Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

A Step beyond Module 3 of "passive" Transdermal Therapeutic Systems ***

Dr. Franz Thannberger (Abschlußjahr: 2011)

This thesis is intended for Regulatory affairs managers dealing with "passive" Transdermal Drug Delivery Systems (TDDS) for the first time. It can be used as a survey and common thread through this complex subject.
Therefore, the objective of this thesis is to impart basic knowledge with regard to module 3 of this modern dosage form and to facilitate dossier preparation by accentuation of special qualities and regulatory aspects of "passive" TDDS.

Owing to the circuitousness of this topic, the main focus is on TDDS of the so-called "drug-in adhesive" matrix type. This type of TDDS is characterized by the use of complex adhesive polymer compositions which form drug containing polymer matrices ("matrix drug reservoirs") with well-defined drug-release characteristics.
Fundamental characteristics and challenges related to the pharmaceutical development, manufacture and quality control of this type of TDDS were identified and assessed. The relevant issues are emphasized as follows.

TDDS-Common Aspects

Besides risks and benefits of TDDS, function and structure of the skin and basic principles of transdermal permeation are presented in this chapter. Because is not possible to understand principles and limitations of "passive" transdermal drug delivery and consequently Transdermal Drug Delivery Systems without some previous knowledge of skin this chapter was included.

Pharmaceutical development

In this section some quality aspects, e.g. in-vitro release and bioequivalence requirements for generic patches are highlighted.

Exemplary topics of TDDS development
This section deals with quality aspects that are crucial in the development of TDDS and may affect adhesion properties and/or drug-flux adversely. In addition the section explains the methods available to test for adhesion properties and to improve formulation development. A system for the classification of adhesion failure is described as well. 

The last part deals with the use, realization and benefit of in-vitro skin permeation testing, a most important tool in formulation. The use of the Franz cell, the classical apparatus for this purpose, and its alternative, the use of flow-through cells are presented briefly.
In this context chapter 2.5.4 deals with the needs and difficulties to establish a reliable in-vivo/in-vitro correlation for TDDS.

Bioavailability or Bioequivalence
This chapter presents the biopharmaceutical requirements that apply to new and generic applications for approval of TDDS. Based on the common definition of a generic medicinal product according to Article 10(2)(b) of Directive 2001/83/EC it is pointed out that generic TDDS usually do not meet all required aspects of the definition. These aspects include bioequivalence, therapeutic equivalence and pharmaceutical equivalence. Generic patches are notably varying with regard to their pharmaceutical comparability to the reference product(s).
It is outlined that specific assessment criteria are lacking and therefore the evaluation of product equivalence between originator and generic patch formulation is not standardized at present.

Manufacturing process
This section presents the main steps and principles of solvent based manufacturing of drug-in adhesive-matrix patches and includes a description of the involved unit operations and crucial control parameters.
Furthermore the section deals with possible influences of process development on physical properties and performance on the final product such as residual solvents and potential skin irritation. As solvent based production of matrix patches is the most commonly used, but not the clearly dominant manufacturing technology, principle and advantages of hot melt coating are presented as well.

Control of excipients
Pressure Sensitive Adhesives (PSAs) are the key excipients for transdermal matrix patches and often Chemical Penetration Enhancers (CPEs) and are indispensable compounds of TDDS. Both hold a certain degree of risk to cause skin irritation or other adverse reactions.
This section discusses the safety aspects of these compounds and summarizes the requirements for biocompatibility and quality control.

Control of drug product
In this section some particular and unique specification parameters of TDDS are discussed. These include appearance, drug release testing, determination of assay, content uniformity, uniformity of dosage units and adhesive properties.

With reference to the current revisional activities of the quality guide of transdermal products both in the EU and US, a possible prospect regarding future specification requirements for TDDS is given.

Container closure system
The primary container closure system of a TDDS is a pouch or sachet.The first part of this section describes the complexity of packaging demands for TDDS and the backing and release liner also serve to contain and protect the drug formulation. Furthermore, the qualification of the used plastic materials is outlined. The last part of this section deals with the necessity to configure the primary packaging material in a child-resistant manner and according to legislative requirements.

Stability
This part gives an overview of possible test parameters for the stability testing of TDDS. Such testing routine must be capable of covering all relevant factors that impact shelf-life, e.g. like
stability of drug substance, drug-flux and adhesion properties. Furthermore, it covers the formation of impurities, the possible interactions of the API with the matrix, adhesive, and container closure components, as well as physical changes in the formulation.

Pages: 80