in which ADI is the acceptable daily intake of the active A1 (%) and is equal to the minimum therapeutic daily dose × safety factor; MDD is the maximum daily dose for product B (mg); BS is the batch size of the product B (mg); SA is the swab area (cm2 ); and ESA is the equipment surface area shared with product A and product B (cm2 )
For the MACO calculation using therapeutic dose unit and safety factor approach, different safety factors have been suggested
for various formulation types (see Table I). Nonetheless, a safety factor of 1000 is widely used because it can be thought
of as comprising a factor of 10 for adjusting a therapeutically effective dose to a therapeutically noneffective dose, a factor
of 10 to accommodate for individual variability in response, and a factor of 10 for making cleaning validation studies robust.
The dose-reduction fraction is a measure of the risk involved and is assessed by the manufacturer depending on the actual
Table I: Safety factors for the determination of cleaning validation acceptance limits.
When it comes to TFs, applying the ADI or therapeutic dose–safety factor approach for MACO calculations is challenging for
several reasons, including:
- TFs are not divided into individual dosage units, unlike solid and liquid formulations.
- Dose size per application varies depending upon the total lesion area. Hence, it becomes difficult to establish minimum or
maximum daily doses.
- No standardized approach exists for determining dose size. That is, the amount of product recommended to be applied per area
of skin per treatment varies from manufacturer to manufacturer.
- The pharmacological effects produced by systemic absorption of the API through oral ingestion are taken into consideration
when determining ADIvalues. In the case of TFs, occasionally enough API is absorbed to cause systemic effects. TFs produce
local toxicity even at low doses.
Therefore, a need arises for establishing a rational method to determine cleaning validation acceptance limits for TFs. This
article establishes a method for the calculation of MACO for the APIof a subsequently manufactured TF by taking into account
possible worst cases.
Worst case I
Assume that active A1 is marketed in strengths of 2%, 3%, and 5% and that product B can be applied on the entire body two to four times per day. The criterion set by Long and Finley can be used to determine
the total amount of TF (e.g., cream and ointment) applied on the entire body in one application (6). The criterion describes
the dosage of TFs in terms of fingertip units (FTUs). One adult FTU is the amount of ointment or cream expressed from a tube
with a standard 5-mm diameter nozzle, applied from the distal crease to the tip of the index finger. One FTU contains approximately
0.5 g of cream, and it is assumed that approximately 20.25 g (~40.5 FTUs) of cream is needed to cover an adult body. On the
basis of the these assumptions, the maximum amount of product B that can be applied daily would be
20.25 g/application × 4 application/day = 81 g/day
To determine the maximum amount of product applied per treatment for other TFs such as medicated shampoos, lotions, toothpaste,
and mouthwash, one could consult the European Commission's Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation or the manufacturer's in-house criteria (7). For these formulations, the amount of product applied per treatment is fixed;
therefore, the maximum amount of product applied per day depends on the maximum number of times the product is used daily.