11

Transdermal Drug Delivery System

Regulatory Issues

Vinod P. Shah
Center for Drug Evaluation and Research, Food and Drug
Administration, Rockville, Maryland, U.S.A.

I. INTRODUCTION

A transdermal drug product is intended to deliver the drug systemically to treat or

prevent disorders in locations distant from the site of topical application. Adhesive
patches and transdermal drug delivery systems (TDS) of defined shape and size
are marketed for systemic action and are intended for the treatment or prevention
of a systemic disease. Drug released from the TDS is absorbed through the stratum
corneum (SC), epidermis, and dermis into blood circulation and transported to
target tissues to achieve therapeutic effect. TDS are considered new drug delivery
systems and often involve a demonstration of clinical safety and effectiveness of
the drug (1,2). TDS products are considered controlled release dosage forms and
should scientifically support in vivo and in vitro claims of controlled release fea-
tures and should assure in vivo as well as in vitro reproducibility.

II. DRUG APPLICATIONS

TDS are regarded as new drugs and therefore have to be approved based on
clinical safety and efficacy studies. If the toxicity and safety of the drug substance
are established during the approval of a different dosage form, then the study
need not be repeated for the approval of the TDS dosage form. Most of the TDS

Copyright 2003 by Marcel Dekker, Inc. All Rights Reserved.

 Table 1 List of TDS Products in US Market

Drug Number of firms Dosage strengths

Clonidine 1 0.1, 0.2, 0.3 mg/24 h

Estradiol 6 0.025, 0.0375, 0.5, 0.075, 0.1 mg/24 h
Estradiol ⫹ Norethindrone 1 0.05 ⫹ 0.14, 0.05 ⫹ 0.25 mg/24 h
Fentenyl 1 0.6, 1.2, 1.8, 2.4 mg/24 h
Nicotine 4 7, 11, 14, 22, 28 mg/24 h
Nitroglycerine 7 0.1, 0.2, 0.3, 0.4, 0.6, 0.8 mg/h, and
15 mg/26 h
Scopolamine 1 1.0 mg/72 h
Testosterone 2 2.5, 4.0, 5.0, 6.0 mg/24 h

approved by the US Food and Drug Administration (FDA) fall into this category.
In general, most of the drug substances were initially approved as oral dosage
forms and subsequently as TDS. Because of this, biopharmaceutical consider-
ations play an important role in regulatory approval of TDS drug products. Table
1 provides a list of TDS drugs and a number of manufacturers and dosage
strengths as approved and marketed in the US.

A. Regulatory Considerations for New Drug

Applications (NDA) as TDS
The key considerations are
TDS are regarded as new drugs and require scientific data to substantiate
clinical safety and efficacy.
Studies for the approval of NDA should be customized based on the critical
nature of the drug, availability of marketed systemic dosage forms of
the same active drug substance, medical and biopharmaceutical rationale,
and literature data on a drug entity.
If the drug substance is marketed in another form, than a comparative bio-
availability employing known routes of administration and TDS should
be determined.
Clinical data to support labeling should be provided.
TDS are regarded as controlled release dosage forms and therefore should
demonstrate controlled release characteristics to support drug labeling.
Biopharmaceutical considerations involve pharmacokinetic measurements
and should define bioavailability (rate and extent) of drug absorption
from TDS. The studies should also evaluate sites of drug administration
for optimizing drug delivery and reproducibility of the system.

Copyright 2003 by Marcel Dekker, Inc. All Rights Reserved.

 B. Regulatory Considerations for Abbreviated New
Drug Applications (ANDA) as TDS
The most important study for an ANDA is a bioequivalence (BE) study.
A BE study should be carried out using the test product and a reference
product at the highest strength, in accordance with the Guidance: “Bio-
availability and bioequivalence studies for orally administered drug
products—general considerations” (3). The approaches discussed in this
general guidance are also applicable to non–orally administered drug
products such as TDS. Generally for modified (extended or controlled)
release drug products, a replicate crossover study design with average
bioequivalence criteria, a 90% confidence interval, and a bioequivalence
limit of 80–125% is required for test product approval. There is less
emphasis now on measurement of metabolite(s). Lower strengths of the
products can be approved based on dose proportionality and in vitro
dissolution profile comparison with the highest strength.
The generic product should employ a drug release mechanism similar to
an approved TDS. If the release mechanism is significantly different, it
may need safety and efficacy data.
The generic product should use approved adhesive and patch material. If
it is different, it may need irritation study data.
The generic product should use approved inactive ingredients. If they are
different, it may need safety data.
The generic product should also establish reproducibility of drug release
characteristics.
In addition, the ANDA manufacturer should meet chemistry, manufactur-
ing, and control (CMC) requirements.
Table 2 provides comparative summary information needed for NDA and ANDA
approval.

Table 2 Requirements for NDA and ANDA Submissions

NDA ANDA

Safety: Toxicity studies

Skin irritation Skin irritation
Cutaneous toxicity Cutaneous toxicity
Cutaneous sensitivity
Contact photodermatitis
Efficacy: Clinical studies
Bioavailability studies Bioequivalence studies
Chemistry, manufacturing and controls Chemistry, manufacturing, and controls
In vitro release studies In vitro release studies

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 III. IN VITRO TESTING

In vitro testing of TDS is considered important in two key areas, (1) defining
skin permeation kinetic studies using a diffusion cell system and cadaver skin
during the drug development process, and (2) in vitro drug release kinetics, to
be used for batch-to-batch release and as a compendial test.
TDS are marketed in varying strengths, sizes, and shapes and contain sig-
nificantly different amounts of drug for a given rate of drug delivery. TDS con-
tain much larger amounts of drug than the amount of drug to be delivered in the
body. The amount of drug varies several fold among different brands for the
same amount of drug delivery (e.g., nitroglycerin patches) (4). This makes it
difficult to have the same amount or percent dissolution for a drug in a given
time. Several methods are described in the US Pharmacopeia for in vitro drug
release of TDS. However, some of the methods are complicated, cumbersome,
and nonuniversal. The FDA has developed a simple, reproducible method of
determining that in vitro release profile of a TDS (5,6). The method employs a
watchglass-patch-teflon mesh sandwich assembly and the paddle method. The
US Pharmacopeia has now adopted this procedure, which is referred as the pad-
dle over disk method (Apparatus 5) (7). The method is applicable to all brands,
shapes, and strengths of all marketed TDS, and is also useful for product stabil-
ity indications.
When developing an in vitro release method, the following points should
be considered: release procedure and its specifications should be designed to
assure quality control and batch-to-batch uniformity; the in vitro release test
should be capable of detecting manufacturing changes that influence product re-
lease properties; where feasible, the in vitro method could be developed to iden-
tify important changes in product performance under accelerated and room tem-
perature stability test conditions, just as in vitro dissolution is used now for solid
oral dosage forms. The method should be economical, simple, reliable, reproduc-
ible, and capable of automation; and it should avoid unnecessary method prolifer-
ation.
TDS are controlled release preparations. Because of different drug release
mechanisms and different amounts of drug in the patches, it is difficult to have
a single in vitro release specification for all brands of a given drug product. This
is the same scenario as with oral controlled release preparations, where different
brands have a different test method and specifications for a given drug.

IV. ENHANCER

For TDS products, a high flux is desired so that the drug can penetrate the stratum
corneum so as to be available in sufficient amounts to the systemic circulation

Copyright 2003 by Marcel Dekker, Inc. All Rights Reserved.

 for therapeutic effect. Drug substances with high molecular weight and drug sub-
stances with polarity are not suitable for transdermal administration. Enhance-
ment or penetration of selected drugs might significantly expand the list of drugs
that could be delivered transdermally. From a regulatory standpoint, development
of a drug for transdermal delivery poses several challenges to the drug develop-
ment process, some of which are amplified with the addition of penetration en-
hancement methods (8).
The skin is structurally and functionally a complex, multilayered organ.
The outermost layer of epidermis, the stratum corneum, is formed by continuous
differentiation of adjacent viable epidermis. The SC is poorly permeable, espe-
cially to water-soluble compounds. The viable epidermis is not thought to present
a significant barrier to drug penetration, except when highly lipophilic drugs are
applied or when the SC is damaged. Because the SC is the dominant rate-limiting
barrier to the skin, transdermal research has focused on facilitating drug transport
across this barrier. The vehicle component of a TDS formulation can significantly
influence drug penetration through the skin.
The primary objective in developing a TDS with chemical penetration en-
hancers has been to identify compounds that significantly enhance drug penetra-
tion without severe irritation or damage to the skin. Ideally, chemical permeation
enhancers should be safe and nontoxic under conditions of use, pharmacologi-
cally inert, nonirritating, and nonallergic. The penetration effect should be pre-
dictable and reversible.
Unfortunately, a chemical penetration enhancer increases the permeability
by reversibly damaging or by altering the nature of the SC to reduce diffusional
resistance. Penetration enhancers can be used as cosolvents to increase the ther-
modynamic activity of the drug in the TDS, e.g., ethanol has been used as an
enhancer-cosolvent in estrogen patches to increase drug penetration.
Enhancement methods usually increase the permeation not only of the drug
but also of formulation excipients and of themselves as well. It is therefore impor-
tant to know the fate of the enhancer in the body. In spite of being excellent
penetration enhancers in TDS, many vehicles are limited because of deleterious
effect on the skin, e.g., dimethyl sulfoxide (DMSO) is a powerful solvent and
increases drug penetration, but at the same time it damages the structural integrity
of the skin.
The enhancer effects should be evaluated to understand general toxicologi-
cal implications, especially irritation potential under conditions of long-term oc-
clusion.
A chemical enhancer should be

Safe and nontoxic

Pharmacologically inert
Nonirritating and nonallergenic

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 Predictable and reversible in its duration of action
Chemically and physically compatible
We need to know, about a chemical enhancer, the mechanism of action and the
fate of the enhancer in the body.
TDS containing chemical enhancers are not considered pharmaceutically
equivalent to TDS formulations lacking chemical enhancers. The enhancement
technology imposes a sufficiently significant change in formulation, so that phar-
maceutical equivalence can no longer be justified.
Physical methods for enhancing drug penetration raise different types of
concerns that include destruction of the SC with high-current setting and general
skin irritation.

V. RESIDUAL DRUG

Labeling should indicate the delivery rate of the drug from TDS. Knowing the
amount of the drug in the TDS, the delivery rate, and the amount remaining in
the TDS after it is removed, it should be possible to compute the apparent amount
of the drug released and delivered to the body (2).

VI. SCALE-UP AND POSTAPPROVAL CHANGES

The manufacturer often makes changes in components and composition, manu-

facturing equipment and/or processing, batch size, or site of manufacturing after
the product is approved. These changes often require additional testing to assure
product sameness between preapproved and postapproval changes in manufactur-
ing. Depending on the type and nature of the changes, additional in vitro testing
or in vivo bioequivalence studies are required (9).

REFERENCES

1. VP Shah, JP Skelly. Regulatory considerations in transdermal drug delivery

systems in the United States. In: YW Chien, ed. Transdermal Controlled
Systemic Medications. New York: Marcel Dekker, 1987, pp 399–410.
2. VK Tammara, RK Baweja, A Dorantes, JP Hunt, FR Pelsor, H Sun, VP
Shah, JK Wilkin. Biopharmaceutical considerations for topical and transder-
mal drug delivery systems. In: TP Ghosh, WR Pfister, SI Yum, eds. Transder-
mal and Topical Drug Delivery Systems. Buffalo Grove, IL, Interpharm
Press, 1997, pp 629–658.

Copyright 2003 by Marcel Dekker, Inc. All Rights Reserved.

 3. FDA Guidance for Industry: Bioavailability and bioequivalence studies for
orally administered drug products—general considerations. October 2000.
4. VP Shah, SV Dighe, YC Huang, F Fang, DB Hare, LJ Lesko, RL Williams.
New and generic transdermal nitroglycerin systems: regulatory consider-
ations. Eur J Pharm Biopharm 41:189–193, 1995.
5. VP Shah, NW Tymes, L Yamamoto, JP Skelly. In vitro dissolution profile
of transdermal nitroglycerin patches using paddle method. Int J Pharm 32:
243–250, 1986.
6. VP Shah, LJ Lesko, RL Williams. In vitro evaluation of transdermal drug
delivery. Eur J Pharm Biopharm 41:163–167, 1995.
7. Transdermal drug delivery systems—general drug release standards. USP
23/NF 18, Apparatus 5, pp 1796–1797.
8. VP Shah, CC Peck, RL Williams. Skin penetration enhancement—clinical
pharmacological and regulatory considerations. In: KA Walters, J Hadgraft,
eds. Pharmaceutical Skin Penetration Enhancement. New York: Marcel Dek-
ker, 1993, pp 417–427.
9. GA Van Buskirk et al. Scale-up of adhesive transdermal drug delivery sys-
tems. Pharm Res 14:848–852, 1997.

Copyright 2003 by Marcel Dekker, Inc. All Rights Reserved.