Transdermal patches present specific attributes that determine their efficacy, safety, and quality, and that must be controlled in the laboratory through analytical techniques to ensure the performance and safety of the transdermal delivery system (TDS). Some correspond to tests common to other pharmaceutical forms. However, due to the particular characteristics of transdermal patches, there are specific procedures described in internationally recognized regulations and pharmacopoeias.
Regulatory Framework: What the Major Agencies Establish
The increasing use of transdermal patches for the treatment of various pathologies — and the advantages this route of administration represents in terms of treatment adherence and absence of characteristic side effects of oral forms — has led pharmacopoeias and international regulations to define the critical attributes that should be considered for quality control of these products.
The most relevant regulatory references include:
- USP: exclusive section for Control of Topical and Transdermal Products (<3> USP), plus specific monographs for Rotigotine, Clonidine, Estradiol, and Nicotine transdermal patches.
- European Pharmacopoeia (EP): transdermal patches are referenced in General Notes 07 on Pharmaceutical Dosage Forms.
- FDA: Guidance on Transdermal and Topical Drug Delivery Systems — Product Development and Quality Considerations (Draft Guidance, November 2019).
- EMA: Guideline on quality of transdermal patches (EMA/CHMP/QWP/608924/2014).
- ANVISA: Guide No. 20/2019 on Quality Requirements for Registration of Topical and Transdermal Products.
Amarin Technologies specializes in the development and production of matrix-type drug-in-adhesive transdermal delivery systems and has Development and Quality Control Laboratories with specific equipment and personnel qualified for this type of analysis.
Critical Quality Attributes (CQAs) for Analytical Control of Transdermal Patches
The following table summarizes the CQAs defined by the major guidelines and pharmacopoeias, distinguishing between those applicable to all pharmaceutical forms (universal) and those specific to TDS:
Atributo / Attribute | Descripción / Description | USP | EP | FDA/EMA | Tipo |
|---|---|---|---|---|---|
Description | Visual evaluation of components, behavior when removed from pouch, liner separation, backing printing, shape, color, matrix opalescence | <3> | Gen. Not. 07 | Yes | Universal |
Identification | Unequivocal identification of active ingredient(s) using specific methods with reference standards | Monographs | Monographs | Yes | Universal |
Assay | Quantification of active content extracted from matrix by chromatographic or spectrophotometric techniques | Monographs | Monographs | Yes | Universal |
Impurities | Control of related substances, residual solvents, elemental impurities, leachables, nitrosamines per risk assessment | Several | Several | Yes | Universal |
Uniformity of Dosage Unit | Individual assay of each patch to evaluate lot homogeneity and process variability | <905> | 2.9.40. | Yes | TDS-specific |
Microbiological Control | Microorganism counts and specific pathogen investigation (non-sterile form) | <61><62> | 2.6.12 / 2.6.13 | Yes | TDS-specific |
Content of Functional Excipients | Control of permeation enhancers, antioxidants, or other excipients with critical formulation function | Per formulation | Per formulation | Yes | TDS-specific |
Crystals | Absence of active ingredient crystallization in adhesive matrix (affects appearance and drug availability) | Microscopy | Microscopy | Yes | TDS-specific |
Dissolution (in vitro release) | In vitro release of active using specially designed TDS devices | <724> | 2.9.4. | Yes | TDS-specific |
Average Weight and Dimensions | Matrix yield and patch dimension control to ensure dose | Gravimetric | Gravimetric | Yes | TDS-specific |
Hermeticity | Primary container integrity during manufacturing and shelf life | Several | Several | Yes | TDS-specific |
Adhesive Properties | Adhesive force, peel force, cohesiveness, tack, cold flow — adhesive behavior on standardized substrate | <3> | Ph.Eur. | Yes | TDS-specific |
Technical Description of TDS-Specific Tests
Uniformity of Dosage Unit
Each patch represents a unit dose. As with other pharmaceutical forms, lot homogeneity must be ensured by individually assaying each patch and evaluating process variability and closeness of content to the labeled claim (<905> USP or 2.9.40. EP).
Microbiological Control
Transdermal patches are non-sterile pharmaceutical forms; therefore, they require analysis of microorganism counts (<61> USP or 2.6.12 EP) and investigation of certain pathogens (<62> USP or 2.6.13 EP).
Content of Functional Excipients
There may be functional excipients in the formulation whose content must be controlled, such as permeation enhancers or antioxidants that prevent chemical degradation of the active ingredient. This test depends on the specific formulation composition.
Crystals
When the active ingredient is dissolved in the adhesive matrix, the absence of crystal formation must be ensured. Their presence not only compromises patch appearance but also reduces the amount of drug dissolved in the matrix available for release and absorption through the skin.
Dissolution / In Vitro Release
The in vitro release of the drug must be controlled to ensure product quality. In transdermal patches, where the skin plays an important role in absorption, this test does not necessarily correlate with in vivo release, but is used as a development tool and to ensure batch homogeneity. Pharmacopoeias describe devices specially designed for transdermal patch control (<724> USP or 2.9.4. EP).
Adhesive Properties
Transdermal patches are formulated with an adhesive layer to ensure intimate contact with the skin and allow delivery of the desired drug dose. TDS adhesives should: allow easy removal of the release liner before use, adhere adequately to human skin after application, maintain adhesion for the prescribed use period, and allow easy removal at the end of application without leaving residue or causing skin damage. In vitro determination of adhesive properties (adhesive force, peel force, cohesiveness, tack, cold flow — all described in <3> USP) is a quality control test that evaluates batch-to-batch reproducibility and adhesive behavior under standardized conditions.
The Role of Laboratories in the Control Strategy
The correct definition of critical quality attributes (CQAs) for transdermal patches enables the establishment of an appropriate control strategy to guarantee the efficacy and safety of this pharmaceutical form. Amarin Technologies Laboratories have the resources and experience to design and carry out these controls effectively and in compliance with Good Manufacturing Practices.
Is your team developing a transdermal system and needs to design or review the analytical control strategy? Contact us at info@amarintech.com.ar.
References
FDA. Transdermal and Topical Delivery Systems – Product Development and Quality Considerations. Draft Guidance, November 2019. https://www.fda.gov/media/132674/download
EMA. Guideline on quality of transdermal patches. EMA/CHMP/QWP/608924/2014, 23 October 2014. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-transdermal-patches_en.pdf
ANVISA. Guide n. 20 — Quality Requirements for Registration of Topical and Transdermal Products. Guide No. 20/2019 – version 2.
USP/NF 2023 and European Pharmacopeia 11.3.
ICH Q6A. Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products. October 1999. https://database.ich.org/sites/default/files/Q6A%20Guideline.pdf
ICH Q8(R2). Pharmaceutical Development. August 2009. https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdf
