Regulatory framework

Due to the increasing use of transdermal patches for the treatment of certain pathologies and the advantages that this route of administration represents in terms of patient compliance with the treatment and the absence of characteristic side effects, for example, of oral forms; Pharmacopoeias and international regulations have shown interest in defining those critical attributes that should be considered for quality control of transdermal patches.

USP has got  an exclusive section for the Control of Topical and Transdermal Products (<3> USP), in addition to encompassing some monographs such as Rotigotine, Clonidine, Estradiol and Nicotine transdermal patches. Patches are also referred to in the General Notes 07. Dosage Forms of the European Pharmacopoeia.

Besides, there are FDA and EMA guidelines and, in the region, ANVISA guide No. 20/2019, which also include to the development of these pharmaceutical forms and define considerations to be taken into account for registration of these products.

Amarin Technologies specializes in the development and production of matrix-type transdermal drug-in-adhesive delivery systems (drug dissolved in the adhesive matric) and has got Development and Quality Control Laboratories with specific equipment and personnel qualified and trained for this type of analysis.

Universal Tests 

The ICH Q6A guide defines the general guidelines for the Specifications of New Drugs and Products, including the following general quality attributes (which apply to all dosage forms):

• Description: the appearance of the patch must be qualitatively described, listing the different components (adhesive matrix, release liner, backing film, overlay, separating foil), evaluating the behavior of the patch when removed from the pouch, detachment of the release liner, characteristics of the printing on the backing film, its shape, color and opalescence of matrix,  
• Identification: the active principle(s) must be unequivocally identified by means of specific and easily implemented methods, using reference standards for comparative purposes.
• Assay: to quantify the active principle content in the patches, the drug must be extracted from the matrix and dissolved in an appropriate solvent and then quantified using separation techniques (chromatographic, spectrophotometric, etc.), avoiding the interference of matrix components, degradation products, reagents, etc.
• Impurities: Same as other pharmaceutical forms, the purity and safety of the patch must be ensured, testing those impurities that may be generated in the manufacturing process or throughout the useful life of the patch. In addition to organic impurities considered related substances of the active principle, risk assessment tools must be applied during the development stage to define, if applicable, the control strategy for monomers, residual solvents, elemental impurities, leachables, nitrosamines, etc.

Specific tests for transdermal patch

• Uniformity of Dosage Unit: Each patch represents a unit dose and, as with other dosage forms, lot homogeneity must be ensured by assaying each patch individually and evaluating process variability and how close the content is to the label claim of the product (<905> USP or 2.9.40. EP).
• Microbiological control: Transdermal patches are non-sterile dosage 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 some functional excipients within the formulation whose content must be controlled, such as permeation enhancers or antioxidants that prevent chemical degradation of the drug. This test depends on the composition of the formulation.
• Crystals: when the active ingredient is dissolved in the adhesive matrix, it is necessary to ensure the absence of crystal formation since, in addition to jeopardizing the appearance of the patch, it reduces the amount of drug dissolved in the matrix available to be released and absorbed through the skin.
• Dissolution: the in vitro release of the drug must be controlled to ensure the quality of the product. In transdermal patches, where the skin plays an important role in the absorption of the active ingredient, this test does not necessarily correlate with in vivo release, but it is used as a development tool and is also important to ensure batch homogeneity. The pharmacopoeias describe devices specially designed for the control of transdermal patches (<724> USP or 2.9.4. EP).
• Average weight and dimensions: the control of matrix yield and patch dimensions assures the drug’s dose and is a simple control that is carried out in the laboratory.
• Hermeticity: Allows to guarantee the integrity of the container during manufacturing and throughout the useful life of the product.
• 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 show easy removal of the release liner before use, adhere adequately to human skin after application, maintain adhesion to the skin for the prescribed period of use, and allow easy removal of the TDS at the end of the application use without leaving residue. or causing skin damage or other undesirable effect(s). The determination of in vitro adhesive properties (adhesive force, peel force, cohesiveness, tack, cold flow, all of them, described in <3> USP) is a quality control test that helps to evaluate lot-to-lot reproducibility and adhesive behavior in a substrate under standardized operating conditions.

The role of the Laboratories

The correct definition  of the critical quality attributes (CQAS) of the transdermal patches makes it possible to set 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 on these controls effectively and in compliance with Good Manufacturing Practices.

References:

– FDA Transdermal and Topical Delivery Systems – Product Development and Quality Considerations Guidance for Industry DRAFT GUIDANCE November 2019 Pharmaceutical Quality/CMC

– EMA Guideline on quality of transdermal patches 23 October 2014 EMA/CHMP/QWP/608924/2014 Committee for Medicinal Products for Human Use (CHMP)

–  Guia n. 20 Guia sobre Requisitos de Qualidade para o Registro de Produtos Tópicos e Transdérmicos. Guia nº 20/2019 – versão 2 

– USP/NF 2023 y European Pharmacopeia 11.3.

– ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, October 1999

– Q8(R2) Pharmaceutical Development, August 2009