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

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 )


Table I: Safety factors for the determination of cleaning validation acceptance limits.
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 manufacturing situation.

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.


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