Residual Drug in Transdermal and Related Drug Delivery Systems: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
Residual Drug in Transdermal
and Related Drug Delivery
Systems
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2011
CMC

Guidance for Industry
Residual Drug in Transdermal
and Related Drug Delivery
Systems
Additional copies are available from:
Office of Communications
Division of Drug Information, WO51, Room 2201
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Silver Spring, MD 20993
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2011
CMC

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	QUALITY BY DESIGN ................................................................................................... 2
IV. 	MINIMIZING RESIDUAL DRUG................................................................................. 3
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Contains Nonbinding Recommendations
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Guidance for Industry1
Residual Drug in Transdermal and
Related Drug Delivery Systems
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6 	This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It
7 	does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
8 	You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
9 	and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
10 	implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
11 	number listed on the title page of this guidance.
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I. 	INTRODUCTION
This guidance provides recommendations to developers and manufacturers of transdermal drug
delivery systems (TDDS), transmucosal drug delivery systems (TMDS), and topical patch
products regarding use of an appropriate scientific approach during product design and
development—as well as during manufacturing and product lifecycle management—to ensure
that the amount of residual drug substance at the end of the labeled use period is minimized.
Existing TDDS, TMDS, and topical patches contain a larger amount of the drug substance than
what is intended to be delivered to the patient. This excess amount of drug substance is needed
to facilitate delivery of the intended amount of the drug to the patient and remains as residual
drug in the used system. The amount of residual drug substance in TDDS, TMDS, and topical
patches has a significant potential to impact the products’ quality, efficacy, and safety (including
abuse potential). Consequently, it is necessary to ensure that an appropriate scientific approach
is used to design and develop these products. The approach should ensure that the amount of
residual drug substance is minimized consistent with the current state of technology.
This guidance is applicable to investigational new drug applications (INDs), new drug
applications (NDAs), abbreviated new drug applications (ANDAs), and supplemental new drug
applications (sNDAs) for TDDS, TMDS, and topical patch products.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
1 This guidance has been prepared by the Office of Pharmaceutical Science in the Center for Drug Evaluation and
Research (CDER) at the Food and Drug Administration.
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Contains Nonbinding Recommendations
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II. 	BACKGROUND
TDDS and TMDS are drug delivery systems designed to deliver at least one therapeutically
active ingredient (drug substance) across the skin or mucosa, respectively, for systemic effect.
The systems’ design can range from drug-in-adhesive matrix systems to more complex systems
that require microelectronics. These include passive systems (e.g., drug in patches, gels, foams,
films, and spray-on films) and active systems (e.g., iontophoresis and sonophoresis). TDDS and
TMDS offer advantages over other dosage forms by delivering prolonged, systemic drug levels
to allow for simplified dosing regimens and overcome limitations in oral bioavailability or first-
pass metabolism. Topical patches, on the other hand, contain a therapeutically active drug
substance designed to provide a local effect.
Currently marketed TDDS, TMDS, and topical patches may retain 10-95 percent of the initial
total amount of drug as the residual drug after the intended use period. This raises a potential
safety issue not only to the patient, but also to others including family members, caregivers,
children, and pets. For example, adverse events due to a patient’s failure to remove TDDS at the
end of the intended use period have been reported and are generally related to an increased or
prolonged pharmacological effect of the drug. Also, some children have died from inadvertent
exposure to discarded TDDS. Reported adverse events resulting from various quality problems
pertaining to TDDS have lead to product recalls, withdrawals, and public health advisories.2
III. 	QUALITY BY DESIGN
To reduce some of these risks, we recommend that a robust design and development approach be
used when developing and manufacturing TDDS, TMDS, and topical patches. One example of
such an approach is Quality by Design (QbD), as described in the International Conference on
Harmonization (ICH) guidance for industry Q8(R2) Pharmaceutical Development.3
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QbD is a scientific, risk-based, and proactive approach to pharmaceutical process and product
development that may or may not include the use of a design space. An application containing
QbD approaches—which may include information such as a quality target product profile
(QTPP), critical quality attributes (CQA), and a control strategy—can lead to a better
understanding of and continual improvement to the product throughout its lifecycle. A QbD
approach can facilitate the development of TDDS, TMDS, and topical patches designed to meet
patient requirements and post-use considerations. In particular, it can aid in developing a
product to deliver the optimum amount of drug across the skin while minimizing the amount of
drug load, thus resulting in the least possible amount of residual drug substance. QbD is
applicable to both new products and reformulation of existing products. Another benefit of a
QbD approach is that the higher level of understanding of the product and manufacturing process
may assist in evaluating the effects of variations in raw materials and the manufacturing process
on drug product quality. This includes, but is not limited to, drug product quality attributes and
2 See www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/default.htm.
3 CDER updates guidances periodically. To make sure you have the most recent version of a guidance, check the
FDA Drugs guidance web page at
www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
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Contains Nonbinding Recommendations
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product performance characteristics such as drug permeation/flux rate, adhesion, application site
reaction, and safety/quality issues (e.g., residual drug substance, cold flow, and seal breakage of
the liquid reservoir systems).
IV. 	MINIMIZING RESIDUAL DRUG
We recognize that a surplus of drug substance is typically required in TDDS, TMDS, and topical
patches to achieve and maintain the desired release rate of the drug substance throughout its
usage period and for TDDS and TMDS to maintain the appropriate systemic drug levels. The
choice of formulation, design, and system components may provide potential pathways to
optimize drug delivery and minimize residual drug. Examples include, but are not limited to, the
following: the use of penetration enhancers, use of self-depleting solvent systems, and judicious
choice of adhesive. Other factors may include the type and concentration of excipients, drug
load, adhesive thickness, and the composition and thickness of the backing layer.
We recommend that sufficient scientific justification to support the amount of residual drug in
TDDS, TMDS, or topical patches be included in an application.4 The justification should
include an evaluation of the safety risks involved with the formulation and system design, as well
as support the amount of drug load in the TDDS, TMDS, or topical patch based on the proposed
QTPP and formulation studies. Most important, the justification for applications of products
with known safety issues—such as those with fentanyl-containing liquid reservoir systems—
should demonstrate that the safety risk factors have been adequately mitigated.
In all cases, the level of information in the justification should be sufficient to demonstrate
product and process understanding and ensure that a scientific, risk-based approach has been
taken to minimize the amount of residual drug in a system after use to the lowest possible level.
It is expected that the amount of residual drug in a newly developed system (including new
generic drug products) will not exceed that of similar FDA-approved products. This discussion
of the product and process development and justification for the final formulation and system
design can be provided in the 3.2.P.2 (Pharmaceutical Development) section of a common	114
technical document (CTD) formatted application.	115
4 See 21 CFR 314.50(d).