The correct adhesion of a transdermal patch to skin throughout the established time of use is key to guarantee the effective administration of the dose declared in the prescribing information.

In this article we dive into the different methods to quantify the adhered percentage of a transdermal patch, analyzing the advantages and disadvantages of each one of them.

The importance of patch adherence

Patch adhesion is currently a regulatory requirement which involves a formal evaluation to grant the approval of a generic product. 

As a consequence, there are international guidelines, mainly those issued by FDA and EMA, that have settled non-inferiority statistical criteria for patch adhesion as a requirement to be accomplished, besides the bioequivalence and sensitization/irritation demonstrations, in order to approve the regulatory package of a generic transdermal medicinal product.

FDA employs a scoring system to quantify patch adhesion (each one comprising ranges of percentages which are different in their span) and, as main indicator, compares the mean adhesion scores observed during the use of the products (Test and Reference). EMA, in turn, mainly considers the percentages of adhesion obtained throughout the use of the products and focuses into the last evaluation time of adhesion for the formal comparison.

To obtain the percentages of  (from which the FDA can be obtained), guidelines recommend to use visual inspection- of trained observers- or the use of dot-matrix templates. This becomes an important defeat when the backing of the transdermal patch is opaque.

Given the condition required to accomplish the non-inferiority criteria on adhesion, and taking into account that the detachments of a transdermal patch during use are mainly irregular and can develop in several parts of the system, the use of templates with or without grid (matrix) seems to be more appropriate than the trained visual observation to obtain an adequate precision.

In this article we evaluate the pros and cons of two methods which have proved to be good in practice and that are being currently used to quantify the adhesion of generic patches during the clinical studies required for the regulatory filing of transdermal medicinal products. An alternative method proposing the use of photos and software is also mentioned.

Quantitative Methods to Evaluate Patch Adhesion

The analysis of two methods used to quantify the percentage of patch adhesion during use follows:

1. Template with Grid and Ratio of Number of Squares: 
   
   It comprises the transcription of the detached zones of the patch to a transparent template having the exact shape of the patch, with a pre-printed grid, and obtaining the following ratio between the number of detached squares and the total number of squares of the grid:
   
   % Adhesion= [(1 – (Sum of squares with detachments) / Total No. of squares] x 100%
   
   According the guidelines which recommend this method, those detachments that involve partial areas of the grid squares should be accounted as if the detachment occupies those full squares.
   
   
2. Template without Grid and Ratio of Area Weights:
   
   It comprises the transcription of the detached zones of the patch to a transparent template having the exact shape of the patch, taking a paper copy of the template, cut the shapes of detached areas and that of total patch area, and obtaining the following ratio between the weights of such areas:
   
   % Adhesion= [1 – (Sum of Weights of detached areas / Total Patch Area Weight)] x 100%

Both of these methods that quantify patch adhesion are mainly affected by operator biases, and the one originated by the need of placing the template onto the applied patch, which could translate into a non-desired pressure over the patch and re-stick it, altering the evaluation in that way (most of transdermal patches use pressure sensitive adhesives in their formulations). Nonetheless, such biases should be compensated if a trained operator performs the evaluation of Test and Reference products in each treatment period of the study evaluating patch adhesion, exercising a gentle and careful placement of the template over the applied patch.

Generally speacking, the detachments of a transdermal system are irregular in shape and/or can appear in different zones of the patch. In this sense, the use of a grid to calculate the detached areas would not offer precision advantages in the measurement when compared to the method that uses weights ratio, this becoming more evident if the backing layer of the patch is opaque. In this latter case, an intensive training is required, including the observation of the patch from lateral angles and appropriate lighting conditions to maximize the precision during the transcription of detached areas onto the template.

Which are the Pros and Cons of these Methods?

Method 1: Template with Grid and Ratio of Number of Squares

Situation: A same area detached of the patch, in different zones of the grid pre-printed in the template. (The example below was magnified to better explain the bias).

Method: Count all squares that involve the transcribed detached shape and relate it to the total number of squares of the grid, to obtain the % of detachment, and by difference, the % of adhesion.