FDA Guidance Aims to Reduce Adhesion Failures of Generic Patches
This article was originally published in The Gold Sheet
Executive Summary
FDA aims to help manufacturers improve the adhesive qualities of transdermal patches in a new guidance. Agency official says that poor adhesion is a major quality problem with these patches and has been the source of numerous recalls.
Manufacturers of transdermal patches should demonstrate that reasonable efforts were made to optimize the adhesive characteristics of the patch, said a new FDA draft guidance.
The guidance aims to help manufacturers design transdermal packages that effectively stick to the skin. It recommends ways to evaluate the adhesion performance of a transdermal delivery system (TDS) or topical patches for abbreviated new drug applications.
An agency official said at a recent industry meeting that poor adhesion is the top quality problem associated with these products.
The guidance is entitled “Assessing Adhesion with Transdermal Delivery System and Topical Patches for ANDAs.” The deadline for public comment is Aug. 1.
The guidance said that the amount of drug delivered into and through the skin from a TDS is dependent in part on the surface areas dosed.
“It is expected that the entire surface areas of a TDS should remain consistently and uniformly adhered to the skin throughout the duration of wear under the conditions of use included in the product label,” it said.
Yet during the course of the product’s wear, a TDS is expected to encounter strains, and the potential for detachment arising from the wearer’s movements, or by changes in temperature or humidity as well as daily exposure to water such as showering and contact with clothing, bedding or other surfaces.
“In such situations where a TDS is partially detached, there may be uncertainty about the resulting drug delivery profile and hence uncertainty about the rate and extent of drug absorption from the TDS. In addition as the potential for complete detachment of the TDS increases, so does the risk of unintentional exposure of the drug product to an unintended recipient.”
Applicants should consider adhesion as part of the Quality Target Product Profile and develop a “comprehensive strategy” to assess the adhesive attributes of the TDS.
The guidance states that “the characterization of the adhesive properties of a TDS should demonstrate that any conditions of labeled use for the R [reference] product relevant to TDS adhesion are substantiated for the T [test] product. Applicants should also ensure that the TDS can be removed from the packaging and peeled off the release liner without difficulty.”
FDA recommends a scoring system to evaluate adhesion and to determine whether the entire surface area of the TDS remains adhered for the duration of wear under the labeled conditions of use.
Applicants should use a five-point numerical scale to evaluate adhesion, with zero the lowest, meaning essentially no lift off the skin to four, meaning the TDS is detached and completely off the skin.
The recommended study design is a single-dose, randomized two-treatment two-period crossover study where all subjects are dosed with the same strength of the test and reference product.
Adhesion of each TDS should be evaluated at multiple time points. “For example, adhesion of a TDS with a seven-day wear period should be assessed at least daily, and at equally spaced time points.”
FDA issued the guidance to counter concerns about the adhesive quality of these products.
Adhesion Is Biggest Sticking Point
Yellela Krishnaiah of FDA noted at the American Association of Pharmaceutical Scientists annual meeting last October that lack of adhesive stability is the most widely reported quality defect of patches, accounting for almost one-third of all quality problems in the Medwatch database.
This is against the backdrop of a growing number of approvals for these products and their increasing popularity as a novel form of drug delivery.
Krishnaiah noted that FDA approved 52 transdermal patches in 2014, representing nine different product types, while only approving two patches in 1981 representing two product types.
He noted that the global sales for “potent” TDDS are significantly higher than for non-potent ones.
For example, the pain patch fentanyl comprises 31% of the market share, while nitroglycerin patches to treat angina constitute 27% of the market share and estradiol to treat hot flashes due to menopause constitute 14%.
Yet there are problems with adhesion failure for these highly potent drugs that are of particular concern to the agency.
Among the problems:
- Shire had to recall its Daytrana fentanyl patch in 2009 because the liner kept coming off.
- In 2004 Janssen Pharmaceutical recalled its painkilling Duragesic fentanyl skin patches because of leakages with the patches.
- There have also been numerous consumer complaints in Medwatch about the excessive stickiness of Climara, a transdermal patch used to relieve the symptoms of menopause.
Krishnaiah also said that crystallization in transdermal patches may lead to adhesion problems. He said that Schwarz Pharma recalled Neupro, a transdermal delivery system to treat early stage Parkinson’s disease in 2008 because of the formation of rotigotine crystals in the patches.