Transdermal patches, or Transdermal Drug Delivery Systems (TDDS), are designed to deliver active substances through the skin directly into the bloodstream at a prolonged and constant rate. Due to their unique attributes, they present different challenges when controlling their quality, efficacy, and safety. In this article, we explore the mechanism in which they work, their regulatory requirements, and how Kymos Group can assist you in their quality control and analysis.

Transdermal patches consist of a multilayered structure, usually comprising a drug reservoir, a control membrane, an adhesive layer, and a protective liner. When the patch is applied to the skin, one or more active substances are released from the reservoir, diffuse through the control membrane and adhesive layer, and then penetrate the intact skin to reach the systemic circulation.

Unlike topical products, which are designed to affect only the area to which they are applied, transdermal patches are intended for systemic effects, so they differ in purpose, mechanism, and formulation complexity. For that very reason, when analyzing topical products, In-Vitro Release Tests (IVRTs) and In-Vitro Permeation Tests (IVPTs) could allow to skip clinical studies (EMA draft guideline of 2018 on “quality and equivalence of topical products”), but when dealing with transdermal patches, IVRT and IVPT cannot substitute the clinical part.

Regulatory Overview and Testing of Transdermal Patches

As mentioned before, due to their characteristics, regulatory agencies have defined suitable tests to characterize and control the critical quality attributes (CQAs) of transdermal patches.

The main reference framework was released by the European Medicines Agency (EMA) in 2014: “Guideline on quality of transdermal patches (EMA/CHMP/608924/2014)”. This document addresses new marketing authorization applications for transdermal drug delivery systems and outlines necessary tests and CQAs that must be evaluated to ensure safety, efficacy, and quality. This document in conjunction with relevant Pharmacopeial monographs and ICH and CHMP/CVMP guidelines is the basis on which we base our service catalogue for transdermal patches.

Kymos Group provides full support during the whole life cycle of a transdermal patch drug product, from formulation, development, and stability to routine analysis and reformulations. We have experience analyzing CQAs referenced in the EMA guidance such as general quality control analyses (assay, related substances, appearance, etc.), residual solvents determination, active substance crystallization, extractables and leachables testing, IVRT and IVPT, and specific transdermal patches tests such as adhesion properties.

CMC & Quality Control Testing of Transdermal Patches

Quality Control and CMC analyses are crucial to ensuring the safety and efficacy of transdermal patches. Suitable tests that are to be performed on all dosage forms including TDDS are:

  • Assay: Determination of the drug content in the transdermal patch, ensuring that it meets the specified concentration of the active substance.
  • Appearance: Assessment of the visual and physical properties of the transdermal patch to ensure that it meets the required standards. In the specific case of TDDS, it comprehends general attributes like color or shape, but it also includes specific ones such as the adhesive matrix or the detachment of the release liner.
  • Related substances: Identification of impurities and degradation products and ensuring that their levels are within acceptable limits.

Then we have specific QC analyses that are specific or present great importance when dealing with transdermal patches:

  • Active substance crystallization: Crystal formation is a quality deficiency since it could affect the efficacy and safety of the patch as it reduces the amount of active substance available to be released and absorbed by the skin. A qualitative analysis for the determination of crystals is crucial.
  • Residual solvents: The detection and quantification of residual solvents is critical in transdermal patches as they may affect adhesion and permeation enhancements, and stricter limits than those in ICH Q3C could be needed.
  • Extractables and Leachables: Due to the nature of the transdermal patch dosage form, detection of extractables that may be extracted from the multilayered structure, drug reservoir, and primary packaging when in the presence of a solvent, and contaminants that leach into the drug product are vital.
  • Adhesive properties: Specific to transdermal patches, the adhesion/cohesion properties should be characterized and satisfactorily controlled to ensure the patch remains attached to the skin for the required duration. They include analyses such as peel force tests, adhesive strength tests, tack tests, etc. with equipment that Kymos could adapt and implement methods for.
  • Microbiology: Depending on the application, sterility testing is of vital importance, and it could also require analysis of microorganisms and investigation of specific pathogens.
  • In-Vitro Release Test (IVRT)/Dissolution Test: To meet the required specifications for consistent and controlled drug delivery, it is mandatory to measure the drug release rate from the patch. As stated in the guidance from the EMA, in vitro release and dissolution tests are described as the same analytical method when dealing with TDDS. This test is performed using Kymos’ paddle class 2 dissolution test apparatus, which employs a specialized membrane to prevent the patch from floating in the dissolution medium. For specific applications vertical diffusion Franz cells are also available.
  • In-Vitro Permeation Test (IVPT): These studies involve testing the patch on synthetic or biological membranes to measure drug penetration through the skin, and, following the guideline, can be performed during the formulation development phase, stability studies and after any change in the excipients of the drug product. At Kymos, this testing is used as a performance indicator of the drug product and is done using vertical diffusion Franz cells and following the methodology updated in the Draft EMA guideline 2018.
  • Stability Studies: The EMA guideline specifies that transdermal patch stability studies should include performance tests with respect to dissolution, drug release, and skin permeation testing and adhesion. At Kymos we perform ICH stability testing, ongoing and in-use studies, real-time storage conditions (including temperature cycling), and stress testing.

Conclusions

Transdermal patches provide a unique and efficient method for releasing active substances directly into the bloodstream through the skin. This controlled drug release and systemic absorption presents distinct challenges in ensuring quality, efficacy, and safety, and for this same reason, regulatory bodies such as the EMA have established specific guidelines to ensure rigorous standards for them.

Kymos Group can provide support during the whole life cycle of TDDS drug products, from formulation development and stabilities to routine analyses and reformulations. We have experience analyzing CQAs referenced in the guideline as well as IVRT/IVPT studies, and we are one the few CROs offering both GLP and GMP-certified studies related to transdermal patches.

We have previously analyzed transdermal patches for the treatment of chronic pain (fentanyl) and cancer (irinotecan), and we can perform the analysis of other chronic or long-term treatment TDDS such as:

  • Medications for the treatment of Alzheimer’s, Parkinson’s, degenerative processes, etc.
  • Psychotropic drugs
  • Pain treatment drugs
  • Contraceptives
  • Nicotine for smoking cessation
  • Hormonal therapies
  • Motion sickness (scopolamine)

If you require assistance with your CMC or bioanalysis projects, please contact us or send us an email to commercial@kymos.com.