Physicochemical and 
Structural (Q3) 
Characterization of 
Topical Drug Products 
Submitted in ANDAs 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (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) Susan Levine 240-402-7936. 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
October 2022 
Generic Drugs
   
 
Physicochemical and 
Structural (Q3) 
Characterization of 
Topical Drug Products 
Submitted in ANDAs  
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/guidance-compliance-regulatory-information/guidances-drugs 
 
 
   
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
October 2022 
Generic Drugs
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 3 
III.  RECOMMENDATIONS FOR Q3 CHARACTERIZATION ...................................... 6 
IV.  Q3 COMPARABILITY AND IMPLICATIONS FOR BIOEQUIVALENCE ........... 9 
A.  Q3 Sameness ................................................................................................................................. 10 
B.  Q3 Similarity ................................................................................................................................ 11 
C.  Q3 Difference ................................................................................................................................ 12 
V.  COMMUNICATIONS WITH THE AGENCY ........................................................... 12 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Physicochemical and Structural (Q3) Characterization of Topical 
2  Drug Products Submitted in ANDAs  
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (Agency or FDA) 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   
15  I.  INTRODUCTION  
16   
17  This guidance is intended to assist applicants who are submitting abbreviated new drug 
18  applications (ANDAs) for liquid-based and/or other semisolid products applied to the skin, 
19  including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called 
20  topical products.2 Because of the complex route of delivery associated with these products, 
21  which are typically locally acting, and the potential complexity of certain formulations, topical 
22  products (other than topical solutions) are classified as complex products.3  
23   
24  This guidance provides recommendations for physicochemical and structural (collectively, Q3) 
25  characterizations that can be used (1) to identify the dosage form of a proposed generic (test) 
26  topical product and (2) to describe properties of the drug product that may be critical to its 
27  performance (to support a demonstration of bioequivalence (BE)4). When comparing the Q3 
28  attributes of two topical products (e.g., to support a demonstration of BE), we generally advise 
29  that applicants conduct a comparative Q3 characterization of their proposed generic product 
30  against the reference standard, which ordinarily is the reference listed drug (RLD).5 This 
 
1 This guidance has been prepared by the Office of Generic Drugs in collaboration with the Office of Pharmaceutical 
Quality, both in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.  
2 Topical products in ANDAs within the scope of this guidance include ointments, creams, lotions, emulsions, 
pastes, shampoos, gels, suspensions, solutions, sprays, aerosols, foams, and other semisolid and/or liquid-based 
dosage forms dispensed with a structured arrangement of matter (which may include more than one phase state). 
This guidance does not address products other than the topical products mentioned in this footnote, although the 
scientific principles discussed herein may be relevant in other contexts and drug products.  
3 A complex product, as defined in the GDUFA Reauthorization Performance Goals and Program Enhancements 
Fiscal Years 2023  2027 (GDUFA III Commitment Letter) (available at 
https://www.fda.gov/media/153631/download), includes, among others, products with complex formulations (e.g., 
colloids) and complex routes of delivery (e.g., locally acting drugs such as dermatological products).  
4 Bioequivalence is defined in  314.3(b). 
5 A reference listed drug is the listed drug identified by FDA as the drug product upon which an applicant relies in 
seeking approval of its ANDA (21 CFR 314.3(b)).  A reference standard, which is selected by FDA, is the specific 
drug product that the ANDA applicant must use in conducting any in vivo bioequivalence testing required to support 
 
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31  guidance does not address Q3 characterization of topical products for purposes of product quality 
32  control. Basic Q3 characterization of a topical product can be used to describe its dosage form 
33  (e.g., an emulsion). See section III of this guidance for more information on (1) a 
34  characterization of appearance and texture, (2) a characterization of phase states, and (3) a 
35  characterization of the structural organization of matter. These three types of characterizations 
36  typically constitute a basic Q3 characterization of a topical product. 
37   
38  Comprehensive Q3 characterization of a topical product can be used to compile a detailed profile 
39  of Q3 attributes that specifically describes the nature of that product and identifies a collection of 
40  attributes that describe the arrangement of matter (e.g., the polymorphic form(s) of the active 
41  ingredient(s) and/or the pH of the drug product) that may modulate the systemic or local 
42  availability of the active ingredient(s) from the product. See section III of this guidance for more 
43  information on the 10 types of characterizations that typically constitute a comprehensive Q3 
44  characterization of a topical product. 
45   
46  Comprehensive Q3 characterization of a reference standard for a topical product provides a 
47  detailed profile of Q3 attributes that is quintessentially characteristic of that reference standard; it 
48  establishes a reference for the arrangement of matter in that drug product. Because Q3 
49  characterization describes essential attributes of a drug product that may be critical to its 
50  performance, differences in Q3 attributes between a test topical product and reference standard 
51  can indicate a risk that the differences may potentially impact the respective bioavailability6 
52  (BA) and/or BE of the two products. Conversely, a demonstration that there are no significant 
53  differences in Q3 attributes between a test topical product and reference standard substantially 
54  mitigates the risk of potential failure modes for BE that may otherwise arise from any significant 
55  differences in Q3 attributes. 
56   
57  It is beyond the scope of this guidance to discuss specific reference standards for topical products 
58  or to enumerate the specific tests and comparative product characterizations that are 
59  recommended for each such product. FDA recommends that applicants consult this guidance in 
60  conjunction with any relevant product-specific guidances (PSGs)7 and in conjunction with any 
61  other relevant guidances for industry8 when considering the design and conduct of Q3 
62  characterization tests that may be appropriate to support a demonstration that a proposed generic 
 
approval of its ANDA (see  314.3(b)). We recommend that the reference standard also be used for in vitro testing. 
There may be circumstances (e.g., when the RLD is no longer marketed) in which the reference standard is a drug 
product other than the RLD.  For more information on RLD and reference standard products, see the guidance for 
industry Referencing Approved Drug Products in ANDA Submissions (October 2020). We update guidances 
periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
6 Bioavailability is defined in  314.3(b). 
7 Generic drug product-specific guidances are available at the Product-Specific Guidances for Generic Drug 
Development web page at https://www.fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-
development.  
8 Other relevant guidances include the draft guidances for industry In Vitro Release Test Studies for Topical Drug 
Products Submitted in ANDAs (October 2022) and In Vitro Permeation Test Studies for Topical Drug Products 
Submitted in ANDAs (October 2022). When final, these guidances will represent FDAs current thinking on these 
topics.  
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Draft  Not for Implementation 
63  topical product and its reference standard are of the same dosage form9 and are bioequivalent. 
64  FDA also recommends that applicants routinely refer to FDAs guidance web pages because 
65  additional guidances may become available that could assist in the development of a generic 
66  topical product.  
67   
68  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
69  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
70  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
71  the word should in Agency guidances means that something is suggested or recommended, but 
72  not required. 
73   
74   
75  II.  BACKGROUND 
76   
77  This guidance has been developed as part of FDAs Drug Competition Action Plan,10 which, in 
78  coordination with the Generic Drug User Fee Amendments (GDUFA)11 program and other FDA 
79  activities, is intended to increase competition in the marketplace for prescription drugs, facilitate 
80  the entry of high-quality and affordable generic drugs, and improve public health. 
81   
82  The Federal Food, Drug, and Cosmetic Act (FD&C Act) generally requires an ANDA to contain, 
83  among other things, information to show that the proposed generic drug product (1) is the same 
84  as the RLD with respect to the active ingredient(s), conditions of use, route of administration, 
85  dosage form, strength, and labeling (with certain permissible differences) and (2) is 
86  bioequivalent to the RLD.12 Thus, an ANDA will not be approved if the test products dosage 
87  form differs from that of the RLD (and no suitability petition under section 505(j)(2)(C) of the 
88  FD&C Act and 21 CFR 314.93 was approved) and/or if information submitted in the ANDA is 
89  insufficient to show that the test product is bioequivalent to the RLD.13 Generally, a generic drug 
 
9 The proposed generic topical product generally must have the same dosage form as its RLD.  See section 
505(j)(2)(A)(iii) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(2)(A)(iii)),  314.94(a)(6) (21 CFR 
314.94(a)(6)), and  314.127(a)(4) (21 CFR 314.127(a)(4)) (requiring ANDAs to contain information to show that 
the dosage form of the drug product is the same as that of the RLD absent an approved suitability petition); see also 
section 505(j)(2)(C) of the FD&C Act  (permitting an ANDA applicant to submit a suitability petition requesting 
certain changes from the RLD, including a change in dosage form).  In cases in which the reference standard is a 
drug product other than the RLD, we generally anticipate that a demonstration using Q3 characterizations that the 
proposed generic topical product has the same dosage form as its reference standard will be sufficient to demonstrate 
that the proposed generic topical product has the same dosage form as its RLD.  However, there may be 
circumstances in which the proposed generic topical product may need to make an additional showing to 
demonstrate that its dosage form is the same as the RLD.  
10 See FDA Drug Competition Action Plan (implemented in 2017 and designed to, among other things, further 
encourage robust and timely market competition for generic drugs), available at 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/fda-drug-competition-action-plan.  
11 In this guidance, GDUFA refers to the generic drug user fee program codified in the Generic Drug User Fee 
Amendments of 2012, Title III, Food and Drug Administration Safety and Innovation Act (Public Law 112-144), the 
Generic Drug User Fee Amendments of 2017, Title III, FDA Reauthorization Act of 2017 (Public Law 115-52), and 
the Generic Drug User Fee Amendments of 2022, Title III of Division F (the FDA User Fee Reauthorization Act of 
2022) of the Continuing Appropriations and Ukraine Supplemental Appropriations Act, 2023 (Public Law 117-180). 
12 See section 505(j)(2)(A), (j)(2)(C), and (j)(4) of the FD&C Act; see also 21 CFR 314.94.  
13 See section 505(j)(2)(A)(iii) and (iv) of the FD&C Act; see also  314.127(a)(4) and (a)(6). 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
90  product intended for topical use shall contain the same inactive ingredients as [its RLD] . . . 
91  [h]owever, an ANDA may include different inactive ingredients provided that the applicant 
92  identifies and characterizes the differences and provides information demonstrating that the 
93  differences do not affect the safety or efficacy of the proposed drug product.14  
94   
95  Additionally, for a drug product that is a solution for application to the skin (i.e., a topical 
96  solution), in vivo BE may be self-evident and a requirement of in vivo data for a product may be 
97  waived.15  The scientific principle is that if there is no difference in any aspect of the test 
98  products formulation compared to the RLDs formulation that may significantly affect systemic 
99  or local availability, then BE between the test product and RLD is considered self-evident. This 
100  scientific principle applies to topical solutions as well as semisolid dosage forms. However, the 
101  Q3 attributes of semisolid dosage forms are generally more complex, compared to solutions. 
102  Therefore, a comprehensive characterization of relevant Q3 attributes in semisolid dosage forms 
103  is recommended to determine whether or not differences may exist in their physicochemical or 
104  structural attributes.   
105   
106  This guidance describes the concepts of sameness, similarity, or difference in Q3 attributes of 
107  topical products and describes specific product characterizations that can be used to demonstrate 
108  the sameness, similarity, or difference in Q3 attributes between test topical products and 
109  reference standards for topical products. These concepts (and relevant product characterizations) 
110  can apply to a drug product that is a solution for application to the skin (e.g., characterization of 
111  physicochemical properties like pH), and are particularly useful when comparing test topical 
112  products and reference standards for topical semisolid products.  
113   
114  As noted above, there are two primary purposes for which Q3 characterization may be useful for 
115  topical products: 
116   
117  1.  To identify the dosage form.  
118   
119  The nomenclature used to describe the dosage form of topical products (e.g., solutions, 
120  suspensions, gels, lotions, creams, shampoos, ointments, pastes, etc.) is not precisely 
121  defined by a systematic classification of the compositional, physicochemical, or structural 
122  attributes of the drug product. Consequently, for topical products, it may not be possible 
123  to infer the Q3 attributes of a particular dosage form based upon the dosage form 
124  nomenclature. For example, a product designated as a cream may be comprised of a 
125  classic oil-in-water emulsion microstructure, or it may be an aqueous dispersion of 
126  different components. An ointment may be comprised of different types of components 
127  with different types of Q3 attributes; as examples, an ointment may have an oleaginous 
128  hydrocarbon base as a single phase with particles of suspended active ingredient(s), or it 
129  may be a water-in-oil emulsion, or it may be comprised of a polyethylene glycol base. In 
130  addition, although lotions are typically considered to be more fluid than creams, this may 
131  not always be true, and some creams may contain a substantially greater percent 
132  composition of water and volatiles than some lotions. Also, although creams and lotions 
 
14  314.94(a)(9)(v). 
15  320.22(b)(3) (21 CFR 320.22(b)(3)). 
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133  are typically considered to be emulsions, structural features like globules or droplets may 
134  not always be evident, and conversely, some gels may be emulsion dosage forms.  
135   
136  For topical products submitted in ANDAs, a comparison of basic Q3 characterizations 
137  (explained in section III of this guidance) for both the test topical product and reference 
138  standard is recommended as a reliable approach to demonstrate that a test topical product 
139  and its reference standard are the same dosage form.16  
140   
141  2.  To describe properties of the drug product that may be critical to its performance, which 
142  can support a demonstration of BE.  
143   
144  Physicochemical attributes of a drug product, such as pH, or structural attributes, such as 
145  globule size, may have the potential to impact product performance, and these 
146  physicochemical or structural characteristics may be sensitive to the formulation design 
147  and manufacturing processes. Thus, comprehensive Q3 characterization establishes a 
148  detailed profile of measurements for Q3 attributes that may be critical to product 
149  performance under relevant conditions (e.g., at different temperatures, at different shear 
150  rates/stresses, at different times during metamorphosis, and/or after being dispensed from 
151  a container closure system).  
152   
153  These Q3 attributes (discussed further in section III of this guidance) may confer 
154  important functionality to topical products. For example, the functional properties of a 
155  petrolatum-based ointment may include a relatively high occlusivity, high apparent 
156  viscosity, and long residence time at the site of administration. By contrast, the functional 
157  properties of an alcohol-based gel may include a relatively low occlusivity, low viscosity, 
158  and relatively rapid evaporation with characteristically rapid changes in the 
159  thermodynamic activity of the active ingredient(s) and in the rate of active ingredient 
160  delivery into the skin.  
161   
162  Additionally, differences in Q3 attributes between a test topical product and its reference 
163  standard may alter BA and/or increase the risk of failure modes for BE. In the context of 
164  this guidance, failure modes are considered to be the mechanisms by which problems 
165  might arise with the BE (or expected therapeutic performance) of a drug product as a 
166  result of a difference in one or more attributes of a test topical product compared to its 
167  reference standard, which could result in undesirable consequences for a patient. For 
168  example, differences in Q3 attributes can affect the solubility or stability of the active 
169  ingredient(s) in the formulation, the number and types of phase states, the diffusion and 
170  partitioning of active and inactive ingredients within the formulation and/or into the skin, 
171  the metamorphosis of the formulation on the skin, and/or the thermodynamic activity 
172  profile of the active ingredient(s), all of which may influence BA and BE. Thus, a 
173  comparison of comprehensive Q3 characterizations of the test topical product and 
174  reference standard for a topical product may be submitted in an ANDA to support an 
175  assessment of whether there are differences in Q3 attributes between the test topical 
176  product and its reference standard that may affect BE.  
 
16 See footnote 9. 
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177   
178  In summary, there are two primary purposes for which it is meaningful to compare the Q3 
179  attributes of test topical products and reference standards for topical products. Basic Q3 
180  characterization (explained in section III of this guidance) can describe the dosage form; thus, a 
181  comparison of basic Q3 characterizations can be used to demonstrate that the test topical product 
182  and its reference standard are the same dosage form.17 Comprehensive Q3 characterization 
183  provides a detailed profile of relevant Q3 attributes that is quintessentially characteristic of the 
184  reference standard; thus, a comparison of comprehensive Q3 characterizations can be used to 
185  support a demonstration of BE when the detailed profile of Q3 attributes for the test topical 
186  product matches the detailed profile of Q3 attributes for the reference standard (discussed further 
187  in section IV of this guidance). 
188   
189   
190  III.  RECOMMENDATIONS FOR Q3 CHARACTERIZATION  
191   
192  Basic Q3 characterization of a topical product, which can be used to describe its dosage form 
193  (e.g., an emulsion), typically includes (1) a characterization of appearance and texture, (2) a 
194  characterization of phase states, and (3) a characterization of the structural organization of 
195  matter. 
196   
197  Comprehensive Q3 characterization establishes a detailed profile of Q3 attributes that may be 
198  critical to product performance under relevant conditions (e.g., at different temperatures, at 
199  different shear rates/stresses, at different times during metamorphosis, and/or after being 
200  dispensed from a container closure system). The Q3 attributes of the dispensed product may be 
201  important to characterize and compare between different packaging configurations for a test 
202  topical product (e.g., tube versus pump).  
203   
204  The particular Q3 attributes that should be assessed for a specific proposed generic topical 
205  product to obtain a comprehensive Q3 characterization will depend on the nature and complexity 
206  of its reference standard. The following list provides general recommendations on the 
207  characterizations that may be used (as feasible) to create a detailed profile of relevant Q3 
208  attributes for a comprehensive Q3 characterization. 
209   
210   
211   
212  1.  Characterization of appearance and texture: includes as complete as possible a 
213  description of the look, feel, and smell of the dispensed product. Observations should 
214  characterize the color, clarity/opaqueness, texture, odor, and other product attributes (e.g., 
215  free from particulate matter or free from particles of the active ingredient). For example, 
216  a specific cream may be described as a white to off-white, smooth, opaque, soft-to-the-
217  touch cream containing uniformly dispersed drug substance with an alcohol smell that is 
218  free from phase separation and foreign particulate matter. As another example, a specific 
219  ointment may be described as a yellowish, opaque, viscous semisolid ointment containing 
220  uniformly dispersed drug substance with a greasy texture and without an unpleasant 
 
17 See footnote 9. 
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221  odor, lumps, or foreign particulate matter. As yet another example, a specific gel may be 
222  described as a translucent, white, hydroalcoholic, flowable gel with an alcohol odor and 
223  no clumping or particulate matter.   
224  2.  Characterization of phase states: includes representative high resolution micrographs 
225  (microscopy images) at multiple magnifications, with detailed sample preparation 
226  information. High resolution micrographs of the drug product at different magnifications 
227  that illustrate the absence of undissolved particulate matter may support a determination 
228  that any active ingredient is dissolved in the dosage form. Similarly, high resolution 
229  micrographs of the drug product at different magnifications, which illustrate the absence 
230  of any visible microstructures, may support a determination that the drug product is a 
231  single-phase dosage form. In this manner, single-phase products, multiple-phase products 
232  (e.g., emulsions), and products with suspended active ingredient(s) (or an absence of 
233  particulate matter) can be differentiated.  
234  3.  Characterization of structural organization of matter: includes an assessment of 
235  particle-size distribution and crystal habit, and/or emulsion globule-size distribution (as 
236  relevant, for multiple phase products). Full profiles of the particle- and globule-size 
237  distributions should be submitted for all relevant samples. In addition, for emulsions, the 
238  type of emulsion (e.g., oil-in-water or water-in-oil) should be assessed for the test topical 
239  product and reference standard using appropriate techniques (e.g., use of a water-soluble 
240  dye followed by microscopic evaluation, or dilution followed by assessment with a 
241  voltmeter).    
242  4.  Characterization of polymorphic form(s) of the active ingredient(s): includes in situ 
243  characterization within the drug product (for products with suspended active 
244  ingredient(s)). An absence of evidence for the existence of polymorphs does not 
245  constitute evidence that polymorphs do not exist. Therefore, a characterization of the 
246  polymorphic form(s) of the active ingredient in the test topical product and reference 
247  standard is typically recommended when the active ingredient (or unidentified particulate 
248  matter) is suspended in the drug product. The control of any polymorphic forms of the 
249  active ingredient in the test topical product should be justified in an ANDA, based upon 
250  the considerations outlined in Decision Tree #4 within the International Council for 
251  Harmonisation (ICH) guidance for industry Q6A Specifications: Test Procedures and 
252  Acceptance Criteria for New Drug Substances and New Drug Products: Chemical 
253  Substances (December 2000). 
254  5.  Characterization of rheological behavior: includes the following characterizations using 
255  a rheometer appropriate for monitoring the (non-Newtonian) flow behavior of liquid and 
256  semisolid dosage forms (more sophisticated rheological characterizations may be 
257  appropriate in some circumstances): 
258  a.  When feasible, complete flow curves (plotted as both shear stress versus shear rate 
259  and viscosity versus shear rate) should consist of multiple data points across the range 
260  of attainable shear rates, typically until low- or high-shear plateaus are identified; at a 
261  minimum, the apparent viscosity at low-, medium-, and high-shear rates should be 
262  characterized. 
263  b.  Yield stress values should be reported if the material tested exhibits plastic flow 
264  behavior. 
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265  c.  The linear viscoelastic response (storage and loss moduli versus frequency) should be 
266  measured and reported, if relevant. 
267  6.  Characterization of water activity and/or drying rate: includes an assessment of 
268  evaporation rate and is recommended for certain drug products with volatile ingredients 
269  (including water). For example, it may be informative to evaluate the water activity for a 
270  topical product that is an emulsion containing less than 50% weight/weight (w/w) of 
271  water, because differences in manufacturing processes may impact the interactions 
272  between the multiple phases in the formulation. Similarly, it may be informative to 
273  measure the drying rate for an alcohol-based gel that is expected to evaporate rapidly 
274  following topical application. However, neither water activity nor drying rate may be 
275  relevant for a petrolatum-based ointment. 
276  7.  Characterization of pH and buffering: includes a measurement of the pH of the product 
277  formulation, for drug products with an aqueous content, as well as a description of any 
278  buffer system, when relevant. 
279  8.  Characterization of oleaginous components: includes using the tests listed in the 
280  relevant United States Pharmacopeia (USP) monograph for petrolatum, for petrolatum-
281  based ointments containing approximately 70% (w/w) or greater oleaginous content; 
282  quantitative results should be reported for each test (not only a pass/fail result). For 
283  example, the average observed melting temperature (drop point) should be recorded when 
284  using the procedure described in USP <741> (Class III), and the pH of the pooled 
285  washings from the alkalinity test should be measured with a calibrated pH meter. A 
286  characterization of the relative proportions of different hydrocarbons in the topical 
287  product is recommended when characterizing or comparing oleaginous formulations 
288  (e.g., petrolatum-based ointments). 
289  9.  Characterization of specific gravity: includes an assessment of the density of the 
290  product, which may be influenced by entrapped air, and should characterize the mass of 
291  drug product in a given volume. 
292  10. Characterization of metamorphosis-related changes: includes an assessment of the 
293  influence of dispensing the drug product from different packaging configurations (e.g., a 
294  tube versus a pump) on the Q3 attributes of the dispensed dose. A characterization of 
295  batches of different ages, ideally age-matched as closely as possible for the test and 
296  reference batches, is recommended to provide information on the metamorphosis of a 
297  formulation during its shelf life (e.g., involving a change in apparent viscosity, globule-
298  size distribution, or particle-size distribution). If any Q3 attribute of a test topical product 
299  batch is outside the range characterized for that attribute among the batches of the 
300  reference standard (i.e., beyond the variability of the reference standard), the 
301  difference(s) in the Q3 attribute between the test topical product and reference standard 
302  may cause a difference in therapeutic performance. 
303   
304  The relevant comparative Q3 characterizations and any associated information described above 
305  should be submitted in the ANDA within the pharmaceutical development section of the 
306  electronic Common Technical Document (section 3.2.P.2). Information about the factors (e.g., 
307  related to the manufacturing process) that influence the Q3 attributes of the test topical product 
308  should also be included within section 3.2.P.2. The relevant comparative Q3 characterizations 
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309  should be performed with a minimum of three batches of the test topical product and with three 
310  batches (as available) of the reference standard.  
311   
312   
313  IV.  Q3 COMPARABILITY AND IMPLICATIONS FOR BIOEQUIVALENCE 
314   
315  A detailed profile of relevant Q3 attributes describes the arrangement of matter in a particular 
316  product formulation. That underlying matter may include hydrogen ions (which can be 
317  characterized by a pH measurement), polymers (whose structural organization and interactions 
318  bestow a formulation with characteristic rheological properties), solvents (whose 
319  physicochemical and structural interactions with other matter bestow a formulation with a 
320  characteristic solvent activity and evaporation profile), or other types of matter.  
321   
322  The Q3 characterization of a product formulation describes the arrangement of matter in that 
323  specific (individual) formulation. Because a Q3 characterization of a product formulation only 
324  describes the arrangement of matter in that specific (individual) formulation, a Q3 
325  characterization does not inherently involve a comparison. Therefore, when comparing the Q3 
326  attributes of two product formulations, separate concepts are needed to describe how the detailed 
327  profiles of Q3 attributes comparei.e., the concepts of sameness, similarity, and difference. 
328   
329  Comparative Q3 characterizations of a test topical product and its reference standard may reveal 
330  that the detailed profiles of relevant Q3 attributes for the two topical products are the same, 
331  similar, or different. This section describes the concepts of Q3 sameness, Q3 similarity, and Q3 
332  difference (with a simplified illustration in Figure 1) and discusses the potential relevance of 
333  each to supporting a demonstration of BE in an ANDA for a topical product. 
334   
335  Figure 1: A Simplified Illustration of Q3 Sameness, Q3 Similarity, and Q3 Difference 
336   
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337   
338  A.  Q3 Sameness 
339   
340  A test topical product that meets the following criteria would generally be considered as Q3 the 
341  same as its reference standard: 
342   
343  a.  Each relevant Q3 attribute of the test topical product, characterized in multiple 
344  batches, is:  
345  i.  demonstrated by the applicant to be within the range characterized for that Q3 
346  attribute of the reference standard for the topical product, potentially 
347  characterized in multiple batches, or  
348  ii.  determined by the Agency to be within the acceptable variability for the 
349  reference standard for the topical product18; and 
350   
351  b.  There is no difference19 in the components or composition of the test topical product 
352  and reference standard for the topical product that may significantly affect systemic 
353  or local availability. 
354   
355  A demonstration of Q3 sameness between a test topical product and its reference standard 
356  substantially mitigates the risk of potential failure modes for BE. Consequently, a test topical 
357  product that is a solution for application to the skin and is Q3 the same as its reference standard 
358  would generally satisfy the criteria for a waiver of evidence of in vivo BA or BE outlined in  
359  320.22(b)(3).20  For a test topical semisolid product that is shown to be Q3 the same as its 
360  reference standard, only limited additional (in vitro, in silico, and/or in vivo) evidence may 
361  generally be recommended to support a demonstration of BE.21 In general, for a test topical 
362  semisolid product that would satisfy the criteria for Q3 sameness (defined above), a 
363  demonstration of BE may include the comparative Q3 characterizations of the test topical 
364  product and reference standard for a topical product (per the recommendations in section III of 
 
18 FDA may supply acceptance criteria for Q3 attributes in a PSG. See footnote 7. 
19 Certain differences in the components or composition of the test topical product and reference standard for a 
topical product may not preclude a demonstration of Q3 sameness where the differences would not be expected to 
significantly affect systemic or local availability. Examples of such differences could include a test topical product 
that (1) contains a quantitative difference in the amount of a pH-adjusting agent (that is used to adjust the pH of the 
test product to be the same as that of the reference standard), (2) uses the same quantitative amounts (or quantitative 
ranges) of each of the same subcomponents of a preblended ingredient used in the reference standard, or (3) uses a 
different grade of the same inactive ingredient that is considered to have the same identity as the inactive ingredient 
used in the reference standard. 
20 We note that  320.22(b)(3) requires a comparison between the formulation of the test topical product and the 
RLD.  Although ordinarily the reference standard is the RLD, in certain circumstances the reference standard is a 
drug product other than the RLD.  See footnote 5.  We additionally note that the inactive ingredients in a generic 
topical product need not match those in the RLD so long as the applicant identifies and characterizes [any] 
differences and provides information demonstrating that the differences do not affect the safety or efficacy of the 
proposed drug product.  21 CFR 314.94(a)(9)(v).  In certain circumstancesi.e., where the reference standard is a 
drug product other than the RLD, and where the reference standard has different inactive ingredients than the 
RLDit is possible that a showing of Q3 sameness between the test product and the reference standard would not 
necessarily satisfy the criteria for a waiver under  320.22(b)(3). 
21 Specific recommendations for demonstrating BE for any particular test topical product compared to its reference 
standard are beyond the intended scope of this guidance. 
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365  this guidance), as well as a demonstration of an equivalent rate of release for the active 
366  ingredient from the test topical product and reference standard for a topical product, based upon 
367  an acceptable in vitro release test (IVRT). In addition, for products that are emulsions, FDA 
368  typically recommends that applicants demonstrate there is no significant difference in the rate 
369  and extent of BA for the active ingredient based upon an acceptable in vitro permeation test 
370  (IVPT), as relevant to the site and mechanism of action. The draft guidances for industry In Vitro 
371  Release Test Studies for Topical Drug Products Submitted in ANDAs (October 2022), and In 
372  Vitro Permeation Test Studies for Topical Drug Products Submitted in ANDAs (October 2022) 
373  provide additional information relating to the IVRT and IVPT studies that can support a 
374  demonstration of BE (when final, these guidances will represent FDAs current thinking on these 
375  topics).   
376   
377  B.  Q3 Similarity 
378   
379  A test topical product that meets the following criteria would generally be considered as Q3 
380  similar to its reference standard: 
381   
382  a.  Each relevant Q3 attribute of the test topical product, characterized in multiple 
383  batches, is:  
384  i.  demonstrated by the applicant to be within the range characterized for that Q3 
385  attribute of the reference standard for the topical product, potentially 
386  characterized in multiple batches, or  
387  ii.  determined by the Agency to be within the acceptable variability for the 
388  reference standard for the topical product22; and 
389   
390  b.  There is a difference in the components or composition of the test topical product and 
391  reference standard for the topical product that may significantly affect systemic or 
392  local availability. 
393   
394  A demonstration of Q3 similarity between a test topical product and its reference standard 
395  substantially mitigates the risk of many potential failure modes for BE, but not those arising from 
396  the specific difference(s) in the components or composition of the test topical product and its 
397  reference standard. Consequently, a test topical product that is a solution for application to the 
398  skin and is Q3 similar to its reference standard would generally not satisfy the criteria for a 
399  waiver of evidence of in vivo BA or BE outlined in  320.22(b)(3).  For a test topical semisolid 
400  product that would satisfy the criteria for Q3 similarity (defined above), demonstrating BE may 
401  include all the evidence recommended for a test topical semisolid product that is shown to be Q3 
402  the same as its reference standard, as well as evidence to mitigate the risk of specific failure 
403  modes for BE associated with the difference(s) in the components or composition of the test 
404  topical product and its reference standard.  
405   
406  For such products, the following should be considered: (1) what failure modes for BE might arise 
407  from the specific difference(s) in the components or composition between the test topical product 
408  and reference standard, and (2) what evidence could mitigate the risk of those specific failure 
 
22 See footnote 18. 
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409  modes for BE. For example, if a test topical product that would satisfy the criteria for Q3 
410  similarity contains only inactive ingredients in proposed amounts that would not exceed the 
411  amounts of the same inactive ingredients in FDA-approved drug products (see information in 
412  FDAs Inactive Ingredient Database23) for a similar context of use, this would mitigate the risk 
413  of some potential failure modes for BE.  
414   
415  C.  Q3 Difference 
416   
417  A test topical product in an ANDA that meets the following criteria would generally be 
418  considered as Q3 different from its reference standard: 
419   
420  a.  One or more relevant Q3 attributes of the test topical product, characterized in 
421  multiple batches, is:  
422  i.  not demonstrated by the applicant to be within the range characterized for that 
423  Q3 attribute of the reference standard for the topical product, potentially 
424  characterized in multiple batches, and  
425  ii.  not determined by the Agency to be within the acceptable variability for the 
426  reference standard for the topical product; and 
427   
428  b.  There may or may not be a difference in the components or composition of the test 
429  topical product and reference standard for the topical product that may significantly 
430  affect systemic or local availability. 
431   
432  Because there are myriad reasons why a test topical product may be shown to be Q3 different 
433  from its reference standard, it is beyond the scope of this guidance to make recommendations 
434  about what additional evidence may be recommended to support a demonstration of BE in such 
435  situations.  
436   
437   
438  V.  COMMUNICATIONS WITH THE AGENCY   
439   
440  If a prospective ANDA applicant is developing a topical product and has questions about a BE 
441  approach (potentially based upon Q3 characterization), the prospective applicant may submit a 
442  controlled correspondence24 to FDA, or if the topical product is a complex product (i.e., not a 
443  topical solution), may request a pre-ANDA meeting with FDA.25 A controlled correspondence is 
444  appropriate if the prospective applicant has a specific and targeted inquiry about the generic drug 
 
23 See, e.g., the draft guidance for industry Using the Inactive Ingredient Database (July 2019). When final, this 
guidance will represent FDAs current thinking on this topic. The Inactive Ingredient Database is available at 
https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm. 
24 See the guidance for industry Controlled Correspondence Related to Generic Drug Development (December 
2020) for information on the types of inquiries accepted as controlled correspondence and on how to submit 
controlled correspondence to the Office of Generic Drugs.   
25 A pre-ANDA meeting may be granted for topical solutions that would not qualify for a waiver under 
 320.22(b)(3), when resources permit and when a meeting would add value to the ANDA development program. 
See the guidance for industry Formal Meetings Between FDA and ANDA Applicants of Complex Products Under 
GDUFA (November 2020) for information on the enhanced pathway for discussions between FDA and a 
prospective applicant preparing to submit an ANDA for a complex product as defined in that guidance. 
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445  development process. For example, a controlled correspondence is particularly useful when a 
446  prospective applicant seeks feedback from the Agency about whether a proposed formulation (or 
447  up to three formulations) would be suitable for a specific BE approach recommended in a PSG. 
448   
449  A pre-ANDA meeting is mainly intended to assist complex generic drug development.  A pre-
450  ANDA meeting is appropriate for a prospective applicant seeking a dialogue with the Agency on 
451  a particular matter that would fall outside the scope of controlled correspondence for a complex 
452  product. A pre-ANDA meeting is particularly useful when a prospective applicant seeks 
453  feedback from the Agency about whether a proposed formulation (or up to three formulations) 
454  would be suitable for a specific BE approach proposed by the prospective applicant as an 
455  alternative to a recommended BE approach in the PSG for that drug product, or in instances 
456  where there is no PSG available for the specific complex product. Prospective applicants 
457  intending to submit an ANDA for a topical product that relies upon a Q3-characterization-based 
458  BE approach, for which relevant recommendations have not been published in a PSG, are 
459  encouraged to request a pre-ANDA meeting with FDA to discuss their proposed BE approach. 
460   
461  FDA recommends that applicants perform, at minimum, basic Q3 characterization (explained in 
462  section III of this guidance) of the reference standard before submitting a controlled 
463  correspondence or pre-ANDA meeting request. In addition, product characterizations relevant to 
464  the nature, complexity, and identification of potential failure modes for BE26 associated with the 
465  test topical product will help to facilitate communication and/or discussion between the applicant 
466  and FDA. Although FDA does not communicate information to prospective applicants about 
467  whether a proposed test topical product is Q3 the same as (or similar to) the reference standard, 
468  the Agency does intend to communicate whether specific proposed formulations may be suitable 
469  ones with which to demonstrate BE using a specific approach proposed by the prospective 
470  applicant or recommended by FDA in a PSG. 
 
26 See the ICH guidance for industry Q9 Quality Risk Management (June 2006). 
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