Comparison of VRL with the health-based limit
Figure 1: Visible residue limit versus 10 ppm (4 μg/cm2) limit. ADI is acceptable daily intake. Refer to Table II for letter key. (ALL FIGURES ARE COURTSEY OF THE AUTHOR)
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The health-based limit is directly related to the ADI as well as to manufacturing equipment and batch size parameters. Health-based
swab limits were calculated for several commercial formulations (see Table II). Other than ADI, a representative set of large
batch parameters was used: MDD = 1 tablet, DUB = 1,000,000 tablets, and SSA = 25,000 cm2. The health-based limits range from 2000 μg/cm2 for Aldomet, Isentress and Sinemet, to 10 μg/cm2 for Zocor (simvastatin). Using the same VRL data, the margin between the VRL data and the health-based limits is shown in
Table II and Figure 2. Differences between the health-based cleaning limit and the VRL cleaning limit range from a factor
of < 18 for Zocor to well over 30,000 for Aldomet.
Comparison of 10 ppm VRL with health-based limits
Figure 2: Visible residue limit versus health-Based and adulteration-based limits. ADI is acceptable daily intake. Refer to
Table II for letter key.
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The cleaning limit for a pharmaceutical residue will initially be determined by the health-based limit calculation. The cleaning
limit for residues that are not highly potent (i.e., that have a health-based limit greater than 10 ppm) or that defaulted
to the 10-ppm or adulteration cleaning limit. However, the visual cleanliness of equipment is a regulatory requirement. For
the category of pharmaceutical compounds that are not highly potent, the VRL is almost always lower than both the health-based
limit and the 10 ppm adulteration limit (see Table I). The average VRL for all APIs, excipients ,and formulations tested to
date is 1.1 μg/cm2 (21). For these compounds, the visual inspection is the most stringent assessment of equipment cleanliness.
With the health-based limit driving patient safety and the visual limit as the lowest cleaning limit, the adulteration-based
limit ceases to be of importance. The 10 ppm adulteration limit is bracketed by the visual limit on the low end and the health-based
limit on the high end. As a result, the VRL is the determining factor for equipment cleanliness.
It is also misleading to compare the visual limit with the adulteration limit as a margin of safety against cleaning failure.
Two examples illustrate this point. The adulteration limit of 10 ppm or 4 μg/cm2 for Demser is two times greater than the VRL of about 2μg/cm2. The health-based limit for Demser is 400μg/cm2, which is about 200 times greater than the VRL, which is a much greater margin of safety. The adulteration limit of 10 ppm
or 4 μg/cm2 for Zocor is about seven times greater than the VRL of < 0.57 μg/cm2. The health-based limit for Zocor is 10 μg/cm2, which is about 18 times greater than the VRL. Relating the VRL to the 10-ppm limit gives an artificially greater risk of
failure compared with an evaluation of the VRL to the health-based limit. Data has consistently shown (18, 21) that when the
ADI for a compound is > 100μg/day, the health-based cleaning limit is higher than the 10-ppm adulteration-based cleaning limit
and the margin is greater compared to the VRL of the compound. It is scientifically justifiable to compare the VRL with the
health-based limit in these cases.
Conclusion
A scientifically determined VRLprogram makes a 10 ppm adulteration cleaning limit obsolete for a large number of pharmaceutical
compounds. When the VRL is lower than 4 μg/cm2, the visual limit satisfies the dual regulatory requirements of providing visually clean manufacturing equipment and eliminating
residual carryover that can lead to toxicological or adulteration concerns of the subsequent formulation.
Richard Forsyth is a private consultant for cleaning validation and good manufacturing practice issues, tel. 610.948.2970, mr.rich.forsyth@gmail.com
Submitted: Mar. 23, 2009. Accepted: Apr. 10, 2009.
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