Statistically Justifiable Visible Residue Limits

The standard of visual cleanliness is
commonly applied to the evaluation of
surface contamination. Numerous published
studies have examined the visually
clean standard as a means of verifying
cleaning effectiveness in pharmaceutical
manufacturing, and methods for the
quantitation of visible residue limits (VRLs)
have been provided. Current methods
for establishing VRLs are not statistically
justifiable, however. The author proposes a
method for estimating VRLs based on logistic
regression.

Visually clean (VC), a term that refers to inspection with the naked eye, is a common cleanliness standard employed for evaluating surface contamination and cleaning in high-technology manufacturing, including that of pharmaceuticals, where surface cleaning is of utmost importance. The importance of the VC standard for pharmaceutical manufacturing is evident in the following facts:

• It is one of the acceptance criteria for establishing the limits for cleaning-validation (CV) studies (1)
• Visual examination of equipment surfaces for cleanliness immediately before use is required by good manufacturing practice (GMP) regulations (2)
• Even before the issuance of the GMP regulations, most companies used to a VC standard (3)
• A VC approach to controlling cross-contamination in processing and manufacturing operations provides a practical and effective method of risk management (4, 5)
• It is one of the means of evaluating cleaned surfaces during the development, optimization, and validation of cleaning processes
• It is the only tool available to operators for examining equipment surfaces to verify that they have been cleaned effectively
• Manufacturers employ it for routine monitoring of the cleaning process.

Table I: Advantages and disadvantages of the visually clean standard.

Many manufacturers believe that compliance with a requirement that the surface be visually clean ensures only the absence of gross amounts of contamination and may be regarded as the lowest cleanliness standard because of its subjectivity and variability. Many studies of VC as one of several criteria for evaluating surface contamination have been published. In light of its advantages and disadvantages, which are listed in Table I, visual inspection of surfaces, combined with a few simple tools, is still regarded as an effective and inexpensive primary way for evaluating surface cleanliness.


Visually clean criterion for CV studies

In the pharmaceutical industry, cleaning is defined as limiting contamination to a level below practical, achievable, justifiable, and verifiable limits. CV is the documented evidence of cleanliness.

Common bases for establishing CV acceptance limits, as described in literature and in regulatory guidance documents, include the following (6, 7):

• Therapeutic daily dose
• Toxicological data
• The 10-ppm criterion
• The VC criterion.

Table II: Definitions of visually clean and visible residue limit from the literature.

The method that yields the lowest acceptance limit is selected, and the value is considered the maximum allowable carryover (MACO) limit for CV studies. The VC criterion still holds, however, and is independent from the established MACO limit. Regardless of whether the established visible residue limit (VRL) is lower or higher than the MACO values, noncompliance with the VC requirement indicates the failure of CV. The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme (PIC/S) requires the VC criterion to be verified through well-documented spiking studies before it can be used for CV studies (1).

Because the VC standard is relevant to many technological areas, tremendous efforts have been devoted to defining and devising novel and efficient ways to develop justifiable and quantifiable VRLs for monitoring and validating cleaning procedures. Table II lists some definitions of the VC standard from the literature. The VC standard and VRLs are based on the following common principles:

• Particles deposited on the surface tend to reduce the reflection of light.
• The unaided human eye (with or without corrected vision) can detect particles as small as 40–50 μm under ideal conditions (8).
• The viewer’s state of mind could affect his or her ability to detect the residue visually (e.g., the residue might be visible but unseen because the observer is inattentive).
• The brighter a residue in comparison with its background, the higher the probability of its detection through visual inspection.

Although the VC standard may be highly subjective, personnel have successfully quantified VRLs by establishing well-controlled experiments and programs. For industries other than pharmaceuticals, variables and parameters associated with the VC standard (e.g., viewing distance and light intensity) have been quantified and well documented (8).

The most popular method, henceforth referred to as the current method, for determining VRLs in the pharmaceutical industry involves spiking the selected material surface with known amounts of residue at concentrations of about 0–10 μg/cm². Trained inspectors then examine the surfaces under controlled viewing conditions (e.g., light, viewing angle, and viewing distance) for the presence of residue (9–11). The lowest level of residue that is detected is then considered the VRL for that particular residue. The only drawback with the method is that it is not statistically justifiable and, hence, not scientifically definable. The primary objective of this article is to establish a method for setting scientifically and statistically justifiable VRLs and to provide a meaningful definition of the VC standard.

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