Transdermal and 
Topical Delivery 
Systems - Product 
Development and 
Quality Considerations 
 
Guidance for Industry 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Mohamed Ghorab 240-402-8940.  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
November 2019 
Pharmaceutical Quality/CMC 
14981899 Dft   
Transdermal and 
Topical Delivery 
Systems - Product 
Development and 
Quality Considerations 
 
Guidance for Industry 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://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) 
 
 
November 2019 
Pharmaceutical Quality/CMC
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
A.  General ............................................................................................................................................ 1 
  B.  Regulatory Status ........................................................................................................................... 3 
III.  TDS PRODUCT DEVELOPMENT ................................................................................ 4 
  A.  Quality Target Product Profile ..................................................................................................... 4 
  B.  Critical Quality Attributes ............................................................................................................ 5 
  1. TDS Product .................................................................................................................................... 5 
  2. Drug Substance ................................................................................................................................ 5 
  3. Excipients and Components ............................................................................................................. 6 
  4.Identifying Labeling .......................................................................................................................... 7 
  C.  Product and Process Development ............................................................................................... 7 
IV.  INFORMATION TO BE SUBMITTED IN AN APPLICATION ............................... 8 
A.  Pharmaceutical Development ....................................................................................................... 8 
1. Batch Formula ............................................................................................................................... 10 
2. Expectations for Registration/Exhibit Batches .............................................................................. 10 
3. Product Characterization Studies .................................................................................................. 11 
4. Proposed Manufacturing Changes ................................................................................................ 16 
B.  Manufacture ................................................................................................................................. 17 
C.  Control of TDS Product .............................................................................................................. 19 
D.  Additional Stability Studies ........................................................................................................ 24 
V.  SPECIAL TOPICS ......................................................................................................... 24 
A.  Product Adhesion Considerations .............................................................................................. 24 
B.  Product Storage and Disposal  Labeling Considerations ....................................................... 25 
 
   
  Contains Nonbinding Recommendations 
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1  Transdermal and Topical Delivery Systems - Product Development 
2  and Quality Considerations 
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14  I.  INTRODUCTION 
15   
16  This guidance provides recommendations to applicants and manufacturers of transdermal and 
17  topical delivery systems (TDS)2 regarding the pharmaceutical development and quality 
18  information to include in new drug applications (NDAs) and abbreviated new drug applications 
19  (ANDAs).3,4 Specifically, the guidance discusses FDAs current thinking on product design and 
20  pharmaceutical development, manufacturing process and control, and finished product control. It 
21  also addresses special considerations for areas where quality is closely tied to product 
22  performance and potential safety issues, such as adhesion failure and the impact of applied heat 
23  on drug delivery. 
24   
25  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
26  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
27  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
28  the word should in Agency guidances means that something is suggested or recommended, but 
29  not required. 
30   
31  II.  BACKGROUND 
32   
33  A.  General 
34   
                                                 
1 This guidance has been prepared by the Office of Pharmaceutical Quality and Office of Generic Drugs in the 
Center for Drug Evaluation and Research, in consultation with the Center for Devices and Radiological Health, and 
the Office of Combination Products, at the Food and Drug Administration. 
2 For the purpose of this guidance, both transdermal and topical delivery systems are referred to by the acronym 
TDS. 
3 Some TDS (such as microneedles, active transport TDS, reservoir TDS, and TDS applied to broken skin) have 
other considerations that are not addressed in this guidance. 
4 The general principles in this guidance can also be applied to nonapplication drug products; for example, over-the-
counter drugs products marketed under the monograph regulatory construct (see 21 CFR part 330). 
 
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35  Transdermal delivery systems are designed to deliver an active ingredient (drug substance) 
36  across the skin and into systemic circulation, while topical delivery systems are designed to 
37  deliver the active ingredient to local tissue.5 Both delivery systems present similar manufacturing 
38  and quality control concerns and similar risks to patients. TDS can be broadly divided into 
39  matrix type and liquid or gel reservoir type delivery systems. 
40   
41  Matrix type TDS contain one or more active ingredients dissolved or partially suspended in a 
42  mixture of various components, including adhesives, penetration enhancers, softeners, and 
43  preservatives, and are typically manufactured using solvent, hydrogel, or hot melt-based 
44  practices. An example of a matrix type TDS is shown in Figure 1, but matrix TDS may include 
45  additional layers and/or more complex designs. 
46   
47  Figure 1. Matrix Type Transdermal or Topical Delivery System 
48   
49   
50   
51  Reservoir type TDS similarly contain a variety of components in liquid or semi-solid form; 
52  however, reservoir type TDS utilize a heat-sealed area to entrap the active gel between the 
53  backing membrane and a microporous membrane. An example of a reservoir type TDS is shown 
54  in Figure 2. Because of the inherent failure modes and safety risks associated with the reservoir 
55  TDS, FDA recommends TDS manufacturers and applicants focus development efforts on matrix 
56  type TDS.6 
57   
                                                 
5 Topically administered liquid and semi-solid drug products without a carrier device (e.g., gels, creams, lotions, 
foams, ointments, or sprays) are not considered to be TDS and are not covered by this guidance, even though they 
can be formulated to provide local, or in some cases, transdermal delivery of the drug. 
6 Applicants are strongly encouraged to consult the Office of Pharmaceutical Quality early in the development 
process prior to pursuing a reservoir design.  
 
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58  Figure 2. Reservoir Type Transdermal or Topical Delivery System 
59   
60   
61  B.  Regulatory Status 
62   
63  Transdermal and topical delivery systems are combination products as defined by 21 CFR part 3, 
64  and must comply with 21 CFR part 4 subpart A (Current Good Manufacturing Practice 
65  Requirements for Combination Products). Within 21 CFR part 4, there is description of how 
66  requirements from 21 CFR parts 210 and 211 (drug CGMPs) and 21 CFR part 820 (device 
67  Quality System regulation) apply to combination products.7 
68   
69  In particular, design controls (21 CFR part 820.30) apply to drug-device combination products 
70  including TDS.8 Essentially, design control activities should confirm that there are no negative 
71  interactions between constituent parts and assure that their combined use results in a combination 
72  product that is safe and effective and performs as expected. Guidance for industry on 
73  pharmaceutical development also addresses product design and development procedures, 
                                                 
7 For related guidance, see FDA guidance for industry and staff Current Good Manufacturing Practice 
Requirements for Combination Products (January 2017). We update guidances periodically. For the most recent 
version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.8 As can be the case for components of other 
single-entity combination products, some components of TDS may be treated as components of both the drug and 
device constituent parts of the combination product. Because the purpose of this guidance is to offer technical 
recommendations relating to product development and assessment, we use the general term component(s) 
throughout the guidance to avoid unnecessary complexity regarding such incidental regulatory issues.9 See FDA 
guidance for industry Q8(R2) Pharmaceutical Development (November 2009). We reference International 
Conference for Harmonisation (ICH) guidelines, which address complex scientific issues or set forth first 
interpretations of regulatory requirements, and correspond to FDA draft and final guidance documents, respectively. 
8 As can be the case for components of other single-entity combination products, some components of TDS may be 
treated as components of both the drug and device constituent parts of the combination product. Because the purpose 
of this guidance is to offer technical recommendations relating to product development and assessment, we use the 
general term component(s) throughout the guidance to avoid unnecessary complexity regarding such incidental 
regulatory issues.9 See FDA guidance for industry Q8(R2) Pharmaceutical Development (November 2009). We 
reference International Conference for Harmonisation (ICH) guidelines, which address complex scientific issues or 
set forth first interpretations of regulatory requirements, and correspond to FDA draft and final guidance documents, 
respectively. 
 
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74  reflecting quality by design principles.9 While quality by design and design controls share 
75  similar characteristics and goals, the device Quality System regulation (21 CFR part 820) 
76  includes specific requirements for design development that manufacturers must satisfy.10 
77   
78  It may be possible to leverage many aspects of pharmaceutical development as described in 
79  International Conference for Harmonisation ICH Q8(R2)11 to achieve compliance with design 
80  controls. For example, the Quality Target Product Profile (QTPP) (see section III.A. below) is 
81  similar to design inputs (21 CFR part 820.30(c)), which ensure that design requirements are 
82  appropriate to address the intended use of the product. Further, studies conducted to verify that 
83  the critical quality attributes (CQAs) are met in the finished product may also address 
84  requirements for design verification and validation (21  CFR part 820.30(f), (g)), which 
85  ensure that the products design outputs (21 CFR part 820.30(d)) result in a product that safely 
86  and effectively achieves its intended effects).12 
87   
88  III.  TDS PRODUCT DEVELOPMENT 
89   
90  The following section provides an overview of considerations for product and process 
91  development, described from a pharmaceutical development perspective. As described above, 
92  development of a TDS product must also be compliant with design controls (21 CFR part 
93  820.30). We recognize that the terminology used in 21 CFR part 820.30 can differ from that used 
94  in a particular pharmaceutical development program. Where pharmaceutical development 
95  practices are leveraged and built upon to demonstrate compliance with design controls for a TDS 
96  product, applicants should be able to communicate to FDA how the terminology they use relates 
97  to design control principles and requirements. 
98   
99  A.  Quality Target Product Profile 
100   
101  Prior to TDS development, the applicant should establish the desired quality target product 
102  profile (QTPP). The QTPP is a prospective summary of the quality characteristics of the TDS 
103  product that ideally will be achieved to ensure the desired quality, taking into account safety and 
104  efficacy of the product (ICH Q8(R2)). In general, QTPP elements and their quality 
105  considerations for TDS may include: 
106   
                                                 
9 See FDA guidance for industry Q8(R2) Pharmaceutical Development (November 2009). We reference 
International Conference for Harmonisation (ICH) guidelines, which address complex scientific issues or set forth 
first interpretations of regulatory requirements, and correspond to FDA draft and final guidance documents, 
respectively. 
10 For example, requirements under 21 CFR part 820 for design control, purchasing controls, management 
responsibility and corrective and preventive action must be met. See FDA guidance for industry Current Good 
Manufacturing Requirements for Combination Products (January 2017) for additional information regarding options 
for complying with the requirements of 21 CFR part 820 for a combination product. 
11 See footnote 9.  
12 Additional requirements for design control include preparation of a design plan (21 CFR part 820.30(b)) and 
holding review meetings with specified personnel in attendance (21 CFR part 820.30(e)). See Current Good 
Manufacturing Requirements for Combination Products for additional information regarding design control 
requirements for combination products and other CGMP requirements for combination products that include a 
device constituent part. 
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QTPP Element  Quality Considerations 
In vivo delivery of active ingredient to  Formulation design and manufacturing 
achieve therapeutic effect   control 
Minimization of residual drug   Formulation design 
Adherence for duration of wear period  Excipient selection, component control, 
physical design (shape, dimensions, 
etc.), and manufacturing control 
Minimization of irritation   Formulation design  
Chemical and physical stability for  Formulation design, container closure 
shelf life  attributes, storage conditions 
Non-drug substance-related impurities  Excipient selection and manufacturing 
control 
107   
108  Other QTPP elements may exist depending on therapeutic need, patient population, or other 
109  functional property requirements. For example, the size of the finished product may be a QTPP 
110  element depending on the location on the body where the product is to be applied or if the patient 
111  population is pediatric. 
112   
113  B.  Critical Quality Attributes 
114   
115  1.  TDS Product 
116   
117  Early in the TDS development process, the applicant should generate a list of potential CQAs. A 
118  CQA is a physical, chemical, biological, or microbiological property or characteristic that should 
119  be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH 
120  Q8(R2)). Knowledge of the QTPP for the product, in combination with prior knowledge, risk 
121  assessments, and/or experimentation, can be used to develop the list of product CQAs. Each 
122  CQA, either alone or in concert with one or more other CQAs, should relate to one or more 
123  elements of the TDS product QTPP. The list of product CQAs can be modified as product 
124  development progresses and new knowledge is gained. The CQAs of the drug substance(s), 
125  excipients, components and container closure system should also be identified in the application. 
126   
127  For TDS, CQAs typically include appearance (such as lack of visible crystals), dimensions, 
128  uniformity of dosage units, assay, permeation enhancer content, impurities and degradants, in 
129  vitro drug release profile, preservative/antioxidant content (if present), peel adhesion, tack, 
130  release liner peel strength, shear strength, cold flow, residual solvents, residual monomers, 
131  microbial limits, and package integrity. 
132   
133  2.  Drug Substance 
134   
135  Selection of a drug substance should be justified based on the physicochemical and biological 
136  properties of the drug substance that can influence the performance of the TDS product and its 
137  manufacturability. In particular, properties that influence the rate of delivery, such as molecular 
138  weight, melting point, partition coefficient, pKa, aqueous solubility, and pH, should be 
139  considered. Other characteristics of the drug substance such as particle size, crystal form, and 
140  polymorphism should be evaluated and justified in terms of product performance. 
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141   
142  3.  Excipients and Components 
143   
144  Excipients and components used in TDS can include various adhesives, permeation enhancers, 
145  rate controlling or non-rate controlling membranes, solubilizers, plasticizers/softeners, or 
146  tackifiers, all of which can influence the quality and performance attributes of TDS. 
147   
148  Rigorous qualification of key excipients and components is important to ensure optimum product 
149  quality attributes in transdermal and topical formulations, and facilitates the postapproval change 
150  process for changes in the raw materials, manufacturing process, or suppliers.  
151   
152  For example, when qualifying the adhesives in a TDS product, an applicant should consider the 
153  following attributes: 
154   
155    For adhesive polymer(s) as raw material(s): molecular weight, polydispersity, 
156  spectroscopic analysis (e.g., infrared radiation (IR) absorption), thermal analysis, intrinsic 
157  or complex viscosity, and measurement of residual monomers, dimers, solvents, heavy 
158  metals, catalysts, and initiators.  
159   
160    For adhesive as a laminate (in the absence of the active ingredient and other excipients): 
161  residual solvents, peel, tack, shear, and adhesion.  
162   
163    For adhesive in the final product (along with drug substance and other excipients and 
164  components): identification, residual monomers, dimers, and solvents; impurities; loss on 
165  drying; and uniformity. Other properties to be considered include the viscoelastic 
166  properties (such as elastic modulus (G), viscous modulus (G), and creep compliance 
167  (J)), and functional properties including, but not limited to, peel, shear, adhesion, tack, in 
168  vitro drug release, and in vitro drug permeation.  
169   
170  The properties of an adhesive as raw material (e.g., rheology, including intrinsic viscosity and 
171  complex viscosity) can impact the final product quality attributes. Adhesive suppliers 
172  specifications are often wide; thus, adhesive raw material received throughout the life cycle of 
173  the product may vary greatly within the adhesive suppliers specifications. For example, the 
174  rheological properties of the adhesive lots used in the pivotal in vivo trial for TDS (e.g., 
175  bioequivalence (BE), Pharmacokinetic (PK), adhesion studies) may not be consistent with the 
176  suppliers previously manufactured adhesive lots or their future adhesive lots. Therefore, 
177  applicants should request historical rheology values from the adhesive manufacturer to better 
178  understand their process capabilities and the potential influence of variability in the adhesive 
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179  rheology on the final product. This can further assist applicants in assessing the need to establish 
180  or tighten internal controls for the raw material.  
181   
182  Identifying, evaluating, and properly controlling similar quality attributes of other key 
183  components of TDS products will enhance product and process understanding of the TDS 
184  throughout its life cycle. 
185   
186  4.  Identifying Labeling 
187   
188  Applicants are encouraged to incorporate a representative label early in development to assure 
189  the labeling process or inks utilized for printing do not interact with the TDS product, and to 
190  properly assess inks during extractable and leachable studies. The identifying label is typically 
191  placed on the backing membrane of TDS and should, at minimum, include the product name and 
192  strength. 
193   
194  Transdermal and topical systems that are clear, translucent, or colored to match human skin tones 
195  can make it difficult to find the TDS on the patient, and have led to medication administration 
196  errors when patients or caregivers fail to remove old systems and apply more than one system at 
197  a time. Clear or translucent TDS may also be difficult to find if they detach prematurely from a 
198  patient, thereby increasing the potential for secondary or accidental exposure of the drug to a 
199  health care provider, caregiver, or child. Therefore, we recommend the backing membrane be 
200  printed with ink that has adequate contrast and remains visible for the duration of system wear 
201  and after disposal. 
202   
203  C.  Product and Process Development 
204   
205  The principles of quality by design (QbD) and elements of pharmaceutical development 
206  discussed in ICH Q8(R2), Q9, and Q1013 should be applied throughout the TDS life cycle to 
207  ensure TDS products have the identity and strength, and meet the quality and purity 
208  characteristics required under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act 
209  (FD&C Act). 
210   
211  TDS can be as simple as a single drug substance dissolved in a single adhesive, or highly 
212  complex, multi-component, multi-adhesive, multi-laminate matrices. Excipients and components 
213  in TDS can include various adhesive systems, permeation enhancers, rate controlling or non-rate 
214  controlling membranes, solubilizers, plasticizers/softeners, or tackifiers. 
215   
216  As a general principle, product development strategies should seek to minimize product 
217  complexity while still achieving the QTPP. Less complex products are likely to have fewer 
218  potential failure modes than more complex products. Product and process controls can be 
219  simplified as product complexity decreases, which can reduce the risk of manufacturing 
220  problems occurring during routine commercial manufacture. 
221   
                                                 
13 See FDA guidances for industry Q8(R2) Pharmaceutical Development (November 2009), Q9 Quality Risk 
Management (June 2006), and Q10 Pharmaceutical Quality System (April 2009). 
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222  Systematic quality risk assessments and process characterizations can support the identification 
223  of appropriate controls for manufacturing process variables, in order to produce TDS products 
224  with acceptable CQAs. Risk assessments can also help define the robustness of certain critical 
225  material attributes (CMAs) and critical process parameters (CPPs), such as raw material 
226  characteristics, hold times and equilibration periods. 
227   
228  IV.  INFORMATION TO BE SUBMITTED IN AN APPLICATION 
229   
230  An applicant must provide technical data and information in sufficient detail to permit the 
231  Agency to make a knowledgeable judgment about whether to approve the application or whether 
232  grounds exist under section 505(d)14 or 505(j)15 of the FD&C Act to refuse to approve the 
233  application. This includes information about the drug substance16 and information about the TDS 
234  product.17 
235   
236  The following sections provide recommendations to applicants about pharmaceutical 
237  development and quality information to be included in the application sections described in ICH 
238  M4Q.18 
239   
240  A.  Pharmaceutical Development 
241   
242  As described in ICH M4Q, section 3.2.P.2 of the application should contain information on 
243  studies conducted to establish that the dosage form, formulation, manufacturing process, 
244  container closure system, microbiological attributes, and usage instructions specified in the 
245  application are appropriate for the intended use of the TDS product. The applicant should 
246  address the following: 
247   
248    A description of the QTPP. 
249   
250    A list of the CQAs of the TDS product, along with the limit, range, or distribution 
251  associated with each CQA and appropriate justification. 
252   
253    Identification of those aspects of the drug substance, excipients, container closure system, 
254  and manufacturing processes important to attaining product quality. 
255   
256    In particular, the selection of excipients and components, their concentrations (as 
o
257  appropriate), and their functional characteristics affecting TDS performance 
258  should be discussed. For example, the applicant should describe the impact of 
259  penetration enhancers on the adhesive properties of the TDS, solubility of the 
260  drug substance in the blend, and skin permeation. 
                                                 
14 See 21 CFR part 314.50(d). 
15 See 21 CFR part 314.94(a)(9).   
16 See 21 CFR parts 314.50(d)(1)(i) and 314.94(a)(9). 
17 See 21 CFR parts 314.50(d)(1)(ii) and 314.94(a)(9). Please note information about the combination product as a 
whole (referred to as TDS product in this guidance) should be provided in those eCTD sections intended for the drug 
product alone. 
18 See FDA guidance for industry M4Q:  CTD  Quality (August 2001). 
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261   
262    Applicants should specify the allowable ranges around the process parameters and 
o
263  material attributes that have a potential to impact TDS product CQAs with 
264  justification and describe how they will be monitored. 
265   
266    A description of the quality risk assessments, potential failure modes, and product and 
267  process control strategies. 
268     
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269   
270  1.  Batch Formula 
271   
272  For processes that use solvated raw materials, batch formulas should be designed to tolerate 
273  variation in the solvent content of raw materials. Drug substance overages and excipient excesses 
274  can be added to a batch to account for evaporation during drying, but the amount of overage or 
275  excess should be controlled and justified by process development studies. Applicants should 
276  describe any cross-linking reactions since these reactions impact the chemical composition and 
277  quality of the finished product. 
278   
279  2.  Expectations for Registration/Exhibit Batches 
280   
281  Applicants should submit data for registration/exhibit batches manufactured from three distinct 
282  laminates, where each laminate is made using different lots of drug substance, adhesives, 
283  backing, and/or other critical elements in the TDS product. Release and stability sampling should 
284  be representative of the full length and width of the laminates to demonstrate that the 
285  manufacturing process is robust. 
286   
287  Any clinical batch (e.g., those used in phase 3, PK, BE, adhesion, or irritation and sensitization 
288  studies) should be included in the formal stability program.19,20 Applicants should provide the 
289  executed batch records and certificates of analysis for all batches used in clinical and BE studies, 
290  including placebo batches. Placebo batches should include all inactive ingredients and 
291  components and representative printing. 
292   
293  Applicants should report the actual yields, theoretical yield, and percentages of theoretical yield 
294  from the conclusion of each appropriate phase of manufacturing, processing, packaging, and 
295  holding. The theoretical yield should be calculated for each batch prospectively. For example, if 
296  a coating process is stopped due to a manufacturing issue, the theoretical yield should be based 
297  on the mass that was intended to be coated rather than the mass that was actually coated. The 
298  yield for TDS processes may be lower than the usual yield for many other drug manufacturing 
299  processes. However, abnormally low yields in the TDS submission batches should be explained 
300  in the application. 
301   
302  Because of the sensitivity of TDS products to small differences in manufacturing process, a 
303  master table comparing the clinical, BE, registration/exhibit, and proposed commercial batches 
304  should be included in section 3.2.P.2.3 of the application. For each batch, this table should 
305  specify the manufacturing process used (including equipment, and manufacturing scale, and 
306  those parameters that could directly or indirectly impact a CQA), and the results of critical in-
307  process tests (specifying the test procedure and acceptance criteria), yield, and reconciliation 
308  data. The table should also include links to any information referenced from other parts of the 
309  submission. It should also clarify whether these batches were packaged to completion at the die 
310  cutting and pouching stage. 
311   
                                                 
19 See FDA guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products. 
20 See FDA guidance for industry ANDAs: Stability Testing of Drug Substances and Products: Questions and 
Answers (May 2014). 
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312  3.  Product Characterization Studies 
313   
314  Because of the uniqueness of the TDS dosage form, specialized developmental studies and 
315  evaluations are recommended to demonstrate full product understanding in both new and 
316  abbreviated new drug applications. Several such studies/evaluations are discussed below. 
317   
318  a.  Skin Permeability 
319   
320  Skin permeability is a function of permeant thermodynamic activity and degree of saturation of 
321  the drug substance in the TDS. The solubility and degree of saturation of the drug substance in 
322  the TDS should be evaluated, and their impact on the performance of the TDS understood. 
323   
324  b.  Crystallization 
325   
326  Generally, crystallization of the drug substance in the TDS product should be avoided. If 
327  crystallization occurs, studies should be conducted to assess its impact on the in vivo 
328  performance and adhesion of TDS. 
329   
330  c.  Thermodynamic Stability of Drug Substance 
331   
332  To confirm thermodynamic stability of the drug substance, the risk of precipitation or salt 
333  formation during manufacturing and storage should be evaluated. If there is an equilibrium 
334  between different salt forms, the kinetics to reach this equilibrium should be thoroughly 
335  characterized. The impact of this equilibrium on TDS performance should be evaluated with 
336  relevant in vitro drug release, permeation, and/or clinical data. 
337   
338  d.  Strength 
339   
340  The strength of a transdermal system should be expressed as a rate (e.g., XX mg/day), whereas 
341  the strength of a topical system should be expressed as a percent total drug load. For transdermal 
342  systems, the strength can be derived from and supported by either PK data or by residual drug 
343  analysis performed on used transdermal systems. The first approach involves the derivation of a 
344  clearance (Cl) value from absolute bioavailability of the drug and multiplying that by the 
345  concentration (C ) at the steady state. The second approach involves the measurement of the 
ss
346  amount of drug left in the transdermal systems at the end of the wear period and dividing the 
347  consumed amount by the wear period. 
348   
349  Although the strength of a topical system is expressed as percent total drug load, a residual drug 
350  analysis should still be conducted. 
351   
352  e.  Residual Drug 
353   
354  Consistent with FDA guidance for industry Residual Drug in Transdermal and Related Drug 
355  Delivery Systems (August 2011), scientific justification sufficient to support the amount of 
356  residual drug in a TDS should be included in the pharmaceutical development section of the 
357  application. To provide a robust analysis of the residual drug, we recommend the following: 
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358   
359  1.  Data should be based on analysis of the used TDS and not on a theoretical 
360  calculation. 
361  2.  The amount of drug left on the skin surface should be assessed. Any drug that may 
362  have been transferred to packaging or other components of the TDS during storage or 
363  use should be accounted for in an attempt to perform a mass balance. 
364  3.  Tape or overlays should not be used in studies where the TDS is used to calculate 
365  residual drug. 
366  4.  TDS adhesion assessments should be conducted over the entire period of wear to 
367  determine whether the TDS diffusional surface area remains in full contact with the 
368  skin during the entire period of the study. 
369  5.  A control study should be performed to provide an estimate of drug load, rather than 
370  simply using the expressed label claim. This study should include analysis of a 
371  minimum of three unused products from the same lot of product used in the study. 
372  6.  Sample storage conditions before and after application of the TDS on the skin should 
373  be validated. Photostability and thermal stability of the active ingredient(s) in the 
374  TDS should also be considered when selecting the appropriate storage conditions. 
375  7.  Appropriately sensitive and valid analytical methods should be used to assay the 
376  residual drug content for the purpose of calculating drug depletion and delivery. 
377  When estimating the amount of residual drug in the TDS, a drug extraction method 
378  with a target extraction efficiency close to 100 percent should be utilized to minimize 
379  error. 
380   
381  f.  In Vitro Permeation Testing 
382   
383  In vitro permeation testing (IVPT) with the use of excised human skin may be utilized to 
384  characterize the rate and extent of transdermal or topical drug delivery, and the study protocols 
385  and results should be described in the application. The following factors should be considered 
386  during IVPT model development: 
387   
388    Selection of the diffusion apparatus and the operating conditions like stirring rate or flow 
389  rate, as well as temperature control to maintain the under-normal-conditions skin surface 
390  temperature (32C 1C) 
391   
392    Source of the skin, skin storage conditions, choice of skin type (i.e., age range, sex , race, 
393  and consistent anatomical region) and the skin preparation technique (e.g., full-thickness, 
394  dermatomed, isolated epidermis) 
395   
396  The IVPT protocol should specify the nominal skin thickness and its range, details of the skin 
397  barrier integrity test, and any occlusion of the product during the IVPT. Visual observations 
398  alone are not sufficient to characterize the barrier integrity of the skin. Acceptable barrier 
399  integrity tests may be based on tritiated water permeation, trans-epidermal water loss (TEWL), 
400  or electrical impedance/conductance measured across the skin. The test parameters and 
401  acceptance criteria used for the skin barrier integrity test should be justified based on relevant 
402  literature references or other information. 
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403   
404  The IVPT protocol should also include details about the receptor solution, system equilibration, 
405  procedures for skin mounting and application of the TDS, as well as any measures to secure the 
406  TDS on the skin surface to prevent lifting. We recommend that an antimicrobial agent be 
407  included in the receptor solution (e.g., ~0.1 percent sodium azide or ~0.01 percent gentamicin 
408  sulfate). 
409   
410  The IVPT study report should include dose duration, sampling duration, sampling time points, 
411  concentration of samples, concentration of the antimicrobial component, and the empirical 
412  stability (at relevant temperatures) and solubility of the active ingredient in the receptor solution. 
413  The study report should also include the number of individuals whose skin was evaluated (i.e., 
414  skin donors) and the number of replicate skin sections per donor per treatment group. 
415   
416  All treatment groups compared in an IVPT study should be dosed on the skin samples from the 
417  same set of donors, with the same number of replicates per donor per treatment group. These 
418  treatment groups should also use the skin samples from the same anatomical site from all donors, 
419  unless varying these parameters is essential to the design of the study and the evaluation of the 
420  TDS. The study report should include the equilibrated skin surface temperature prior to dose 
421  application, and the ambient temperature and relative humidity in the laboratory, as well as the 
422  extent of qualification of the sample analytical methods (e.g., HPLC). 
423   
424  g.  Extractable and Leachable Testing 
425   
426  All TDS should be evaluated for potential compounds that could be transferred from the product 
427  to the patient. This evaluation should include assessments of extractables and leachables, 
428  consistent with USP <1663> and <1664>. 
429   
430  As defined in United States Pharmacopeia (USP)21 General Chapter <1663> Assessment of 
431  Extractables Associated with Pharmaceutical Packaging/Delivery Systems, extractables are 
432  organic and inorganic chemical entities that are released from a pharmaceutical packaging/ 
433  delivery system, packaging component, or packaging material of construction and into an 
434  extraction solvent under laboratory conditions. The extraction conditions should accelerate or 
435  exaggerate the normal conditions of storage and use for a packaged dosage form. 
436   
437  As defined in USP General Chapter <1664> Assessment of Drug Product Leachables Associated 
438  with Pharmaceutical Packaging/Delivery Systems, leachables are foreign organic and inorganic 
439  entities that are present in a packaged drug product because they have leached into the packaged 
440  drug product from a packaging/delivery system, packaging component, or packaging material of 
441  construction under normal conditions of storage and use or during accelerated drug product 
442  stability studies. 
443   
444  In the context of this guidance, extractable impurities are chemical entities that can be drawn out 
445  of the backing membrane, release liner, pouching material, printed ink, internal membranes, and 
446  components other than the drug substance and adhesive matrix by a solvent system. 
447  Additionally, an extraction study can detect compounds introduced into the TDS from the 
                                                 
21 USP references in this guidance refer to USP 41NF 36. 
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448  manufacturing process, which can impact the final impurity profile of the TDS product. In the 
449  context of this guidance, leachables are chemical entities present in a packaged TDS because 
450  they leached into the adhesive matrix (or where applicable, reservoir) under normal conditions of 
451  storage or during accelerated stability studies. These compounds may transfer from the adhesive 
452  matrix (or reservoir) to the patient during use. 
453   
454  Extractable studies are used to inform the leachable study design. The leachable data should be 
455  correlated, if possible, with the extractables profile(s) determined under the various control 
456  extraction study conditions. Both extractable and leachable studies should have adequate 
457  sensitivity to detect compounds potentially released at a level associated with patient exposure 
458  when a product is used at the maximum daily dose (e.g., 1.5 mcg/day for standard mutagenic 
459  compounds in a chronic-use drug product22), unless otherwise justified. For some products, the 
460  maximum daily dose may require applying more than one TDS.  
461   
462  Adhesive impurities such as residual monomers, initiator byproducts, and aldehydes are not 
463  considered extractables or leachables because these impurities are present at peak concentrations 
464  before product manufacture. Control of adhesive impurities is discussed elsewhere in this 
465  guidance (see section IV. INFORMATION TO BE SUBMITTED IN AN APPLICATION, C. 
466  Control of TDS Product). However, the leachable studies discussed below may be leveraged to 
467  justify adhesive impurity limits or as part of the toxicological risk assessment for adhesive 
468  impurities because a leachable study is performed on the proposed commercial product. 
469   
470  To aid in the extractable and leachable analyses described below, applicants should contact raw 
471  material suppliers to identify potential extractables of toxicological concern, such as residual 
472  monomers from backing materials. 
473   
474  i.  Extractable Studies 
475   
476  Extractable studies should be conducted early in the pharmaceutical development process to 
477  understand the potential leachables from components of the proposed commercial TDS. These 
478  studies should be conducted on components such as backing membrane, release liner, rate 
479  controlling or other internal membranes, ink and pouching. The testing components should be 
480  extracted in a variety of solvents with a range of polarities under vigorous laboratory extraction 
481  conditions to maximize the levels of extractables and identify as many potential leachables as 
482  possible. One of the extraction solvents used in the extractable studies should include the solvent 
483  of the proposed commercial adhesive(s) platform or the known residual solvents for the finished 
484  TDS. The choices of solvents used should be justified. 
485   
486  ii.  Leachable Studies 
487   
488  The conditions of the leachable studies should mimic as closely as possible the worst-case 
489  clinical conditions of the skin (e.g., sweating during rigorous exercise). The solvent/solution 
490  selection (such as salt concentrations), temperature, level of agitation, duration of exposure to the 
491  solvent, etc., selected for the studies should be justified. The release liner should be removed 
                                                 
22 See FDA guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in 
Pharmaceuticals To Limit Potential Carcinogenic Risk (March 2018). 
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492  from the system during the study to adequately expose the adhesive layer to the biologically 
493  relevant solvent. Applicants should conduct a multi-timepoint leachable analysis (e.g., 0, 6, 12, 
494  24 months) to provide a comprehensive leachable profile and identify any trends in leachables as 
495  these data could impact the shelf life of the product. At the time of application submission, data 
496  should be submitted from a leachable study performed on samples from multiple batches stored 
497  at a minimum of 6 months under accelerated and long term conditions. We recommend 
498  conducting leachable studies on the same three distinct laminates of TDS placed on stability 
499  testing. 
500   
501  h.  Assessing the Effects of Heat 
502   
503  Heat from external sources such as a heating blanket, and potentially from a rise in internal body 
504  temperature due to strenuous exercise or fever, may affect the rate of drug release from the TDS 
505  and the absorption of drug into and through the skin. We recommend that applicants study the 
506  impact of an elevated TDS/skin surface temperature on the delivery profile of TDS relative to its 
507  delivery profile at a normal TDS/skin surface temperature. 
508   
509  For a TDS product to be submitted in an NDA, we recommend that the heat effect studies be 
510  conducted as part of a clinical study using the proposed commercial product. In designing the 
511  heat effect studies, critical factors such as appropriate elevated test temperature(s), heat exposure 
512  onset time(s), duration(s), and cycles (if any), as well as mechanisms of heat exposure (e.g., 
513  heating lamp, heating pad, etc.) should be identified. 
514   
515  For a TDS product to be submitted in an ANDA, the applicant should evaluate whether the test 
516  TDS, used under elevated temperature conditions, increases drug delivery compared to the 
517  reference (R) TDS. The ANDA applicant should provide the results of an IVPT study comparing 
518  the drug delivery characteristics for the test TDS and the R TDS at normal and elevated 
519  temperatures using skin from multiple individuals (donors), with multiple replicate diffusion 
520  cells evaluated per donor, per treatment (test versus R), and per temperature condition. An IVPT 
521  study with a sufficient number of donors and replicates per donor per treatment per temperature 
522  condition is recommended to obtain meaningful data. A study with fewer than four donors and 
523  four replicates per donor per treatment per temperature may be difficult to interpret. 
524   
525  We recommend a parallel evaluation and comparison of the test and R TDS under the following 
526  baseline and elevated temperature conditions: 
527   
528  1.  BASELINE: Both the test and R products should be maintained at a TDS/skin surface 
529  temperature of 32 1C for the entire study duration. 
530   
531  2.  ELEVATED TEMPERATURE: Both the test and R products should be maintained at 
532  a TDS/skin surface temperature of 32 1C until a specified time, approximately 
533  when the peak flux is observed, and then maintained at a TDS/skin surface 
534  temperature of 42 2C for a period thereafter, which may be the remainder of the 
535  study duration. 
536   
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537  It should not be assumed that a set temperature for a circulating water bath will provide the target 
538  temperature at the TDS/skin surface. The TDS/skin surface temperature should be directly 
539  measured using an infrared thermometer or other temperature probe. The study duration for a 7-
540  day wear TDS need not encompass the entire labeled duration of wear. It may be adequate to 
541  perform an IVPT study for a 48 or 72 hour duration, if that duration is sufficient to reach the 
542  peak drug delivery rate under baseline conditions. Alternatively, an applicant may justify 
543  evaluating other conditions or scenarios of exposure to elevated temperatures that represent the 
544  worst-case scenario for a given TDS product or indicated patient population. 
545   
546  i.  Microscopic Matrix Evaluation 
547   
548  Due to complexities of many TDS formulations, adhesive matrices often do not form true 
549  solutions, rather they manifest as dispersions. If rearrangements of the dispersed-like system 
550  occur over time within the matrix, they can possibly lead to lack of adhesion or changes in drug 
551  delivery and release. As such, it is important to have a good understanding of the TDS 
552  formulation, the way the drug substance and excipients are dispersed within the adhesive matrix, 
553  and the tendency of the matrix to change over time from product release through its expiry 
554  period. Therefore, it is informative to assess surface and cross-sectional changes in the TDS 
555  matrix throughout the shelf life of the developmental batches using high-powered microscopy, 
556  elemental mapping, or other appropriate tools. These tools may not be appropriate for every 
557  TDS; applicants should provide a scientific justification for the tools used. These assessments 
558  will help achieve comprehensive understanding of product and process, mitigate quality-related 
559  risks, and assure that the TDS meets the requisite quality attributes through its expiry period. 
560   
561  4.  Proposed Manufacturing Changes 
562   
563  Scale-up proposals and other process changes may be proposed in an original NDA or ANDA, 
564  but the level of additional information needed to support these changes will generally be 
565  commensurate with the risk of the change to adversely impact product quality. In general, 
566  changes to TDS after the conduct of pivotal clinical studies should be avoided when possible 
567  because of the sensitivity of TDS to small changes in formulation and manufacturing process. 
568   
569  Low-risk changes may be adequately supported with updated master batch records and batch 
570  formulas. Examples include scale-up of solvent-based and aqueous mixtures within a factor of 10 
571  using equipment of the same design and operating principles, or proposing a change to 
572  converting and pouching equipment of the same design and operating principle. 
573   
574  Moderate-risk changes may warrant additional developmental studies and stability data on 
575  commercial scale batches to demonstrate that they will not result in an adverse impact on the 
576  quality of the product.  Examples of such changes may include scale-up of hot-melt mixtures 
577  within a factor of 10, scale-up of screw-based mixing processes, and changes to 
578  coating/drying/laminating equipment of the same design and operating principle. 
579   
580  Changes that pose a high risk to quality may warrant additional in vivo studies. An example is 
581  changing the manufacturing process to incorporate equipment of a different design and operating 
582  principle. 
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583   
584  B.  Manufacture 
585   
586  As described in ICH M4Q, section 3.2.P.3 of the application should contain information about 
587  where and how the TDS product will be manufactured. The batch formula and a description of 
588  the manufacturing process and process controls should be provided. A detailed schematic 
589  diagram of the proposed production process, including descriptions of the equipment, operating 
590  conditions, and process controls, should also be provided.23 
591   
592  During process development, the applicant should identify process variables that have a potential 
593  to impact TDS product CQAs. These process development studies inform commercial process 
594  qualification and continued process verification later in the product life cycle. 
595   
596  Typical TDS manufacturing steps/unit operations are listed below (a non-exhaustive list). For 
597  processes that incorporate these steps, the applicant should describe how each operation and 
598  associated controls were developed, addressing the considerations below, specifically, the CQAs 
599  that may be impacted by the operation, and the relevant process parameters and material 
600  attributes that may impact the output of each operation: 
601   
602    Mixing: Mixing operations produce bulk mixtures for the coating step. Mixing can 
o
603  impact CQAs such as assay, stability of drug substance and/or excipients, content 
604  uniformity, microscopic appearance, and physical properties of the adhesive. The 
605  control strategy should address the impact of equipment design, order of material 
606  addition, and process parameters (such as mixing speeds, mixing times, temperatures, 
607  redispersion or recirculation conditions, and deaeration conditions) on CQAs, and 
608  should be justified, as necessary, based on development studies. CMAs that can 
609  impact mixing include drug substance particle size, polymorphic form, raw material 
610  rheological attributes, and percent solids for materials supplied in solvent-based 
611  mixtures. 
612   
613    Coating, drying, and lamination: Coating is the application of a mixture to a substrate. 
o
614  Depending on the equipment used, coating can impact CQAs such as content 
615  uniformity and microscopic appearance. Though CPPs are equipment dependent, 
616  firms should demonstrate that the control strategy (e.g., process parameters to be 
617  controlled) is adequate to ensure content uniformity and microscopic appearance for 
618  the full duration of the coating operation. CMAs that can impact coating include the 
619  rheology of the bulk mixture and within-roll uniformity of the substrate to be coated. 
620   
621  Drying involves the removal of solvent from the mixture following the coating 
622  process. This process step can impact CQAs such as assay, permeation enhancer 
623  content, antioxidant content, water content (for hydrogels), content uniformity, 
624  microscopic appearance, drug release, product stability, residual solvents, residual 
625  adhesive impurities, and physical properties of the adhesive matrix. Therefore, CPPs 
626  for drying that may need to be considered during process development include line 
                                                 
23 See 21 CFR part 314.50(d)(1)(ii)(c). 
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627  speed, the pump or screw speed, zone temperatures, air flow rates, temperature of the 
628  drying air, and humidity of the drying air. Process development should also consider 
629  the CMAs that can impact drying such as solvent and adhesive impurity content in the 
630  bulk mixture. Applicants should also provide data to justify any drug substance 
631  overage or excipient excess that may be needed to compensate for any evaporation 
632  during drying. 
633   
634  Lamination involves the combining of multiple layers of a given transdermal system 
635  design into a single common laminate. Applicants should provide development data 
636  for corona treatments if such a process is used to bond the adhesive to a backing film 
637  or rate-controlling membrane.  
638   
639    Slitting and Printing: The bulk product is typically slit longitudinally into narrower 
o
640  rolls of laminate for further processing. Slitting and printing are typically low risk 
641  steps; however, if certain aspects of the printing processes, e.g., excessive penetration 
642  depth or heat input, can adversely affect product quality, then printing processes 
643  should be characterized and controlled. 
644   
645    Converting and pouching: Converting and pouching typically involve cutting a 
o
646  continuous laminate into individual units and sealing the unit in a heat-sealed pouch. 
647  CQAs affected by these processes include usability of the product (e.g., the ability to 
648  remove a release liner) and pouch integrity. Common CPPs for these steps include 
649  heat sealing temperatures and dwell times. 
650   
651    Curing: Some TDS have processing steps to complete a curing reaction after drying 
o
652  or pouching. Curing time and curing conditions are common CPPs for this step. 
653  Curing should be completed before batch release testing if curing could impact test 
654  results. 
655   
656    Hold times: Hold times must be defined and justified for in-process materials held 
o
657  between unit operations (21 CFR part 211.111). Applicants should use a risk-based 
658  approach to determine which CQAs to monitor during hold time studies. 
659   
660    Other considerations: Tubing and other product-contact equipment must be qualified 
o
661  as non-reactive, non-additive, and non-absorptive (21 CFR part 211.65(a)). The 
662  selection of the tubing and certain product-contacting equipment should be risk-
663  based, i.e., dependent on the duration of contact, process temperature, solvent system, 
664  material considerations, clearance of leachables during manufacturing, and clinical 
665  use considerations.  
666   
667  In-process controls (IPCs) for TDS are an integral part of the control strategy. The description of 
668  the proposed IPCs should address the following: 
669   
670    At the mixing stage, IPCs can provide assurance of assay, viscosity, uniformity, and 
671  pH for aqueous mixtures. If multiple samples are taken from a dispersed mixture, 
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672  applicants should specify the mean, range for individual samples, and percent relative 
673  standard deviation. 
674   
675    IPCs for coating, drying, and lamination can provide assurance of uniformity across 
676  the laminate and throughout the run. For example, measurements for film appearance, 
677  coat weight, and/or a test for residual solvents may be applicable IPCs for coating and 
678  drying. Film appearance measurements that allow detection and rejection of defects 
679  affecting continuity of an adhesive laminate (e.g., streaks) should be described in the 
680  application. Additionally, for films that are dispersions at the microscopic scale (e.g., 
681  acrylic adhesive dispersed in silicone, povidone dispersed in silicone, or solid drug 
682  substance dispersed in adhesive), applicants should describe the IPCs established to 
683  monitor uniformity throughout a coating run in the application. Samples for testing 
684  coat weight and uniformity should be representative of the full length and width of a 
685  laminate. Alternatively, these attributes can be monitored continuously (e.g., by the 
686  use of in-line coating measurement tools). In cases where the upstream controls can 
687  be used to confirm certain finished TDS specifications, such as residual solvents and 
688  residual adhesive impurities, IPC testing can be used in lieu of release testing for 
689  these attributes.24 
690   
691    For converting and pouching, IPCs can provide assurance of pouch integrity, product 
692  placement within the pouch, and product appearance (e.g., adequacy of the printed 
693  label, die-cuts, and kiss-cuts). An automated system can perform in-process checks 
694  for product appearance in lieu of human operators if the automated system is 
695  demonstrated to be suitable for the intended task(s). 
696   
697  C.  Control of TDS Product 
698   
699  Section 3.2.P.5 of the application should contain the following information on control of the 
700  TDS product: 
701   
702    Specification 
703    Analytical procedures 
704    Validation of analytical procedures 
705    Characterization of impurities 
706    Batch analyses 
707    Justification for the proposed specification 
708   
709  Typical CQAs included in TDS specification:  
710   
711    Description 
712    Identification 
713    Assay 
                                                 
24 See Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 
Guidance - Records and Reports at the following site: 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124787.htm. 
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714    Impurities and degradation products 
715    Uniformity of dosage units 
716    Permeation enhancer content, when applicable 
717    Adhesion 
718    Release liner peel  
719    Tack  
720    Shear 
721    Cold flow 
722    In vitro drug release  
723    Drug substance crystal presence 
724    Pouch integrity 
725    Microbial limits, when applicable25 
726    Moisture content, when applicable 
727    Residual solvents 
728   
729  The proposed analytical procedures should be documented in sufficient detail that they can be 
730  reviewed and reproduced in FDA laboratories. In some cases, if upstream controls can be used to 
731  confirm that a batch of product meets a CQA listed on the specification, that attribute may not 
732  need to be tested at release for every batch, but should be indicated as such on the 
733  specification.26 Applicants proposing a control strategy using such an approach should provide 
734  justification. 
735   
736  Some of the methods and criteria associated with CQAs typical for TDS are described below. 
737   
738  a.  Adhesive Impurities 
739   
740  Adhesives may contain residual monomers, initiator byproducts, aldehydes, etc. The safety of 
741  these compounds should be assessed, as some of these compounds are classified as neurotoxic 
742  (e.g., tetramethylsuccinonitrile) or mutagenic (e.g., crotonoaldehyde). Manufacturers are 
743  encouraged to contact the raw material suppliers to discuss the selected adhesive raw material 
744  and all potential impurities, as some impurities may not be reported on the certificates of analysis 
745  provided by the supplier. Applicants should discuss the potential impurities arising from the raw 
746  material in the application. A control strategy for any impurity of toxicological relevance should 
747  be established and justified. The control strategy may include testing at the raw material stage, 
748  demonstrating that the manufacturing process is capable of consistently removing the impurities 
749  of concern, testing of the final laminate, or a combination of the above. 
750   
751  To support a proposed control strategy based on the capability of the manufacturing process to 
752  consistently remove any impurities of concern, applicants should provide data to demonstrate a 
753  reduction in the level of the impurity in the final laminate (or finished product) compared to the 
                                                 
25 When applicable, we recommend manufacturers assess the risk of microbiological contamination to their TDS in 
order to establish the appropriate microbiological tests, specification, and manufacturing operations for their 
product. Based on this risk assessment, manufacturers should leverage existing approaches (ICH guidelines, USP 
standards, FDA guidance, etc.) to determine the testing necessary for their product. 
26 See FDA guidance for industry Q8(R2) Pharmaceutical Development. 
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754  level in the same batch of raw material.These data are necessary to quantitatively demonstrate 
755  effectiveness of the manufacturing process in removing the impurity and to establish controls for 
756  adhesive impurities based on levels in the raw material rather than on the final product. 
757   
758  Applicants may consider leveraging the leachable study discussed in the pharmaceutical 
759  development section of this guidance by testing adhesive impurities in the leachate. The 
760  leachable information can be used to provide toxicological justification for impurity limits or the 
761  information can be included as part of the toxicological risk assessment. 
762   
763  b.  Uniformity of Dosage Units 
764   
765  TDS specifications should include a test and acceptance criterion for content uniformity for the 
766  dosage units. If the finished TDS is designed to be cut by the user, uniformity should also be 
767  demonstrated among pieces cut from a single unit. 
768   
769  c.  Permeation Enhancer Content 
770   
771  Products that utilize permeation enhancers to establish or maintain drug delivery should include 
772  a test and acceptance criterion for permeation enhancers at release and throughout stability. An 
773  acceptance criterion that is wider than the typical range for a particular permeation enhancer may 
774  require in vivo justification in the absence of an in vitro in vivo correlation. 
775   
776  d.  Adhesion Testing (Peel Adhesion, Release Liner Peel, Tack, and Shear Tests) 
777   
778  Using currently available methods, in vitro adhesion testing does not correlate to in vivo 
779  adhesion, but in vitro adhesion testing can be useful for quality control (QC) purposes. In vitro 
780  adhesion testing should include peel adhesion, release liner removal, tack, and shear (dynamic or 
781  static).27 There are multiple methods and different experimental parameters for each of the tests. 
782   
783  The peel adhesion test measures the force required to remove (peel away) a TDS that has been 
784  applied to a standard test panel (e.g., polished stainless steel). The measurement of peel adhesion 
785  is influenced by the test parameters such as dwell time, substrate (e.g., stainless steel, high 
786  density polyethylene (HDPE)), peel angle, and peel speed. 
787   
788  A release liner peel test measures the force required to separate a TDS from its release liner. The 
789  measurement of release liner peel is influenced by experimental parameters such as peel angle 
790  and peel speed. 
791   
792  The probe tack test measures the force required to separate the test probe from the adhesive of 
793  the TDS. Tack measurement is influenced by the test parameters such as the contact area, the 
794  contact pressure, the time of contact (or dwell time), and rate of separation. 
795   
796  There are two categories of shear testing, namely dynamic and static. In the dynamic test, the 
797  TDS is pulled from a standard test panel (e.g., polished stainless steel). Dwell time, speed, type 
798  of test panel, mode of failure, and sample size are the typical test parameters reported for the 
                                                 
27 See USP 41NF 35 General Chapter <3> Topical and Transdermal Drug Products-Product Quality Tests. 
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799  dynamic shear test. In the static shear test, the TDS sample is applied to a test panel that is at an 
800  angle 2 from the vertical, and the sample is subjected to a shearing force by a means of a given 
801  weight (e.g., 1000 g) suspended from the TDS; the time required to detach a standard area of the 
802  TDS from a stainless steel test panel under a standard load is measured. Dwell time, weight used, 
803  type of test panel, mode of failure, and sample size are the typical test parameters reported for 
804  the static shear test. The time taken for the TDS sample to detach from the test panel is also 
805  reported. 
806   
807  e.  Cold Flow 
808   
809  Cold flow is the creeping or oozing of the adhesive matrix beyond the perimeter of the backing 
810  membrane or through the release liner slit. Cold flow may be present on the TDS, release liner, 
811  pouch, or disposable films (sometimes termed slip sheets or protective films, such as a film over 
812  the backing and a film over the release liner). Though a quantitative method of assessing cold 
813  flow can provide a meaningful measurement, it may not describe the difficulty in removing the 
814  TDS from the pouch or the protective films from the TDS. The most accurate cold flow 
815  assessment for TDS will likely come from a combination of product-specific quantitative and 
816  qualitative methods. 
817   
818  The test methods should be discriminating and scientifically justified. Manufacturers should 
819  propose product-specific acceptance criteria with justification supported by product development 
820  research. 
821   
822  f.  In vitro Drug Release 
823   
824  USP General Chapter <724> describes the apparatuses to use for in vitro release testing and the 
825  acceptance criteria for each apparatus; however, method development and validation is not 
826  addressed. General recommendations for in vitro release testing of TDS are described below 
827  along with considerations for method design and validation. 
828   
829  In vitro drug release testing of TDS products is typically performed using specific, qualified 
830  apparatus such as: Paddle over Disk (Apparatus 5), Cylinder (Apparatus 6), or Reciprocating 
831  Holder (Apparatus 7). 
832   
833  The NDA or ANDA submission for the TDS product should include a method development and 
834  validation report with complete information/data supporting the proposed drug release method 
835  and acceptance criteria. 
836   
837  Sufficient detail and data should be included in the method development and validation report so 
838  the adequacy of the method for batch release and stability testing can be properly assessed. 
839  Examples of parameters to evaluate during method development include selection of USP 
840  apparatus/other equipment, drug release medium, rotation or agitation speed, temperature, pH, 
841  sink conditions, use of a surfactant, and other technical aspects of the test. An in vitro drug 
842  release method should be simple, reliable, reproducible, discriminating, and robust. Applicants 
843  should strive to develop a method that releases as much drug as possible. 
844   
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845  The validation section of the report should include complete information/data regarding: i) the 
846  discriminating ability of the selected method, ii) the validation of the drug release methodology, 
847  and iii) the validation/verification of the analytical method selected to assay the drug release 
848  samples. The selected method should be able to differentiate the release profiles of TDS that are 
849  intentionally manufactured with meaningful variations in critical process parameters and 
850  formulation components. Validation data should demonstrate the range and sensitivity of the 
851  method for proportional drug release across different strengths of the TDS. In addition, 
852  validation data should demonstrate reproducibility of the method for drug release across different 
853  runs of the same batch and its robustness, i.e., its capacity to remain unaffected by changes in 
854  receptor medium temperature, paddle rate, and other method parameters. 
855   
856  The acceptance criteria for the in vitro drug release test should be based on the proposed TDS 
857  product batch release data, including data from bio-batches (e.g., BE, PK, Clinical), 
858  registration/exhibit batches, and commercial batches (if available). To set the acceptance criteria 
859  for the in vitro drug release test, a complete drug release profile should be established by 
860  collecting data until there is no increase in drug release over three consecutive time points 
861  (sampling every 2 hours). The drug release profile of TDS products typically encompasses 
862  initial, middle, and terminal phases; thus, for setting the acceptance criteria, there should be at 
863  least one sampling time point covering each phase. The drug release data should be reported as 
864  the cumulative percent of drug being released with time. The acceptance criteria range for each 
865  specific timepoint should be based on the mean percentage value of drug released  10 percent 
866  using the drug release data generated at these times. The percentage should be determined based 
867  on the TDS products label claim. If less than 100 percent drug is released, but no drug increase 
868  is observed over three consecutive sampling timepoints (i.e., incomplete drug release), the 
869  amount of drug reached at the plateau should be considered 100 percent for the purposes of 
870  estimating the percent of drug release over time. 
871   
872  Wider acceptance criteria range for the drug release test may be acceptable if they are supported 
873  by an approved in-vitro in-vivo correlation model. 
874   
875  g.  Crystal Presence 
876   
877  The presence of crystals or crystallization of the drug in the TDS over time can negatively 
878  impact the product performance. Therefore, it is important to establish a test and acceptance 
879  criteria to confirm the absence of crystals to be used at release and on stability. Microscopic and 
880  photometric methods are preferred rather than a simple visual count. It is recognized that some 
881  products are designed to be suspensions, however, this design does not preclude the need for a 
882  crystal specification. Suspension products should still include tests and acceptance criterion to 
883  ensure against crystal propagation, which may impact drug delivery or adhesion properties of the 
884  product. 
885   
886  h.  Pouch Integrity 
887   
888  The pouch for a TDS is critical to the stability and integrity of the product. Pouch integrity 
889  testing should be conducted as part of finished product release unless justification is provided for 
890  an alternative approach that assures the finished product specification is met. 
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891   
892  D.  Additional Stability Studies 
893   
894  In addition to the standard battery of formal stability and photostability studies for drug 
895  substance and drug products discussed in ICH Q1A and ICH Q1B,28 TDS applicants and 
896  manufacturers should conduct stability studies under challenge conditions that include 
897  temperature excursions, freeze/thaw, and/or crystal seeding. These additional studies are 
898  intended to address certain product quality issues such as crystal formation and growth. 
899  Moreover, in-use photostability testing may be appropriate to conduct for certain TDS 
900  formulations, depending on backing membrane opacity, duration of wear, and its expected 
901  exposure to light when in use. 
902   
903  V.  SPECIAL TOPICS 
904   
905  A.  Product Adhesion Considerations 
906   
907  In vivo adhesion studies provide the greatest prediction of adhesion, a CQA, for a proposed 
908  commercial product. Applicants should demonstrate that reasonable efforts were made to 
909  optimize adhesive characteristics of the TDS. This optimization should balance properties such 
910  as adhesiveness, cohesiveness, and stability to ensure a consistent and uniform adhesion of its 
911  entire surface area to the skin for the entire duration of wear. Applicants should develop a 
912  comprehensive strategy for assessing the adhesive attributes of the TDS. In vivo adhesion studies 
913  are necessary to demonstrate adequate adhesion of the TDS. Therefore, when possible, such as in 
914  efficacy studies for an NDA, subject diaries describing the actual in-use product adhesion 
915  performance should be used. This information bolsters adhesion data collected from the studies 
916  described below and in other guidances.29 
917   
918  Characterization of the adhesive properties of a TDS should demonstrate that the labelled uses 
919  are substantiated. For example, if the TDS is intended to be worn during bathing and showering, 
920  applicants should demonstrate that the TDS will continue to adhere during and after such 
921  incidental exposure to water. Product reinforcement, such as taping the edges or use of overlays, 
922  or occluding the product from water during bathing should not be permitted during the in vivo 
923  adhesion evaluation. 
924   
925  We recommend that when assessing the adhesion of a TDS, applicants use a 5-point numerical 
926  scale in which each score corresponds to a specified range of adhered surface area of the TDS, as 
927  follows: 
928   
929  0 =  90% adhered (essentially no lift off the skin)  
930  1 =  75% to < 90% adhered (some edges only lifting off the skin)  
931  2 =  50% to < 75% adhered (less than half of the TDS lifting off the skin)  
                                                 
28 See FDA guidances for industry Q1A(R2) Stability Testing of New Drug Substances and Products (November 
2003), and Q1B Photostability Testing of New Drug Substances and Products (November 1996). 
29 See FDA draft guidance for industry Assessing Adhesion with Transdermal Delivery Systems and Topical Systems 
for ANDAs (October 2018). When final, this guidance will represent the FDAs current thinking on this topic. 
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Draft  Not for Implementation 
932  3 = > 0% to < 50% adhered (not detached, but more than half of the TDS lifting off the 
933  skin without falling off)  
934  4 = 0% adhered (TDS detached; completely off) 
935   
936  Additionally, the following information should be collected: 
937   
938    At each time point when adhesion is assessed on the above described 5-point scale, 
939  the scorer should also record their actual percent adherence estimate (e.g., if the 
940  observer scores the product as a two on the five point scale and estimates that the 
941  product appears to be 60 percent adhered, a score of two and a 60 percent should be 
942  recorded for that time point). 
943   
944    Photographic evidence showing the extent of TDS adherence to the skin at each time 
945  point should be provided. 
946   
947  B.  Product Storage and Disposal  Labeling Considerations 
948   
949  TDS storage conditions should be supported by stability data and stated in the label. Generally, 
950  we recommend controlled room temperature for the storage of TDS. Excursions, if permitted, 
951  should be indicated on the label. The label should also state that TDS should not be stored 
952  outside of the pouch if that is necessary to preserve the safety, efficacy, and quality of the TDS. 
953   
954  Transdermal and topical delivery systems often contain post-use residual drug in the delivery 
955  system. Considering the therapeutic nature of the drug compound and potential adverse events 
956  resulting from unintended exposure, the instruction for product disposal should be clearly 
957  outlined in the labeling. It is important that the disposal process prevents exposure of the residual 
958  drug to the environment and/or other people. Depending on the nature of the product, special 
959  instructions may be required to prevent exposure to children and caregivers, which could result 
960  in significant safety-related consequences. 
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