Setting Cleaning Validation Acceptance Limits for Topical Formulations - Pharmaceutical Technology

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Setting Cleaning Validation Acceptance Limits for Topical Formulations
There is a need for current cleaning validation methods to be used for topical formulations. The authors highlight the issues and challenges encountered.


Pharmaceutical Technology
Volume 32, Issue 1

For calculating minimum daily dose for product A, A = 1.75 mg/cm2 , C = lowest available strength/concentration of the API in the product A = 2%, and F = 1 (day–1 ). Therefore, the minimum daily dose for product A = 0.04 mg/cm2 /day, and the maximum daily dose for product B = 6.99 mg/cm2 /day (using A = 1.75 mg/cm2 , C = 100%, and F = maximum number of times product B is applied per day = 4). One point to remember is that the calculation for the maximum daily dose for product B is independent of the concentration of API present. Therefore, for a batch size of 300 kg (product B) the MACO value may be calculated as

MACO = (minimum daily dose for product A batch size for product B) / (safety factor maximum daily dose for product B)

MACO = (0.04 mg/cm2 /day 300 kg 106 mg/kg) / (1000 6.99 mg/cm2 /day) = 1500 mg

Comparing the previous cases, one can observe that the MACO value obtained from the second worst-case scenario is four times less than the value obtained from the first worst case. After thorough analysis of the calculations, however, it can be concluded that the MACO value obtained from worst case II is equal to the MACO value from worst case I divided by the maximum number of applications per day for product B. Therefore, if MF is the maximum number of times product B that can be applied daily, the MACO value from worst case II can be mathematically expressed as:

MACO = (0.1% C BS SA) / (MF ESA)

Therefore, it is the concentration (i.e., percentage) of active A1 and the number of doses per day for product B make a difference when it comes to the calculation of MACO values.

Criterion based on permitted daily exposure

Another approach for determining MACO uses toxicity data. This strategy is generally used in the industry when dealing with contaminants for which therapeutic doses are not known (e.g., intermediates, precursors, and cleaning agents).

For many drugs, using a safety factor of 0.1% of the lowest recommended therapeutic dose may be reasonable and will produce MACO values at a safe level. This approach cannot be used indiscriminately, however, for several reasons. First, for topical products, the therapeutic doses are not well defined, as discussed previously. A second issue is the mechanism by which toxic effects are produced by the drug. For many drugs, the mechanism by which the toxic effects are produced might be unrelated to the mechanism of pharmacological action. For instance, a drug may cause developmental toxicity (e.g., birth defects) or cancer by a mechanism unrelated to its pharmacological effects. In these cases, using the 0.1% safety factor on the therapeutic dose may still be appropriate but would need to be used with greater caution because the toxic effects may be produced below the safe therapeutic levels.

For these reasons, many manufacturers also include an approach based on toxicity data to calculate MACO values. For many drugs, this approach may be reasonable and has produced MACO values similar to the traditional therapeutic dose/safety factor approach. The basic value of this approach is that a limit can be calculated for cleaning validation purposes based solely on the toxicity of the API present in the TF.


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