be compared to health based exposure limits (calculated utilizing the PDE) to assess if appropriate visual inspection can prove that a piece of equipment is clean and safe to be used in a GMP process.

In 1993, Fourman and Mullen suggested only 4 ug/cm2 as the visible residue limit of many materials used in pharmaceuticals. Subsequent studies brought this threshold below 1 ug/cm2. This shows the ability of visual inspection to detect product residues at very low concentrations. Moreover, the ability to visually detect very low surface residues encouraged some researchers to recommend visible residue limits as a replacement of chemical analysis. In 2018, EMA Q&A publication on health-based exposure limits and cross contamination justified the use of visual inspection as an alternative to analytical testing at each change over conditional that a documented risk assessment can prove that the visible residue limit is higher than the established health-based exposure limits.

However, the determination of the visible residue limit is a problematic process. In the lab setting, it is possible to spike known quantities of product on the surface of a coupon then determine the minimum concentration that is visibly detectable. In manufacturing settings, many variables can affect the ability to visually detect certain residues in equipment. The solvent in use, surface material of construction, lighting condition, inspection distance, inspection angle, and the light color (light temperature). While in the lab, inspecting a soiled coupon can be a hassle-free, it is usually difficult to provide similar inspection condition to dirty manufacturing equipment or to specific parts of these equipment which brings the same question again, is visually clean = clean? from what we presented above, this can only be a valid assumption once a robust quality risk assessment has been completed based on the outcome of a controlled visible residue limit study.

References

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

EMA Questions and answers on implementation of risk-based prevention of cross-contamination in production and ‘Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’ 2018

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).

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