Setting Cleaning Validation Acceptance Limits for Topical Formulations - Pharmaceutical Technology

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PharmTech Europe

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

The lowest available strength of active A1 in the TF is 2%. This means that approximately 1.62 g (2% of 81 g) of active A1 if present in 81 g of product B will produce its pharmacological effects. Taking into account a safety factor of 1000, active A1 should not exceed 0.00162 g (1.62 g divided by 1000) in 81 g of product B.

Assuming that the batch size for product B is 300 kg, MACO of active A1 to product B can be calculated as

MACO = (0.00162 g 300 kg 106 mg/kg)/81 g = 6000 mg

In other words, MACO of the active A1 to a batch of product B should not be more than 0.1% of the lowest marketed strength–concentration for active A1. For the example above, MACO can also be calculated by

MACO = 0.1% 2% 300 kg 106 mg/kg = 6000 mg

From the previous example, it is clear that to calculate MACO of the API in any subsequently manufactured TF, the only information needed is the lowest marketed strength of the API in the TF being cleaned and the batch size of subsequently manufactured finished product. The MACO calculation is independent of minimum and maximum daily dose for product A and product B, respectively.

MACO in terms of amount of API per surface area of equipment (for swab sampling) can be determined by using the following equation:

MACO = (0.1% C BS SA)/ESA

in which, C is the lowest available strength of the API in the product A (%), BS is the batch size of the product B (mg); SA is the swab area (cm2 ); ESA is the equipment surface area shared by product A and product B (cm2 ). This equation can be further modified to calculate the residue limits (mg/mL) in the rinse sample by using total volume (TV) of rinse or wash solvent portion (mL) and volume (V) of rinse sample collected (mL) in place of ESA and SA, respectively.

Worst case II

Following the same assumptions and examples described in worst case I, therapeutic doses for TFs may be established in terms of mg/kg body weight/day or mg/cm2 /day units. According to Long and Finley, 1 FTU covers about 286 cm2 of skin surface area. This implies that approximately 1.75 mg of the TF is applied per each square centimeter of skin surface area. The dose size for TF may be calculated using the following equation,

Daily dose (mg/cm2 /day) = A C F

in which, A is the amount of TF applied in one application per unit area of skin (mg/cm2 ), C is the concentration of the API in the TF (%), and F is the frequency of application per day (day–1 ).


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