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 
i 
  Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
1 
Residual Drug in Transdermal and  
2 
Related Drug Delivery Systems 
3 
4   
5   
6  This guidance represents the Food and Drug Administrations (FDAs) 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.  
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  This guidance provides recommendations to developers and manufacturers of transdermal drug 
18  delivery systems (TDDS), transmucosal drug delivery systems (TMDS), and topical patch 
19  products regarding use of an appropriate scientific approach during product design and 
20  developmentas well as during manufacturing and product lifecycle managementto ensure 
21  that the amount of residual drug substance at the end of the labeled use period is minimized. 
22   
23  Existing TDDS, TMDS, and topical patches contain a larger amount of the drug substance than 
24  what is intended to be delivered to the patient.  This excess amount of drug substance is needed 
25  to facilitate delivery of the intended amount of the drug to the patient and remains as residual 
26  drug in the used system.  The amount of residual drug substance in TDDS, TMDS, and topical 
27  patches has a significant potential to impact the products quality, efficacy, and safety (including 
28  abuse potential).  Consequently, it is necessary to ensure that an appropriate scientific approach 
29  is used to design and develop these products.  The approach should ensure that the amount of 
30  residual drug substance is minimized consistent with the current state of technology.   
31  This guidance is applicable to investigational new drug applications (INDs), new drug 
32  applications (NDAs), abbreviated new drug applications (ANDAs), and supplemental new drug 
33  applications (sNDAs) for TDDS, TMDS, and topical patch products.   
34   
35  FDAs guidance documents, including this guidance, do not establish legally enforceable 
36  responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
37  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
38  cited.  The use of the word should in Agency guidances means that something is suggested or 
39  recommended, but not required.  
40   
41   
                                                 
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.  
  1 Contains Nonbinding Recommendations 
 
42  II.  BACKGROUND 
43   
44  TDDS and TMDS are drug delivery systems designed to deliver at least one therapeutically 
45  active ingredient (drug substance) across the skin or mucosa, respectively, for systemic effect.  
46  The systems design can range from drug-in-adhesive matrix systems to more complex systems 
47  that require microelectronics.  These include passive systems (e.g., drug in patches, gels, foams, 
48  films, and spray-on films) and active systems (e.g., iontophoresis and sonophoresis).  TDDS and 
49  TMDS offer advantages over other dosage forms by delivering prolonged, systemic drug levels 
50  to allow for simplified dosing regimens and overcome limitations in oral bioavailability or first-
51  pass metabolism.  Topical patches, on the other hand, contain a therapeutically active drug 
52  substance designed to provide a local effect. 
53   
54  Currently marketed TDDS, TMDS, and topical patches may retain 10-95 percent of the initial 
55  total amount of drug as the residual drug after the intended use period.  This raises a potential 
56  safety issue not only to the patient, but also to others including family members, caregivers, 
57  children, and pets.  For example, adverse events due to a patients failure to remove TDDS at the 
58  end of the intended use period have been reported and are generally related to an increased or 
59  prolonged pharmacological effect of the drug.  Also, some children have died from inadvertent 
60  exposure to discarded TDDS.  Reported adverse events resulting from various quality problems 
61  pertaining to TDDS have lead to product recalls, withdrawals, and public health advisories.2 
62   
63   
64  III.  QUALITY BY DESIGN 
65   
66  To reduce some of these risks, we recommend that a robust design and development approach be 
67  used when developing and manufacturing TDDS, TMDS, and topical patches.  One example of 
68  such an approach is Quality by Design (QbD), as described in the International Conference on 
69  Harmonization (ICH) guidance for industry Q8(R2) Pharmaceutical Development.3   
70   
71  QbD is a scientific, risk-based, and proactive approach to pharmaceutical process and product 
72  development that may or may not include the use of a design space.  An application containing 
73  QbD approacheswhich may include information such as a quality target product profile 
74  (QTPP), critical quality attributes (CQA), and a control strategycan lead to a better 
75  understanding of and continual improvement to the product throughout its lifecycle.  A QbD 
76  approach can facilitate the development of TDDS, TMDS, and topical patches designed to meet 
77  patient requirements and post-use considerations.  In particular, it can aid in developing a 
78  product to deliver the optimum amount of drug across the skin while minimizing the amount of 
79  drug load, thus resulting in the least possible amount of residual drug substance.  QbD is 
80  applicable to both new products and reformulation of existing products.  Another benefit of a 
81  QbD approach is that the higher level of understanding of the product and manufacturing process 
82  may assist in evaluating the effects of variations in raw materials and the manufacturing process 
83  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. 
  2 Contains Nonbinding Recommendations 
 
84  product performance characteristics such as drug permeation/flux rate, adhesion, application site 
85  reaction, and safety/quality issues (e.g., residual drug substance, cold flow, and seal breakage of 
86  the liquid reservoir systems).  
87   
88   
89  IV.  MINIMIZING RESIDUAL DRUG 
90   
91  We recognize that a surplus of drug substance is typically required in TDDS, TMDS, and topical 
92  patches to achieve and maintain the desired release rate of the drug substance throughout its 
93  usage period and for TDDS and TMDS to maintain the appropriate systemic drug levels.  The 
94  choice of formulation, design, and system components may provide potential pathways to 
95  optimize drug delivery and minimize residual drug.  Examples include, but are not limited to, the 
96  following:  the use of penetration enhancers, use of self-depleting solvent systems, and judicious 
97  choice of adhesive.  Other factors may include the type and concentration of excipients, drug 
98  load, adhesive thickness, and the composition and thickness of the backing layer.   
99   
100  We recommend that sufficient scientific justification to support the amount of residual drug in 
101  TDDS, TMDS, or topical patches be included in an application.4  The justification should 
102  include an evaluation of the safety risks involved with the formulation and system design, as well 
103  as support the amount of drug load in the TDDS, TMDS, or topical patch based on the proposed 
104  QTPP and formulation studies.  Most important, the justification for applications of products 
105  with known safety issuessuch as those with fentanyl-containing liquid reservoir systems
106  should demonstrate that the safety risk factors have been adequately mitigated. 
107   
108  In all cases, the level of information in the justification should be sufficient to demonstrate 
109  product and process understanding and ensure that a scientific, risk-based approach has been 
110  taken to minimize the amount of residual drug in a system after use to the lowest possible level.  
111  It is expected that the amount of residual drug in a newly developed system (including new 
112  generic drug products) will not exceed that of similar FDA-approved products.  This discussion 
113  of the product and process development and justification for the final formulation and system 
114  design can be provided in the 3.2.P.2 (Pharmaceutical Development) section of a common 
115  technical document (CTD) formatted application. 
                                                 
4 See 21 CFR 314.50(d). 
  3