Guidance for Industry 

 
Bioavailability  and

Bioequivalence 

Studies  for  Nasal Aerosols  

and 
 
Nasal Sprays  for Local Action 

 
 
 
 
 
 
DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only.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publication of the Federal Register notice announcing the availability  of the draft guidance. Submit 
comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1601, Rockville, MD 20857.  All comments should be identified with the 
docket number listed in the notice of availability that published in the Federal Register. 
 
For questions on the content of the draft document contact Wallace Adams, 301-594-5618. 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
Biopharmaceutics 
 
April 2003 
 Guidance for Industry 

 
Bioavailability  and

Bioequivalence 

Studies  for  Nasal Aerosols  

and 
 
Nasal Sprays  for Local 

Action 

 
 
Additional copies are available from:  

 
Division of Drug Information (HFD-240)  

Center for  Drug Evaluation and Research  (CDER)  

5600 Fishers  Lane,  

Rockville,  MD 20857  (Tel)  301-827-4573  

Internet at  http://www.fda.gov/cder/guidance/index.htm
  
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
Biopharmaceutics
  
April 

2003 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
TABLE OF CONTENTS  
 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 2
  
A.   BA and BE Data ........................................................................................................................... 3 

  1.  Local Delivery BA/BE Concepts. ..................................................................................................... 3 

  2.  Systemic Exposure and Systemic Absorption BA/BE Concepts. ...................................................... 4 
 
B.   CMC and In Vitro BA Tests (Noncomparative) Versus BE Tests (Comparative) .................. 5
  
III.   FORMULATION AND CONTAINER AND CLOSURE SYSTEM......................... 5 
 
A.   Formulation.................................................................................................................................... 5
  
B.   Container and Closure System.................................................................................................. 6 
 
IV.   DOCUMENTATION  OF BA AND BE ........................................................................ 6 
 
A.   NDAs ............................................................................................................................................... 6
  
B.   ANDAs ............................................................................................................................................ 6 

1.  Solution Formulations.  .................................................................................................................... 7
 
  2.  Suspension Formulations with PK Systemic Exposure Data.  .......................................................... 7 

  3.  Suspension Formulations without PK Systemic Exposure Data. ..................................................... 7 

C.  Postapproval Change ................................................................................................................. 8 

V.   IN VITRO  STUDIES ...................................................................................................... 8 
 
A.   Batches and Drug Product Sample  Collection........................................................................ 8 

1.  NDAs. ............................................................................................................................................... 8
 
  2.  ANDAs.  ............................................................................................................................................ 9
  
B.   Tests and Metrics ......................................................................................................................... 9 

  1.  Single Actuation Content (SAC) Through Container Life. ............................................................ 11 
 
  2. Droplet Size Distribution by Laser Diffraction. ............................................................................. 12 

    a. Nasal sprays. .............................................................................................................................. 12  

    b. Nasal aerosols. ........................................................................................................................... 13 
 
  3.  Drug in Small Particles/Droplets, or Particle/Droplet Size Distribution by Cascade Impactor... 14 

    a. Nasal sprays: Drug in Small Particles/Droplets. ........................................................................ 14  

    b. Nasal aerosols: Particle/Droplet Size Distribution. .................................................................... 15 
 
  4.  Drug Particle Size Distribution by Microscopy. ............................................................................ 15 

  5.  Spray Pattern. ................................................................................................................................ 16 

    a. For nonimpaction systems. ......................................................................................................... 17 
 
    b. For impaction systems. .............................................................................................................. 17 

    c. For both nonimpaction and impaction systems. ........................................................................ .18  

6.  Plume Geometry.  ........................................................................................................................... 18 

  7.  Priming and Repriming.................................................................................................................. 20 
 
VI.   CLINICAL STUDIES FOR LOCAL DELIVERY ................................................. 20 
 
A.   General  Information................................................................................................................. 20 

1.  NDAs. ............................................................................................................................................. 20 

  2.  ANDAs.  .......................................................................................................................................... 21 
 
B.   Clinical Study Batches............................................................................................................... 21 
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C.   Clinical BE Study Design and Subject Inclusion Criteria.................................................. 22 
 
D.   Clinical BE Study Endpoints ................................................................................................... 23 
 
VII.   PK STUDIES FOR SYSTEMIC EXPOSURE ......................................................... 24 

A.   General  Information................................................................................................................. 24 

B.   Study Batches .............................................................................................................................. 25 
 
C.   Study Design and Subject Inclusion Criteria ....................................................................... 25 
 
D.   Study Measures ............................................................................................................................ 26 
 
VIII.   PD OR CLINICAL STUDIES FOR SYSTEMIC ABSORPTION....................... 26 
 
A.   General Information .................................................................................................................. 26 

B.   Clinical Study Batches............................................................................................................... 27 
 
C.   Clinical BE Study Designs and Subject Inclusion Criteria ................................................ 27 
 
D.   Clinical BE Study Endpoints for Corticosteriods ............................................................... 28 

IX.    NUMBER OF RESERVE SAMPLES FOR BA AND BE  TESTING.................... 29
  
X.   MULTIPLE STRENGTHS......................................................................................... 29
  
A.   Solution  Formulation Nasal Sprays........................................................................................ 30 
 
B.   Suspension Formulation Nasal Sprays................................................................................... 30 
 
XI.   SMALLER CONTAINER SIZES ............................................................................... 31 
 
REFERENCES.......................................................................................................................... 31 

TABLE 1...................................................................................................................................... 32
  
 
Note: The following stand alone documents will be provided when completed. 
 
APPENDIX A:  DECISION TREE FOR PRODUCT QUALITY STUDIES 
APPENDIX B:  STATISTICS FOR IN VITRO BA DATA  
APPENDIX C:  NONPROFILE IN VITRO BE DATA  USING PBE STATISTICS 
APPENDIX D:  NONPROFILE IN VITRO BE DATA  USING PBE STATISTICS 
APPENDIX E:  STATISTICS FOR IN VITRO PROFILE COMPARISONS 
APPENDIX F:  STATISTICS FOR  ALLERGIC  RHINITIS STUDIES  
APPENDIX G:  STATISTICS FOR SYSTEMIC EXPOSURE AND ABSORPTION   Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1 
Guidance for Industry  
1 
 
2 
Bioavailability  and Bioequivalence Studies for Nasal Aerosols 
3 
and Nasal Sprays for Local Action 
4 
5   
6   
7  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current 
8  thinking on this topic.  It does not create or confer any rights for or  on any  person and does not operate to 
9  bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of 
10  the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 
11  staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call 
12  the appropriate number listed on the title page of this guidance.  
13   
14   
15   
16  I.  INTRODUCTION  
17   
18  This guidance is intended to provide recommendations to applicants who are planning product 
19  quality studies to measure bioavailability (BA) and/or establish bioequivalence (BE) in  support 
20  of new drug applications (NDAs) or abbreviated new drug applications (ANDAs) for locally 
21  acting drugs in nasal aerosols (metered-dose inhalers (MDIs)) and nasal sprays (metered-dose 
22  spray pumps). This guidance addresses BA and BE studies of prescription corticosteroids, 
23  antihistamines, anticholinergic drug products, and the over-the-counter (OTC) mast-cell 
24  stabilizer cromolyn sodium. Applicability of the guidance to other classes of intranasal drugs 
25  that may be developed in the future should be discussed with the appropriate CDER review 
26  division. 
27   
28  This guidance does not cover studies of nasal sprays included in an applicable OTC monograph2 
29  or studies of (1) metered-dose products intended to deliver drug systemically via the nasal route 
30  or (2) drugs in nasal nonmetered dose atomizer (squeeze) bottles that require premarket 
31  approval. 
32   
33  The first draft of this guidance was issued in June 1999 for comment. Because of changes made 
34  as a result of comments received to the docket, internal discussions, and deliberations of the 
35  Advisory Committee for Pharmaceutical Science, we have decided to issue the guidance once 
36  again in draft. A series of  attachments are being developed and will be posted with this draft 
                                                 
1  This guidance has been prepared by  the Oral Inhalation  and Nasal Drug  Products Technical Committee, Locally 
Acting Drug Products Steering Committee, Biopharmaceutics Coordinating Committee, with contributions  from  the 
Inhalation Drug  Products Working  Group, the Chemistry, Manufacturing,  and Controls  Coordinating  Committee, in  
the Center for Drug Evaluation  and Research  (CDER)  at  the  Food and Drug  Administration.  
 
2  21  CFR 341.  Cold, Cough, Allergy,  Bronchodilator,  and Antiasthmatic  Drug Products  for Over-the-Counter  
Human Use.  
 
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37  guidance as stand alone documents on the Internet as soon as they have been completed. 
38   
39  FDAs guidance documents, including this guidance, do not establish legally enforceable 
40  responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
41  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
42  cited. The use of the word should in Agency guidances means that something is suggested or 
43  recommended, but not required.  
44   
45   
46  II.  BACKGROUND 
47   
48  Product quality studies provide information that pertains to the identity, strength, quality, purity, 
49  and potency of a drug product. These studies include information on chemistry, manufacturing, 
50  and controls (CMC), microbiology, BE and certain aspects of BA.   A BE study is normally used 
51  to compare a test product (T) to a reference product (R):  the to-be-marketed product is compared 
52  to a pivotal clinical trial material, and a generic product is compared to a reference listed drug.  A 
53  BE study thus provides information on product quality. BA studies for ensuring product quality 
54  relate to the release of the active ingredient or active moiety from the drug product (Williams  et 
55  al., 2000).  BA studies may also address biopharmaceutical and clinical pharmacology issues, 
56  such as absorption, distribution, and elimination of the active ingredient and its metabolites and 
57  dose proportionality. These latter BA/PK studies provide information beyond product quality BA 
58  characterization and would also  be included in the Human Pharmacokinetics section (Item 6) of 
59  an NDA. These latter studies are not the subject of this guidance. Rather, this guidance discusses 
60  studies that focus on product performance (i.e., release of a drug substance from  a drug product). 
61  Subsequent references to BA studies in this guidance refer only to BA  studies for ensuring 
62  product quality.  
63   
64  This guidance should be used with other, more general CMC and BA and BE guidances available 
65  from CDER.3   Product quality information is different from, yet complementary to, the clinical 
66  safety and efficacy information that supports approval of an NDA.  For information on the type of 
67  safety and efficacy studies that may be requested for a new active ingredient/active moiety 
68  intended for local action in the nose, or for a new product such as a nasal aerosol that may include 
69  an active ingredient/active moiety previously approved in a nasal spray, we recommend  
70  appropriate CDER review staff be consulted. 
71   
72  Note: Detailed CMC information relevant to nasal aerosols and nasals sprays is presented in the 
73  final guidance Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products 
74  Chemistry, Manufacturing, and Controls Documentation.4     The document provides 
75  complementary information on the BA/BE testing methods recommended in this guidance. 
76   
                                                 
3  Guidances are available on the Internet at http://www.fda.gov/cder/guidance/index.htm.  
 
4  A draft  guidance, Metered  Dose Inhaler (MDI) and Dry Powder  Inhaler  (DPI) Drug  Products:  Chemistry, 
Manufacturing, and Controls Documentation,  was issued  in October 1998.  Once finalized, it will represent 
the Agencys thinking  on  this topic.  
 
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77  A.  BA and BE Data  
78   
79  Bioavailability  is defined at 21 CFR 320.1 as the  rate and extent to which the active ingredient  or 
80  active moiety is absorbed from a drug product and becomes available at the site of action. For 
81  drug products that are not intended to be absorbed into the bloodstream, bioavailability may be 
82  assessed by measurements intended to reflect the rate and extent to which the active ingredient  or 
83  active moiety becomes available at the site of action.  Bioequivalence is defined as the absence 
84  of a significant difference in the rate and extent to  which the active ingredient or  active moiety in  
85  pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug 
86  action when administered at the same molar dose under similar conditions in an appropriately 
87  designed study.   BA and BE are closely related, and the same  approach used to measure BA in an 
88  NDA can generally be followed in establishing BE  for an NDA or ANDA.  Although BA may  be 
89  comparative, establishing BE specifically involves a comparison of the BA of one product with 
90  the BA of another product. BE is usually established using (1) a criterion  to allow the 
91  comparison, based on means and/or variances for BA measures, (2) a confidence interval for the 
92  criterion, and (3) a BE limit (goalpost) for the criterion. 
93   
94  BA and BE data must be provided in accordance with the regulations.5   BA and BE can be 
95  established using in vivo (pharmacokinetic (PK), pharmacodynamic (PD), or clinical) and in 
96  vitro studies, or, in certain cases, using in vitro studies alone.6   BA and BE assessments for 
97  locally acting nasal aerosols and sprays are complicated because delivery to the sites of  action 
98  does not occur primarily after systemic absorption. Droplets and/or drug particles are deposited 
99  topically. The drug is then absorbed and becomes available at local sites of action. A drug 
100  administered nasally and intended for local action has the potential to produce systemic activity,  
101  although plasma levels do  not in general reflect the amount of drug reaching nasal sites of 
102  action. Systemic exposure following nasal administration can occur either from  drug absorbed 
103  into the systemic circulation from  the nasal mucosa, or after ingestion and absorption from the 
104  gastrointestinal tract (Daley-Yates et al., 2001).  For these reasons, BA and BE studies generally 
105  would consider both local delivery and systemic exposure or systemic absorption. 
106   
107  1.   Local Delivery BA/BE Concepts  
108   
109  For local delivery, BA is a function of several factors, including release of the drug 
110  substance from the drug product and availability  to local sites of action. Release of the 
111  drug from the drug product produces droplet or drug particle sizes and distribution 
112  patterns within the nose that are dependent  upon the drug substance, formulation, and 
113  device characteristics. Availability to  local sites of action is usually a function of droplet 
114  or drug particle sizes and distribution patterns,  as well as drug  dissolution in the case of  
115  suspension products, absorption across mucosal barriers to nasal receptors, and rate of 
116  removal from the nose.  From a product quality perspective, the critical issues are release 
117  of drug substance from  drug product and delivery to the mucosa. Other factors are of 
                                                 
5  21 CFR  320.21, Requirements  for submission  of in  vivo  bioavailability and bioequivalence data.  
 
6  21 CFR 320.24, Types of evidence to establish  bioavailability or  bioequivalence. 
 
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118  lesser importance.  
119   
120  A critical question in assessing product quality BA  and BE is the extent  to which one can 
121  rely on in vitro methods alone, or upon in vitro methods plus clinical endpoints, to 
122  measure (benchmark) BA and/or establish BE. In vitro methods are less variable 
123  (Newman et al., 1995; Borgstrom  et al., 1996; Suman et al., 2002), easier to control, and 
124  more likely to detect differences between products if they exist, but the clinical relevance 
125  of these tests, or the magnitude of the differences in the tests, can not always be clearly 
126  established. Clinical endpoints may be highly variable (Welch et al., 1991; Meltzer et al., 
127  1998) and relatively insensitive to dose differences over an eightfold or higher dose range 
128  (Advisory Committee for Pharmaceutical Science, 2001), thus insensitive in detecting 
129  potential differences between products. However, clinical studies can unequivocally 
130  establish effectiveness of the drug product. 
131   
132  In this guidance, the recommended approach for solution formulations of locally acting 
133  nasal drug products, both aerosols and sprays, is to rely on in vitro methods to assess BA. 
134  To establish BE, the recommended approach relies on (1) qualitative and quantitative 
135  sameness of formulation of test and reference products, (2) comparability in container 
136  and closure systems, and (3) in vitro methods that demonstrate equivalent performance. 
137  This approach is based on  the premise that in vitro studies would be more sensitive 
138  indicators of drug delivery to nasal sites of action than would be clinical studies. For 
139  solution formulations, see Section IV.B.1. 
140   
141  The recommended approach for establishing  BA and BE of suspension formulations of 
142  locally acting nasal drug products, both aerosols and sprays, is to conduct in vivo studies 
143  in addition to in vitro studies.7   As with the solution formulation aerosols and sprays, to 
144  establish BE, the approach  also relies on qualitative and quantitative sameness of 
145  formulation of test and reference products and comparability in container and closure 
146  systems. We recommend that in vitro studies be coupled with a clinical study for BA, or 
147  a  BE study with a clinical endpoint (Section VI), to determine the delivery of drug 
148  substance to nasal sites of action. In vivo studies are recommended because of an 
149  inability at the present time to adequately  characterize drug particle size  distribution 
150  (PSD) in aerosols and sprays (Sections V.B.3, 4).  Drug PSD in suspension formulations 
151  has the potential to influence the rate and extent of  drug availability to nasal sites of  
152  action  and to the systemic circulation. 
153   
154  2.  Systemic Exposure and Systemic Absorption BA/BE  Concepts 
155   
156  Locally acting drugs are intended to produce their effects upon delivery to  nasal sites  of  
157  action without relying on systemic absorption. Although systemic absorption may 
158  contribute to  clinical efficacy for certain corticosteroids and antihistamines, the 
                                                 
7  Types of in vivo  BE studies that may be  submitted  in  support of an ANDA include, in  addition  to pharmacokinetic 
studies,  tests in  humans in  which an  acute pharmacological  effect is measured as a function of time and appropriately  
designed comparative clinical trials for demonstration of  BE (21 CFR  320.24).  
 
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159  consequences of systemic  absorption (e.g., hypothalamic-pituitary-adrenal (HPA) axis 
160  suppression by corticosteroids) are generally undesirable. In the absence of validated in 
161  vitro methodology for characterizing drug PSD for suspension products and when 
162  measurable plasma  levels can be obtained, this guidance recommends PK studies to 
163  measure systemic exposure BA or to establish systemic exposure BE (see Section VII). 
164  For suspension products that do not produce sufficient plasma  concentrations to allow 
165  assessment of systemic exposure, clinical studies or BE studies with a pharmacodynamic 
166  or clinical endpoint are recommended to measure systemic absorption BA and establish 
167  systemic absorption BE, respectively (Section VIII).  For a schematic representation of 
168  recommended studies, see Appendix A: Decision Tree. 
169   
170  B.  CMC and In Vitro BA Tests (Noncomparative) Versus BE Tests 
171  (Comparative) 
172   
173  Generally, CMC tests help characterize the identity, strength, quality, purity, and potency of the 
174  drug product and assist  in setting specifications (tests, methods, acceptance criteria) to allow 
175  batch release. These tests have a different purpose than do BA/BE tests, which focus on the 
176  release of the drug substance from  the drug product. Some of the in vitro BA/BE tests described 
177  in this guidance may be the same  as CMC tests for characterization and/or  batch release. CMC 
178  and in vitro  BA tests have  acceptance criteria. In vitro BE tests have BE limits. A specification 
179  (test, method, acceptance criterion) for a CMC test for batch release or an in vitro  BA test is 
180  usually based on general or specific manufacturing experience. For example, a CMC test such as 
181  dose content uniformity has acceptance criteria based on repeated manufacturing of batches. In 
182  contrast, BE tests have limits that are not usually based on manufacturing experience, but are 
183  part of equivalence comparisons between test and reference products. BE limits may be based 
184  on a priori judgments and may be scaled to the variability of the reference product (see 
185  Appendices C, E). When  conducted premarket for an NDA, some  of the in vitro BA tests 
186  described in this guidance can be noncomparative and serve primarily to document (benchmark) 
187  the product quality BA of a pioneer product. 
188   
189   
190  III.   FORMULATION AND CONTAINER AND CLOSURE SYSTEM    
191   
192  A.  Formulation 
193    
194  Particle size, morphic form, and state of solvation of an active ingredient have the potential to 
195  affect the BA of a drug product as a result of different solubilities and/or rates of dissolution. 
196  We  recommend for an ANDA of a suspension formulation, data demonstrating comparable PSD 
197  and morphic form of the drug particles, size and number of drug aggregates in the dosage form, 
198  and hydrous or solvate form  of the active drug in the dosage form to the reference listed drug, be 
199  provided, where possible. Where impossible, the rationale for not providing this full set of 
200  comparative data is requested. For suspension formulations marketed in more than one strength, 
201  we recommend that the drug substance in each strength product be micronized under identical 
202  parameters, and the PSD of the resultant bulk drug used in each product strength be identical. 
203   
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204  B.  Container and Closure System  
205   
206  Nasal aerosols usually consist of  the formulation, container, valve, actuator, dust cap, associated 
207  accessories, and protective packaging, which together constitute the drug product. Similarly, 
208  nasal sprays usually consist of the formulation, container, pump, actuator, protection cap, and 
209  protective packaging, which together constitute the drug product. 
210   
211  For nasal aerosols and nasal sprays approved under an ANDA, we recommend BE be  
212  documented on the basis of validated in vitro and vivo tests, or, in the case of solutions, validated 
213  in vitro tests alone may be appropriate. Assurance of equivalence on the basis of in vitro tests is 
214  greatest when the test product uses the same  brand and model of devices (particularly the 
215  metering valve or pump and the actuator) as used in the reference product. If this is infeasible, 
216  we recommend that valve, pump, and actuator designs be as close as possible in all critical 
217  dimensions to those of the reference product. We  recommend that metering chamber volumes and  
218  actuator orifice diameters be the same. For a nasal spray, spray characteristics can be affected by 
219  features of the pump design, including the precompression mechanism,  actuator design, including 
220  specific geometry of the orifice (Kublic and Vidgren 1998), and the design of the swirl chamber. 
221  The external dimensions of the test actuator  are expected to ensure comparable depth of  nasal 
222  insertion to the reference actuator. A test product is expected to attain prime within the labeled 
223  number of actuations for the reference product. We recommend you consider the volume of 
224  components of the device that must be filled to deliver an actuation, including the internal 
225  diameter and length of the diptube because this volume can influence the number of actuations 
226  required to prime a spray pump. 
227   
228   
229  IV.  DOCUMENTATION  OF BA AND BE  
230   
231  A.   NDAs  
232   
233  For product quality, we recommend that in vitro BA studies be provided in NDAs for solution 
234  and suspension products, and in vivo BA studies be provided for suspension products. These 
235  data are useful as a benchmark to characterize the in vitro performance, and for suspensions, the 
236  in vivo performance of the product. Where the formulation and/or method of manufacture of the 
237  pivotal clinical trial product changes in terms of physicochemical characteristics of the drug 
238  substance, the excipients, or the device characteristics, BE data using in vitro tests (for solution 
239  and suspension products) and in vivo tests (for suspension products) may be useful in certain 
240  circumstances to ensure that the to-be-marketed product (T) is comparable to very similar 
241  clinical trial batches and/or to batches used for stability testing  (R) (Section V.A.1).  We  
242  recommend sponsors discuss the usefulness of these BE approaches with the appropriate CDER 
243  review staff. 
244   
245  B.   ANDAs  
246   
247  For product equivalency, we recommend that the drug concentration in the test and reference 
248  product formulations not differ by more than 5 percent.  In addition, we recommend that the 
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249  inactive ingredients in the test product formulation be qualitatively (Q )8 the same and 
1
250  quantitatively (Q ) essentially the same as the inactive ingredients in the formulation of  the 
2
251  reference listed drug, and the container and closure recommendations of Section III be followed. 
252  Quantitatively essentially the same  has been determined by CDER to mean that the 
253  concentration or amount of the inactive ingredient(s) in the test product would not differ by more 
254  than 5 percent of the concentration or amount in the reference listed drug.  We recommend a 
255  side-by-side Q and Q comparison of  the compositions  of  the test and reference listed drug 
1  2 
256  formulations be provided. Please also provide a side-by-side comparison of the components of 
257  the container and closure system, listing brand and model, dimensions of critical components 
258  (Section IIIB), and engineering drawings if possible. 
259   
260  1.  Solution Formulations  
261   
262  We believe in vitro tests alone can be relied on to document BE for nasal solution 
263  formulation products intended for local action. This approach is based on an 
264  understanding that for solution products, equivalent in vitro performance and adherence 
265  to Q and Q recommendations and to container and closure recommendations will 
1  2 
266  ensure  comparable delivery to the nasal mucosa and to the respiratory and 
267  gastrointestinal tracts. Suggested methodology and validation approaches for the 
268  recommended tests are provided in Section V.  Suggested statistical methods to allow 
269  comparisons will be discussed in the appendices to this document. When in vitro data 
270  fail to meet acceptance criteria, the applicant is encouraged to modify the test product to 
271  attain equivalent in vitro performance. Because of insensitivity to potential differences  
272  between T and R, in vivo studies would not be sufficient in the face of failed in vitro 
273  studies. 
274   
275  2.  Suspension Formulations with PK Systemic Exposure Data  
276   
277  To document BE for suspension formulation products intended for local action, we 
278  recommend both in vitro and in vivo data be used.  In vivo studies would include both a 
279  BE study with a clinical endpoint (local delivery) and a pharmacokinetic study (systemic 
280  exposure). This approach is only applicable for those suspension formulation products 
281  that produce sufficiently high plasma  concentrations of the moiety(ies) to be measured to 
282  allow reliable analytical measurement for an adequate length of  time  after nasal 
283  administration. Suggested methodology and validation approaches for the recommended 
284  tests are provided for in vitro studies in Section V, and for in vivo studies in Sections VI 
285  and VII.  As with solutions, in vivo studies would not be sufficient in the face of failed in 
286  vitro studies (i.e., in vitro BE studies that fail to meet the statistical tests) even though the 
287  BE study with a clinical endpoint or the PK study meets the statistical test. Conversely, 
288  ANDAs with acceptable in vitro data, but with in vivo data that fail to meet the statistical 
289  tests,  would be insufficient to establish BE. 
290   
291  3.  Suspension Formulations without PK  Systemic Exposure Data  
                                                 
8  See 21  CFR 314.94(a)(9)(v). 
 
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292   
293  For those products intended for local action that produce blood or plasma  levels that are 
294  too low for adequate measurement, given current assay constraints, a BE study with a 
295  clinical endpoint to establish equivalent local delivery to nasal sites (Section VI) and a 
296  study with a pharmacodynamic or clinical endpoint to establish equivalent systemic 
297  absorption (Section VIII) are recommended. In vivo studies that meet the statistical test 
298  would not be sufficient in the face of in vitro studies that fail to document BE. As for 
299  suspensions with PK data, ANDAs with acceptable in vitro data, but with in vivo data 
300  that fail to meet the statistical  tests, would be insufficient to establish BE. 
301   
302  C.  Postapproval Change  
303   
304  This document does not cover postapproval changes. Sponsors planning such changes can 
305  consult the guidance for industry Changes to an Approved NDA or ANDA and contact the 
306  appropriate review division prior to instituting the change. 
307   
308   
309  V.  IN VITRO  STUDIES  
310   
311  A.  Batches and Drug Product Sample Collection  
312   
313  1.  NDAs  
314   
315  We  recommend in vitro BA studies for nasal aerosols and sprays be performed on 
316  samples from three or more batches: a pivotal clinical trial batch to provide linkage of  in 
317  vitro performance to in vivo data; a primary stability batch; and if feasible, a production- 
318  scale batch.  This selection of  batches will ensure  consistency of  in vitro performance 
319  among the three types of batches. If a production-scale batch is unavailable, a second 
320  pivotal clinical trial batch or second primary stability batch can be substituted. When 
321  three batches are studied, we recommend the batches be manufactured, preferably from 
322  three different batches of  the drug substance,  different batches of  critical excipients,  and 
323  different batches of container and closure components. However, the container (canister 
324  or bottle) can be from the same batch. We prefer  that the three batches be studied at the 
325  same time, if possible, to remove interstudy variation from  the estimation of between 
326  batch means and variances. 
327   
328  The BA batches to be studied would be equivalent to the to-be-marketed product and 
329  representative of production scale. The manufacturing process for these batches would 
330  simulate that of  large-scale production batches for marketing (additional information on 
331  large-scale batches is provided in the International Conference on Harmonisation (ICH) 
332  guidance for industry Q1A Stability Testing of New  Drug Substances and Products, 
333  Section II.B.3).  Complete batch records, including batch numbers of device 
334  components used in the batches, would accompany the BA submission. 
335   
336  In vitro BA studies are intended to characterize the means and variances of measures of 
337  interest for canisters (nasal aerosols) or bottles (nasal sprays) within a batch and between 
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338  batches, where applicable. However, under 21 CFR 320.1 and 320.21, the studies can be  
339  noncomparative to other formulations or products. The in vitro tests and metrics are 
340  described in Section V.B of this guidance. The recommended number of canisters or 
341  bottles of each batch to be used in the above studies, and recommendations for statistical 
342  analyses, are described in Appendix B. 
343   
344  2.  ANDAs  
345   
346  In vitro BE studies for nasal aerosols and sprays would generally be performed on 
347  samples from each of three or more batches of  the test product and three or  more batches 
348  of the reference listed drug.  Test product samples would be from the primary stability 
349  batches used to establish the expiration dating period. When three batches are studied, 
350  we recommend the test product be manufactured, preferably from three different batches 
351  of the drug substance, different batches of critical excipients, and different batches of 
352  container and closure components. However, the container (canister or bottle) can be 
353  from  the same  batch. For nasal sprays formulated as solutions, in vitro BE  tests can 
354  alternatively be performed on three sublots of  product prepared from one  batch of the 
355  solution.9 
 
356   
357  The BE batches to be studied would be equivalent to the to-be-marketed product. The 
358  manufacturing process of these batches would simulate that of large-scale production 
359  batches for marketing. Complete batch records, including batch numbers of device 
360  components used in the batches or sublots (for solution nasal sprays) would accompany 
361  the BE submission. 
362   
363  Reference product samples would be from three different batches available in the 
364  marketplace. The recommended in vitro tests and metrics are described in Section V.B. 
365  The recommended number of canisters or bottles of each product and batch to be used in 
366  the above studies, and recommended statistical approaches, are described in Appendices 
367  C, D and E. 
368   
369  B.  Tests and Metrics  
370   
371  In vitro BA and BE for locally acting drugs delivered by nasal aerosol or nasal spray are usually 
372  characterized using seven tests: 
373   
374  1.  Single Actuation Content Through Container Life 
375  2.  Droplet Size Distribution by Laser Diffraction  
376  3.  Drug in Small Particles/Droplets, or  Particle/Droplet Size Distribution by Cascade 
377  Impactor  
378  4.  Drug Particle Size Distribution by Microscopy 
                                                 
9  For solution  formulation  nasal sprays, variability in in vitro  BE study data between  batches is expected to be  due 
primarily to  variability in  the device components of the product  rather than  in the solution. Therefore, a single batch  
of solution can be  split-filled  into three equal  size sublots of  product. The sublots would be  prepared  from three 
different  batches of the same  device  (pump and actuator) components.  
 
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379  5.  Spray Pattern 
380  6.  Plume Geometry 
381  7.  Priming and Repriming 
382   
383  These tests are relevant to all nasal aerosols and nasal sprays, whether formulated as solution or 
384  suspension products, with the exception of drug particle size distribution by microscopy, which 
385  applies only to suspension products. The in vitro tests are summarized in Table 1. 
386   
387  We recommend you validate all in vitro tests for accuracy and precision prior to the study. For 
388  applicable studies, instrument settings established during prestudy validation would be used in 
389  the study. For comparative studies, use of the same  settings will ensure that T and R are studied 
390  under the same instrumental conditions. The in vitro tests would be conducted on canisters or 
391  bottles selected in a random manner from the test batch, including units from the beginning, 
392  middle, and end of the production run.  Actuation should be conducted in a manner that removes 
393  potential operator bias, either by employing automatic actuation, or by employing blinded 
394  procedures when manual actuation is used.  However, we recommend automated actuation 
395  systems for all comparative in vitro BE tests. These systems are expected to decrease variability 
396  in drug delivery due to operator factors, thereby increasing the sensitivity for detecting potential 
397  differences between products in the above tests.10  In addition,  it is important that the analyst 
398  performing the postactuation evaluations of the collected data be blinded to the identity of the 
399  samples. We  recommend analytical methods used for analysis of samples from  the in vitro tests 
400  be validated.11    Unexpected results and deviations from protocol or SOPs, with justification for 
401  deviations, would be reported. Examples include, but are not limited to, canisters or bottles 
402  replaced during in vitro analyses, failure to use the specific actuations required by the protocol, 
403  and experiments rejected due to assignable causes (e.g., instrument failure, sample collection, or 
404  processing errors).  The original and reanalyzed  data, with the reason for reanalysis, would be 
405  tabulated in the study report. The validation reports for the in vitro tests and analytical methods, 
406  the randomization procedure, and all test methods or SOPs for each test would accompany the 
407  data in the submission. When appropriate, we recommend the test method or SOP include a 
408  standardized shaking procedure prior to testing, following labeled instructions, if any. 
409   
410  In addition to submission of all raw data, the agency would like to see supporting documentation 
411  for the following tests: Droplet Size Distribution by Laser Diffraction, Spray Pattern, and Plume 
412  Geometry. Documentation includes instrument output reports and photographic or graphic 
413  material as applicable. We recommend that documents be clearly labeled to indicate the product 
414  (e.g., T or R), batch number, and testing conditions (e.g., distance, lifestage, delay time), as 
                                                 
10  Automatic actuation systems can be  stand-alone or accessories for spray characterization instruments. 
Systems can include settings for force, velocity, acceleration, length of stroke, and other relevant parameters. 
Selection of  appropriate settings would be relevant  to  proper  usage of  the product  by  the trained patient, and for 
nasal sprays, may  be available  from  pump suppliers  for  tests such as Droplet  Size Distribution by  Laser  
Diffraction and Spray Pattern. In the absence of recommendations from  the pump  supplier, we recommend that  
settings should  be  documented based  on exploratory  studies in which  the relevant  parameters are varied  to  
simulate  in  vitro performance upon hand actuation.  Selected  settings  used for the in  vitro studies would be  
specified in the test method or SOP  for each  test for which the system  is employed.  
 
11  A draft guidance for industry entitled  Analytical Procedures and Methods Validation was issued in August 2000.  
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415  appropriate. For Droplet Size Distribution by Laser Diffraction, profiles of droplet size and 
416  obscuration or percent transmission over the complete life of the single sprays would be 
417  submitted. For Spray Pattern and Plume Geometry, we recommend each image display the 
418  relevant BA/BE measures described in this guidance. Supporting documentation for Droplet 
419  Size Distribution by Laser Diffraction, Spray Pattern, and Plume Geometry would include 
420  representative copies, preferably electronic, of >20 percent of the total observations. For Spray 
421  Pattern and Plume Geometry quantitated  by automatic image analysis, representative  electronic 
422  images rather than paper copies of >20 percent of the total observations would be submitted, as 
423  electronic files are definitive.  For automated image analysis of Spray Pattern and Plume 
424  Geometry, in addition to  the electronic images, we recommend paper copies of a few screen 
425  images be submitted as reference samples. 
426   
427  1.  Single Actuation Content (SAC) Through Container Life 
428   
429  For noncomparative data, SAC through container life testing is used to characterize the 
430  delivery of drug discharged from  the actuator of an aerosol or nasal spray relative to label 
431  claim through container life. For comparisons of  T and R products, this test ensures that 
432  the T product delivers an equivalent amount of drug relative to the R product over the 
433  labeled number of actuations. The tests are distinct from and do not apply dose content 
434  uniformity (DCU) or spray content uniformity (SCU) acceptance criteria.  
435   
436  The dosage unit sampling apparatus for collection  of an emitted dose from  an aerosol is  
437  described in U.S. Pharmacopeia (USP) 25, <601>. We  recommend a suitable apparatus 
438  be used for collecting an  emitted dose from  a nasal spray.  For both solution and 
439  suspension formulations of nasal aerosols  and nasal sprays, the mass of drug per 
440  actuation would be based on a stability-indicating chemical assay unless use of a 
441  nonstability-indicating method is justified. Because the data at beginning (B) lifestage  
442  will also be  used for confirmation of priming (Section V.B.7), SAC through container life 
443  would be based on single actuation data per determination.  For BA and BE 
444  submissions, the tests would determine delivered (emitted or ex-actuator)  drug mass from 
445  primed units at the beginning of unit life, at the middle of unit life, and at the end of unit 
446  life12 for nasal aerosols, and at beginning and end of unit life for nasal sprays.  The 
447  delivered mass of drug substance would be expressed both as the actual amount and as  a 
448  percentage of label claim.  We  recommend that mean and variability in SAC through 
449  container life be determined based on within and between unit (container) data and 
450  between batch (or sublot) data. For BE data, equivalence of T and R data would be based 
451  on the statistical methodology of Appendix C. 
452   
453  To use the SAC through container life data for priming studies, we recommend aerosols 
454  and sprays be unprimed prior to the conduct of the tests. Therefore, for aerosols, the test 
                                                 
12  Based  on the labeled number of actuations, this guidance uses the terms beginning  lifestage  (B),  middle lifestage  
(M),  and end lifestage (E) interchangeably with  the terms beginning  of unit life (the first actuation(s) following  the 
labeled number  of  priming actuations); middle of  unit life (the actuation(s) corresponding  to  50  percent of the labeled  
number of actuations);  and end of  unit life (the actuation(s) corresponding to  the label claim  number of  actuations).  
 
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455  would be performed at such time that the product meets two conditions: (1) after the 
456  lagering period and (2) not less than one month after the last actuation conducted as part 
457  of batch release testing. During the time  period between batch release and SAC through 
458  container life testing, the aerosol product would not be actuated. Also, during this one 
459  month period, both T and R aerosols would be stored in the valve upright position, unless 
460  labeling indicates that the product be stored in the valve down position,  in which case the 
461  test would be  conducted on products stored in the valve down position. For sprays, the 
462  SAC through container life test would be conducted not less than one month after 
463  completion of batch release testing. During the time period between batch release and 
464  SAC testing, the product would not be actuated. 
465   
466  2.  Droplet Size  Distribution by Laser Diffraction  
467   
468  Droplet size distribution is an important property influencing the nasal deposition of  
469  aerosols and sprays, and we recommend that it be thoroughly characterized. 
470   
471  a.  Nasal sprays 
472   
473  We recommend that droplet size distribution be determined using laser diffraction 
474  or an appropriately validated alternate methodology. 
475   
476  Laser diffraction is a nonaerodynamic optical method of droplet sizing that 
477  measures the geometric size of droplets in flight. Modern laser diffraction 
478  instrumentation can provide plots of obscuration (optical concentration) or 
479  percent transmission (%T) and droplet size distribution (D , D , D ) over the 
10 50 90
480  entire life of a single spray.  Span ((D - D )/D ) can be computed from these 
90   10 50
481  data. These profile data indicate that each plume can be characterized by three 
482  phases: formation, fully developed, and dissipation. For nasal sprays, the general 
483  profile for obscuration or percent T versus time can be characterized by a rapid 
484  increase in obscuration, or decrease in percent T, early in the life of the spray 
485  (formation phase), followed by attainment of a plateau (fully developed phase), 
486  then a rapid decrease in obscuration, or increase in percent T, late in the life of the 
487  spray (dissipation phase). Changes in droplet size occur coincident with the 
488  changes in obscuration or percent T, with droplet sizes attaining plateau values 
489  within the same approximate time period as the plateau in obscuration or percent  
490  T.  Profiles of the droplet size and obscuration or percent T over the complete life 
491  of the single sprays are recommended to be determined at each of two distances 
492  (see below) to establish the fully developed phase during which data would be 
493  collected. Droplet size distribution and span during the fully developed phase are 
494  requested. The sponsors protocol or SOP would state the criterion selecting the 
495  region of the plateau at which droplet size data will be determined (e.g., the 
496  average of all scans over the entire plateau, the data of a single scan (sweep) only 
497  at the maximum  obscuration (or minimum percent T), or the average of a 
498  specified range of scans around this obscuration or percent T). This criterion 
499  would be established prior to the study for each of the two distances and 
500  implemented consistently during the study. 
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501   
502  We would also like to see instrument setup and operation conditions.  We  
503  recommend the instrument be operated within the manufacturers recommended 
504  obscuration or  percent T range, which would be stated in the submission, to 
505  avoid or minimize multiple scattering (due to high droplet  concentration). 
506  Avoidance of  multiple scattering is preferred to use of  a correction algorithm that 
507  compensates for this effect.  
508   
509  Single spray droplet size distribution and span would be reported based on 
510  volume (mass) rather than count (number of droplets). We  would like to request 
511  data be provided for nasal sprays at: 
512   
513         Fully developed phase only 
514    B and E lifestages  
515    Two distances from  the actuator orifice. For increased ability  to detect  
516  potential differences between products, it is recommended that the studies be 
517  performed within a range of 2 to 7 cm  from the orifice, with the two distances 
518  separated by 3 cm  or more. 
519   
520  b.  Nasal aerosols 
521   
522  Droplet size distribution can be determined using laser diffraction or 
523  appropriately validated alternate methodology. 
524   
525  We would like to see instrument setup and operation conditions. We recommend 
526  the instrument be operated within the manufacturers recommended obscuration 
527  or percent T range, which would be stated in the submission, to avoid or 
528  minimize  multiple scattering (due to high droplet concentration). Avoidance of  
529  multiple scattering is preferred to use of a correction algorithm  that compensates 
530  for this  effect.  
531   
532  Beam steering resulting from refractive index effects due to evaporation of 
533  propellant is an additional concern for nasal aerosols. Droplet  size distribution 
534  would be characterized at distances from  the actuator that eliminate or minimize 
535  beam  steering, if possible. If a correction algorithm  is used, we recommend an 
536  explanation of the corrections be provided. 
537   
538  We ask that single-spray droplet size distribution and span be reported based on 
539  volume (mass) rather than count (number of droplets). Data would be provided 
540  for nasal  aerosols  at: 
541   
542     Fully developed phase only 
543    B and E lifestages  
544    Two distances from  the actuator  orifice 
545   
546  For both nasal sprays and nasal aerosols, mean D , D , D values for a given bottle or 
10 50 90  
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547  canister can be computed from the mean of up to three consecutive sprays from  that unit 
548  at each lifestage. However, to assess precision, the data of each spray would also be 
549  reported. 
550   
551    3.  Drug in Small Particles/Droplets, or  Particle/Droplet Size  Distribution by 
552  Cascade Impactor  
553   
554    Sizing of droplets or particles by multistage cascade impactor (CI) measures 
555  aerodynamic diameter based on inertial impaction, an important factor in the 
556  deposition of drug in the nasal passages. Analytical data should be based on a 
557  validated chemical assay.11   We recommend that analytical runs include at least 
558  three or  more concentrations of  quality control samples that represent the entire 
559  range of the standard curve or the expected concentration range of samples from 
560  the various stages of the CI.  An analytical validation report would accompany the 
561  CI data report. The SOP or validation report would indicate the minimum 
562  quantifiable mass of drug deposited on each location reported. 
563   
564    a.  Nasal Sprays: Drug in Small Particles/Droplets  
565   
566  For nasal sprays, the majority of the emitted dose is deposited prior to or on the 
567  first stage of  the CI test.  Small droplets, for this test and dosage form  defined as 
568  smaller in size than the nominal effective cutoff diameter (ECD) of the top stage 
569  of a suitable CI, may potentially be delivered to regions of the airways beyond 
570  the nose. This test is intended to determine the amount of drug in small 
571  particles/droplets. For example, for USP 25 Apparatus 1 (<601>), an eight 
572  stage CI operated with the standard 28.3 liter per minute configuration, small 
573  droplets are those under 9.0 microns. For BA, the CI test is intended to quantify 
574  the mass of drug in small droplets. For BE, the mass of drug in small droplets 
575  for the T product would be less than or equivalent to the corresponding mass of 
576  drug from the R product. The comparative test addresses a potential safety 
577  concern  an excess of small droplets due to T relative to R might deliver to 
578  regions beyond the nose excipients with possible adverse pulmonary effects. 
579  The CI test for nasal sprays is not  intended to provide PSD of drug or 
580  aerosolized droplets. 
581   
582  Measurable levels of drug below the top stage of the CI would be a function of the 
583  specific drug product and the experimental  setup and procedure, including the  
584  number of actuations and assay sensitivity.  Thus, we recommend a validated, 
585  highly sensitive assay be used.  In Agency experience, a two-liter or larger 
586  induction port (expansion chamber) is preferred to a one-liter chamber. We  prefer 
587  studies use the fewest number of actuations (generally not exceeding 10) justified 
588  by the sensitivity of the assay, to be more reflective of individual doses.  Drug 
589  deposition would be reported in mass units. Mass balance accountability would 
590  be reported.  Mass balance would be based on drug deposition  on each of 
591  valvestem, actuator, adapters, induction port, any other accessories, the top stage, 
592  and all lower stages to the filter. The total mass of  drug collected on all stages 
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593  and accessories is recommended to be between 85 and 115 percent of label claim  
594  on a per actuation basis.  The total mass of drug below the top stage is of primary 
595  interest. Therefore the pooled mass of drug deposited on all lower stages and 
596  filter can be reported. 
597   
598  For BA and BE, CI test would be data requested only at the beginning lifestage. 
599  Statistical approaches will be provided  in Appendices B and D, respectively. 
600   
601  b.  Nasal Aerosols: Particle/Droplet Size  Distribution  
602   
603  CI studies for nasal aerosols would use an induction port (expansion chamber) 
604  that maximizes drug deposition  below the top stage of the CI.  For this reason, a 
605  one-liter induction port is preferred to the USP 25 (<601>) induction port, 
606  although other sizes may also be appropriate. Agency experience indicates that 
607  with a suitable induction port and CI, the amount of drug deposited below the top 
608  stage from  nasal aerosols formulated with either chlorofluorocarbon or 
609  hydrofluoroalkane propellants is of the same order of magnitude as from orally 
610  inhaled aerosols. Therefore, unlike for nasal sprays in which the total mass  of 
611  drug below the top stage is of interest, we recommend a particle/droplet size 
612  distribution be provided for this dosage form. Selection of the most suitable CI 
613  may be influenced by the effective cutoff diameters (ECDs) of stages of various  
614  brands of cascade impactors, the geometry of the induction port, and other factors. 
615  The number of actuations recommended for the CI study of aerosols is described 
616  in the draft guidance Metered Dose Inhaler (MDI) and Dry Powder Inhaler 
617  (DPI) Drug Products: Chemistry, Manufacturing, and Controls Documentation. 
618  Drug deposition would be reported in mass units. Mass balance accountability 
619  would be reported. 
620   
621  For BA and BE, CI data would be requested only at the beginning lifestage. At 
622  this time, it is recommended that studies of nasal aerosols use USP 25 Apparatus  
623  1 (<601>) operated at the standard 28.3 liter per minute configuration. We  
624  recommend determination of a profile based on drug deposition at 11 sites: (1) 
625  sum of valve stem plus actuator; (2) induction port; (3 - 10) eight individual 
626  stages; and (11) filter. Deposition in the valve stem  plus actuator would be  
627  included to provide a profile of drug deposition ex-valve rather than  ex-actuator.  
628  It should be noted that the in vitro BE  limit for the profile comparison depends on 
629  the number of stages and other accessory deposition sites. Statistical approaches 
630  for BA and BE will be provided in Appendices B and E, respectively.  
631   
632  4.   Drug Particle Size  Distribution by Microscopy 
633   
634  For suspension products, drug particle size may be important for rate of 
635  dissolution and availability to sites of action within the nose.  Therefore, drug 
636  particle size distribution (PSD) and extent of agglomerates would be 
637  characterized in the spray or aerosol formulation prior to actuation, and in the 
638  spray following actuation. Determination of PSD and agglomerates in both the 
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639  formulation and following actuation are intended to characterize the potential 
640  influence of the device on deagglomeration. Determination in the spray is only 
641  requested at the beginning lifestage. Nasal spray formulations frequently contain 
642  suspended drug substance in the presence of insoluble suspending agent, which 
643  complicates the particle size characterization. When examining formulations  
644  containing suspending agents, and currently available technology cannot be 
645  acceptably validated to determine drug  particle size, a qualitative and semi
646  quantitative method for examination of drug and aggregated drug particle size 
647  distribution can be used.  We  recommend studies of nasal sprays include placebo 
648  product to provide an estimate of the occurrence of apparent drug particles (false 
649  positives) due to excipient. Evaluation may use light microscopy or other 
650  appropriate means. 
651   
652  For NDAs and ANDAs of both sprays and aerosols, we recommend drug PSD 
653  and agglomerates data be provided in the BA or BE submission, along with a 
654  description of the test method. Sponsors can submit representative 
655  photomicrographs, if desired. For BE, PSD by light microscopy, even if 
656  qualitative or semi-quantitative, can be useful to the applicant to estimate 
657  particle size relative to the precursor product prior to further product 
658  development and testing. These data are supportive, and formal statistical 
659  testing is not applicable.  
660   
661  5.  Spray Pattern  
662   
663  Spray pattern studies characterize the spray either during the spray prior to 
664  impaction, or following impaction on an appropriate target such as a thin-layer 
665  chromatography (TLC) plate. Spray patterns for certain nasal spray products 
666  may be spoked  or otherwise irregular in shape. 
667   
668  Spray patterns can be characterized and quantitated by either manual or 
669  automated image analysis, if  validated. Both analyses will allow shape and size 
670  to be determined. Automated analysis  systems may also allow determination of  
671  center of mass (COM; unweighted for image intensity) and/or center of gravity 
672  (COG; weighted for image intensity)  within the pattern to be determined. COG 
673  is of greater interest and is preferred in  the automated analyses of spray patterns. 
674  Automated image analysis is expected to increase objectivity in spray pattern 
675  measurement. The technology enables the perimeter of the true shape of the 
676  spray pattern to be determined, identifies COM and/or COG, and enables the area 
677  within the perimeter to be quantitated, thus its use is encouraged. 
678   
679  Equivalence of spray patterns between T and R products can be established 
680  based on a combination of qualitative  and quantitative  measures: 
681   
682           Comparative visual inspection for shape. For the automated analyses, the true 
683  shapes identified by the software serve as the basis of comparison 
684  (qualitative). Establishment of qualitative sameness of T and R spray pattern 
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685  shapes is a prerequisite to the quantitative analyses in the following two 
686  bullets.  
687          Equivalent  area within the perimeter of  the true shape for automated 
688  analysis, or equivalent D for manual analysis (quantitative). 
max  
689        Equivalent ovality (ellipticity) ratio (quantitative).  
690   
691  a.  For nonimpaction systems  
692   
693  Spray patterns can be visualized using a system  based on a laser light sheet and 
694  high-speed  digital camera that enables visualization of a pattern perpendicular to 
695  the axis of the nasal spray.  The perimeter of  the true shape, area within the 
696  perimeter (to include a high proportion, e.g., >95 percent of the total pattern), 
697  COG, and  D (longest diameter) and D (shortest diameter)  that pass through 
max   min  
698  the COG and extend to the perimeter of the true shape, can be determined based 
699  on automated analysis using time-averaged  images over the duration of a single 
700  spray. Software settings can be established during prestudy validation and the 
701  settings should be used consistently in the study. Statistical analysis at each 
702  distance would be based  on equivalence of area within the perimeter and ovality 
703  ratio (D divided by D ). 
max   min
704   
705  b.  For impaction systems 
706   
707  The number of sprays per spray pattern would preferably be one. We  recommend 
708  that the visualization technique be specific for the drug substance. If exploratory 
709  studies document that a drug-specific reagent cannot be found, a nonspecific 
710  visualization  reagent can be used.  We recommend that application of the reagent 
711  be controlled  to maintain the details of the image intensity of the pattern.  
712   
713  Manual analysis 
714   
715  The approximate COM would be identified, and D and D drawn through this 
max   min  
716  center. The two lines may not be orthogonal to each other. Representative plots 
717  can be submitted, and each figure can be marked with the COM, D and D , 
max   min
718  each based on  visual analysis. The ovality ratio would be provided for each spray 
719  pattern. Statistical analysis at each  distance would be based on equivalence of 
720  D and ovality ratio. 
max   
721   
722  Automated analysis  
723   
724  The automated image analysis software can define  the perimeter of the true shape 
725  of the spray pattern to include a high proportion (e.g., >95 percent) of the total 
726  pattern. T and R would both be sprayed on each TLC plate to ensure 
727  measurement of the spray pattern at the same intensity range for a given plate. 
728  D and D would pass through the COM or the COG, as appropriate, and 
max   min  
729  extend to the perimeter of the true shape. Statistical analysis at each distance 
730  would be based on equivalence  of area  within the perimeter and ovality ratio. 
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731   
732      c.  For both nonimpaction and impaction systems 
733  The information above would apply to spray patterns in which the COM or COG 
734  falls within the perimeter of  the image of  the actual spray pattern, and the D
max  
735  axis doesnt extend outside of the perimeter. Infrequently, the COM or COG may 
736  fall outside the perimeter of the spray pattern, and/or the D axis may cross the 
max  
737  perimeter. Horseshoe-shaped and certain other patterns may cause such an effect. 
738  When this occurs, automated analysis  using a system that has the capability of 
739  fitting the perimeter with an appropriate geometric shape is recommended. 
740  Statistical analysis at each distance would be based on equivalence of area within 
741  the perimeter of  the true shape  of the spray pattern (not within the fitted 
742  geometric shape), and ovality ratio, where D and D are computed from  the 
max   min  
743  fitted geometric shape (e.g., ellipse). 
744   
745  For all cases above, we recommend spray patterns be determined based on: 
746   
747          Single actuations (nonimpaction systems), or preferably single actuations  
748          (impaction systems) 
749          Beginning lifestage only 
750          Two distances from  the actuator orifice, which allow discriminatory 
751          capability between individual pump units and between T and R products.  
752  For nasal sprays, these distances are recommended to be at least 3 cm  
753  apart within the range of 3 to 7 cm. 
754   
755  For manual quantitation of spray patterns based on impaction studies such as TLC 
756  plate methodology, we recommend the submission include copies, preferably 
757  electronic, of images of representative  spray patterns at two distances, and each 
758  figure would clearly indicate the estimated COM (manual analysis), D and 
max  
759  D . When automated image analysis software is used for impaction studies, data  
min
760  would be presented in electronic files. For automated image analysis of either  
761  impaction or nonimpaction studies, electronic files would be definitive. 
762  Submission of electronic files is recommended to avoid printer-dependent 
763  variations in  spatial calibration of  images. These files would contain the images, 
764  showing the COG or COM and the perimeter of  the true shape of the spray 
765  pattern, and the accompanying quantitation reports. Each image would also  
766  include a legible scale used for measurement. 
767   
768  Some automated image analysis software may not include automated quantitation 
769  of spray pattern images. For such cases, the analyst would determine and display 
770  the quantitative parameters on the electronic image. As mentioned above, 
771  quantitation of electronic images would be definitive. 
772   
773  6.  Plume Geometry 
774   
775  Plume geometry describes a side view of the aerosol cloud parallel to the axis of 
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Draft  Not for Implementation 
776  the plume, and we recommend it be based on high-speed photography, a laser 
777  light sheet and high speed digital camera,  or other suitable methods. The image 
778  would be snapshot, not time-averaged. Quantitation can be by manual analysis or  
779  automated image analysis.  
780   
781  During the very early life of an aqueous nasal spray plume, formulation may exit 
782  the actuator  orifice as a narrow stream  that subsequently forms a relatively stable, 
783  fully developed, conical plume prior to separating from the orifice. We  
784  recommend plume angle, width, and height, all quantitated  by  the same  analytical 
785  method, be reported at a single delay time while the fully developed phase of the 
786  plume is still in contact with the actuator tip. The applicant would provide 
787  documentation that the plume is fully  developed at the selected delay time. The 
788  angle would be based on the conical region of the plume extending from a  vertex 
789  that occurs at or near the actuator tip. Plume angle based on spray pattern 
790  dimensions and distance from  actuator tip to an impaction surface is not 
791  appropriate. For this guidance, the recommended plume width would be the 
792  width at a distance equal to the greater of the two distances selected for 
793  characterization of the spray pattern. Plume width data would thus be  
794  complementary to spray pattern data obtained at the same  distance. Plume  height 
795  would be the distance from  the actuator orifice (sprays) or end of the inhaler tube 
796  (aerosols) to the leading edge of the plume. We  request that the criteria for 
797  defining the plume angle, width, and height borders be provided. 
798   
799  Plume geometry would be performed at: 
800   
801        Beginning lifestage only 
802        One side view only 
803        A single delay time 
804   
805  The submission would include photographs when quantitation is by manual 
806  analysis, or digital images when quantitation  is by automated image analysis. 
807  Each image would also include a legible scale used for measurement, and the 
808  delay time would be clearly indicated. Images would clearly indicate the plume 
809  angle, width, and height. When automated image  analysis is used, quantitation of 
810  electronic images would be definitive. Manual quantitation based on paper copies 
811  of electronic images would not be appropriate. 
812   
813  We recommend plume geometry measurements be summarized as mean, 
814  geometric mean, and %CV.  Comparative data would be supportive, thus  for BE 
815  studies, the ratio of the geometric mean of the three batches of T to that of the 
816  three batches of R, based on log transformed data, would fall within 90  111 
817  percent (point estimates) for plume angle and width. Due to subjectivity in the 
818  measurement of plume height, point estimates would not be applicable. 
819   
820    7.  Priming and Repriming  
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821   
822  Priming and repriming data will ensure  delivery of the labeled dose of drug 
823  following labeled instructions for use.  Priming would be established based on the 
824  same  B lifestage data obtained for the  single actuation content (SAC) through 
825  container life study (Section V.B.1).  For products approved under an NDA, 
826  priming and repriming data based on single actuations would be provided in the 
827  CMC portion of the submission. 
828   
829  For products approved under an ANDA, the labeling would be the same  as that for 
830  the R product, except for specific changes described in the regulations (21 CFR 
831  314.94(a)(8)(iv)). For nasal sprays and some nasal aerosols, the R product 
832  labeling (package insert and/or patient package insert) describes the number of 
833  actuations to prime the product on initial  use and on repriming following one or 
834  more periods of nonuse (e.g., 24 hours and 7 days following last dose).  For these 
835  products, we request priming and repriming data for T and R products. Studies 
836  would follow the recommended time periods described in Section V.B.1 between 
837  lagering and/or batch release testing and conduct of the priming test. Priming 
838  and/or repriming studies would not be requested when the R product lacks priming 
839  and/or repriming instructions, respectively. 
840   
841  We recommend that priming and repriming data for T in multiple orientations 
842  be provided in the CMC portion of the ANDA submission. Therefore, for the 
843  BE submission, studies can be based on products stored in the valve upright 
844  position, with the exception of nasal aerosols in which R labeling recommends 
845  storage in the valve down position.  For the latter products, priming data, and 
846  repriming data when applicable, would be provided following storage in the 
847  valve down position. Priming studies would be based on the emitted dose of the 
848  single actuation at B lifestage immediately following the specified number of 
849  priming actuations in the R product labeling. For ANDAs, priming would be 
850  established  providing that the geometric mean emitted dose of  the 30 canisters 
851  or bottles calculated from  the SAC data  at B lifestage falls within 95  105 
852  percent of label claim.  Repriming would be similarly established based on a 
853  single actuation following the specified number of repriming actuations in the R 
854  product labeling. Although noncomparative to R, the priming studies would be 
855  essential to the BE submission to document that each product delivers the 
856  labeled dose within the number of actuations stated in the R product labeling, 
857  thus ensuring that the SAC through container life studies are conducted on 
858  primed T and R products. 
859   
860   
861  VI.  CLINICAL STUDIES FOR LOCAL DELIVERY  
862   
863  A.  General  Information  
864   
865  1.  NDAs  
866   
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  Contains Nonbinding Recommendations 
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867  At the present time, of the classes of drugs covered in this guidance, only certain 
868  corticosteroids are formulated  as suspension formulation nasal aerosols and nasal 
869  sprays and require in vivo studies as a component of the BE or BA submission 
870  (21 CFR 320.21). The same  adequate and well-controlled clinical trials in humans 
871  conducted under an authorized IND, used to establish the safety and effectiveness 
872  of a drug product in support of a forthcoming NDA (21 CFR 314.126), can be 
873  used in some  cases to establish BA or, when comparative, BE (21 CFR 320.24). 
874   
875  2.  ANDAs  
876   
877  Clinical studies are at times incapable of showing a dose-response relationship 
878  and may not be consistently reproducible. However, a showing of dose
879  response is not necessary for BE studies with a clinical endpoint, as these studies 
880  are intended only to confirm  the lack of important clinical differences between T 
881  and R suspension formulation nasal aerosol and nasal spray products (Advisory 
882  Committee for Pharmaceutical Science, 2001).   For an ANDA, an authorized 
883  Bio-IND will be needed for the conduct of a BE study with a clinical endpoint.13  
884   
885  A determination of bioequivalence of rhinitis BE study with a clinical endpoint 
886  for locally acting nasal suspension drug products would be based on the 
887  following premises for T relative to R products:  
888   
889     Qualitative and quantitative sameness of  formulation 
890    Comparability in container and closure systems 
891    Equivalence of in vitro tests 
892    Equivalence of systemic exposure or systemic absorption 
893    Equivalence of the local delivery study. 
894   
895  A number of FDA guidances provide information about the general conduct of 
896  clinical studies, including  clinical studies to document BA and BE: General 
897  Considerations for Clinical Trials  (International Conference on Harmonisation 
898  (ICH) E8); Structure and Content of Clinical Study Reports (ICH E3);  Good 
899  Clinical Practice: Consolidated Guidance (ICH E6);  Statistical Principles for 
900  Clinical Trials (ICH E9), and Choice of Control Group and Related Issues in 
901  Clinical Trials  (ICH E10). 
902   
903  B.  Clinical Study Batches  
904   
905  We recommend that the batch used for the BA study be the same pivotal clinical trial batch used 
906  in the in vitro BA studies (Section V.A).  Where BE studies are conducted for an NDA, the 
907  batches of test and reference products would be the same  batches employed in the in vitro testing.  
                                                 
13  Office of Generic Drugs Policy  and Procedure Guide # 36-92,  Submission  of an  "Investigational New Drug  
Application"  to the Office of Generic Drugs (OGD),  October  13, 1992. 
 
 
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908  Each of the T and R batches used to establish local delivery BE  for an ANDA would be one of 
909  the three batches used for the in vitro BE studies.  We recommend that the inactive ingredients of 
910  the placebo (P) product meet Q and Q recommendations relative to the R product (Section 
1  2 
911  IV.B); the P container and closure would meet the recommendations of Section III.B.  
912   
913  C.  Clinical BE Study Design and Subject Inclusion Criteria  
914   
915  The study design would be the traditional treatment study in which T and R are assessed for a 
916  two-week duration. The two-week duration, in addition to allowing a comparison of equivalent 
917  efficacy, will also allow for an assessment of  safety and tolerability over a reasonable period of  
918  use.  We recommend the study be conducted at the lowest labeled adult recommended dose in 
919  an attempt to optimize study sensitivity.  Prime products according to labeling instructions prior 
920  to dosing. Ensure that priming occurs out of range of the patients, to avoid inhalation of drug 
921  fired to waste. Documentation would rely on the inclusion of a test product placebo (P) dosed 
922  at the same  frequency and number of actuations per nostril as T and R.  
923   
924  A study population consisting of seasonal allergic rhinitis (SAR) patients will allow 
925  documentation of BE, which may extend to all indications in product labeling for locally acting 
926  nasal corticosteroids.  In addition to a history of SAR, we recommend patients have a positive 
927  test for relevant specific allergens (e.g., allergen skin test) and be experiencing a defined 
928  minimum level of symptom severity at the time of study enrollment.  We discourage the 
929  inclusion  of  patients with  other  significant diseases  including asthma, with the exception of  mild 
930  intermittent asthma. 
931   
932  The recommended design for this study is a randomized, double-blind, placebo-controlled, 
933  parallel group study of 14 days duration, preceded by a 7-day placebo run-in period to  establish a 
934  baseline and to identify placebo responders.14  We recommend placebo responders be excluded 
935  from  the study to increase the ability to show a significant difference between active and placebo 
936  treatments (efficacy analysis), and to increase sensitivity to detect potential differences between 
937  T and R products (equivalence analysis).  The protocol would define placebo responders a 
938  priori. Whether the drug is labeled for once or twice daily dosing, clinical evaluations would be 
939  made twice daily (AM and PM, 12 hours apart at the same times daily) throughout the 7-day 
940  placebo run-in period and the 14-day randomized treatment period. Scoring should be made 
941  immediately prior to each dose, to reflect the previous 12 hours (reflective scores) and how the 
942  patient is feeling at the time  of evaluation (instantaneous or snapshot scores).  Because  the 
943  primary BE endpoint would be based on reflective symptom scores, placebo responders should 
944  be identified based on reflective scores, although BE endpoints would include both reflective and 
945  instantaneous scores.  
946   
947  We recommend baseline scoring preferably consist of reflective AM and PM scoring on Days 5, 
948  6, and 7 of the placebo run-in period, and AM scoring (prior to drug dosing) on Day 1 of the 14 
949  day randomized treatment period, resulting in 7 total AM and PM ratings.   Placebo responders 
950  would be identified based on the mean total nasal symptom  score (TNSS) over the 7 total AM and 
                                                 
14  A draft guidance for industry entitled  Allergic Rhinitis: Clinical  Development  Programs for Drug Products was  
issued in April 2000. This guidance discusses general  protocol issues including  blinding. Once finalized, it will 
represent the Agencys thinking  on this topic. 
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951  PM ratings.  The study protocol would state the minimum  qualifying reflective TNSS for 
952  enrollment at screening, and the same minimum qualifying TNSS would be met based on the 
953  mean of the 7 total AM and PM ratings prior to each patients  participation in the randomized 
954  portion of the study.  We recommend randomization occur after evaluation of the 7 total AM and 
955  PM ratings, and the randomized portion of the study can start in the morning of Day 1 after the 
956  AM baseline scoring. 
957   
958  Symptom scores during the randomized treatment period would consist of the PM score on Day 1, 
959  and the 26 AM and PM ratings on Days 2 to 14, resulting in 27 total ratings.  We  recommend 
960  the study be multicenter to avoid potential investigator bias.  A double dummy  design is not 
961  recommended for study blinding of aqueous nasal sprays due to a concern that the doubled fluid 
962  volume may result in washing the drug from its nasal deposition sites, potentially  resulting in an 
963  altered safety and efficacy profile.  However, study blinding is a critical consideration, and we 
964  recommend a description of how the T, R and P products are to be masked be carefully described 
965  in the study protocol. 
966   
967  We recommend the equivalence analysis  be conducted as an evaluable (per protocol) analysis 
968  rather than an intent-to-treat analysis.  The evaluable population would consist of compliant 
969  patients who missed no more than a specified number of days of symptom  scores, took no 
970  contraindicated concurrent medications, and had no protocol violations.  The protocol would 
971  describe the specific criteria used to exclude randomized subjects, resulting in the reduced subset 
972  of subjects for analysis (FDA Guideline for the Format and Content of the Clinical and 
973  Statistical Sections  of an Application, Section III.B.9).  In addition to the equivalence analysis, 
974  an efficacy analysis  would be conducted to demonstrate study sensitivity to the T and R 
975  products.  The efficacy analysis would be conducted as an intent-to-treat analysis, and the intent- 
976  to-treat population would  be clearly defined. Because specific study recommendations are not 
977  provided in this guidance, we recommend a protocol  for a BE study with a clinical endpoint for a 
978  specific suspension drug product be submitted prior to the conduct of the study to the appropriate 
979  review division at FDA. 
980   
981  D.  Clinical BE Study Endpoints  
982   
983  The endpoints for the equivalence and efficacy analyses should be patient self-rated TNSS. 
984  These most often include a composite score of runny nose, sneezing, nasal itching, and 
985  congestion, although addition of non-nasal symptoms to the composite score maybe pertinent 
986  for certain drug products.15  TNSS is a categorical variable, classified into a number of discrete 
987  categories, as opposed to a continuous variable.  A common allergic rhinitis rating system  uses 
988  a four-point scale with signs and symptoms  ordered in severity from 0 (no symptoms) to 3 
989  (severe symptoms), as follows16: 
990   
991     0 = absent symptoms  (no sign/symptom  evident) 
                                                 
15 Draft guidance Allergic Rhinitis: Clinical  Development  Programs for Drug  Products, was issued in April 2000, 
once finalized it will represent  the Agencys thinking  on this topic. 
16  Other scoring systems were proposed in  the draft guidance Allergic Rhinitis: Clinical  Development  Programs for  
Drug Products April 2000. Once finalized, it  will represent  the Agencys thinking  on this topic.  
 
  23
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Draft  Not for Implementation 
992     1 = mild symptoms (sign/symptom clearly present, but minimal awareness; easily 
993  tolerated)  
994     2 = moderate symptoms  (definite awareness of sign/symptom that is bothersome but 
995  tolerable)  
996     3 = severe symptoms  (sign/symptom that is hard to tolerate; causes interference with 
997  activities of  daily living and/or sleeping) 
998   
999  We recommend the endpoints for the equivalence and efficacy analyses be expressed as  mean 
1000  change from baseline (pretreatment) of  the TNSS, expressed in absolute units, rather than 
1001  percent change from baseline.  The study report would include  the daily AM  and PM 12-hour 
1002  reflective symptom  scores.  In addition, the report would include the mean symptom  score over 
1003  the 7 total AM and PM ratings of the placebo run-in period and the mean symptom  score over 
1004  the 27 ratings of the randomized treatment period.  For the equivalence and efficacy analyses, 
1005  the primary  endpoint would be reflective scores for the 12-hour pooled TNSS over the two
1006  week randomized portion of the study.  However, instantaneous scores would also be 
1007  provided as a secondary endpoint. Statistical approaches for analysis of the rhinitis study data 
1008  are provided in Appendix F. 
1009   
1010  Safety assessments would be made before (at screening or baseline) and at end-of-treatment. 
1011  Adverse events would be reported daily. 
1012   
1013   
1014  VII.  PK STUDIES FOR SYSTEMIC  EXPOSURE 
1015   
1016  A.  General  Information  
1017   
1018  The Agency recommends that plasma  concentration-time profiles from BA and BE studies be 
1019  used to evaluate systemic exposure for suspension drug products that produce sufficiently high 
1020  concentrations of the moiety(ies) to be measured to allow reliable analytical measurement for an 
1021  adequate length of  time after nasal administration.  The recommended moiety(ies) to be 
1022  measured in the BA and BE studies are described elsewhere.17 
 
1023   
1024  Systemic drug levels that occur with locally acting drug products are generally in the low ng/mL  
1025  or low pg/mL  range, depending on the drug and the drug product.  Validated bioanalytical 
1026  methodology may be available for many of the nasal corticosteroid drugs.  For these drugs, pilot 
1027  studies are not needed prior to conducting the full-scale PK study.  If validated methodology is 
1028  unavailable, a small-scale, single-dose pilot study, or when appropriate, a small-scale, multiple- 
1029  dose pilot study, may be helpful in assessing the proposed analytical methodology and 
1030  determining whether sufficiently high drug concentrations are attained.  A PK study for 
1031  systemic exposure would be preferred to a PD or clinical study for systemic absorption (Section 
1032  VIII). If a sponsor has convincing data based on unsuccessful  attempts to conduct the PK study 
1033  in order for a PD or clinical study for systemic absorption could be used.  If systemic exposure 
1034  were established based on a PK study, a PD or clinical study for systemic absorption (Section 
                                                 
17 Guidance for  Industry, Bioavailability and Bioequivalence  Studies for Orally  Administered  Drug Products - 
General Considerations  (October 2000). Once finalized  it will represent the Agencys thinking  on this topic. 
  24
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1035  VIII) would not be requested.  
1036   
1037  B.  Study Batches  
1038   
1039  The Agency recommends that the BA batch used for the PK systemic exposure study be a 
1040  pivotal clinical trial batch.  Alternatively, a PK  batch similar to the batch used in a pivotal 
1041  clinical trial can be used, in which case we recommend that any differences between the PK 
1042  batch and the pivotal clinical trial batch be discussed with  the appropriate CDER review 
1043  division prior to the study.  If the PK batch is not one of the three batches used for the in 
1044  vitro BA studies (Section V.A.1), make sure that  in vitro BA data are provided for the PK 
1045  batch using the same protocols as for the three batches. 
1046   
1047  For a BE study, the batches of T and R would be the same  batches used for the clinical study for 
1048  local delivery, and each of these batches would be one of the three batches used for the in vitro 
1049  BE studies. 
1050   
1051  C.  Study Design and Subject Inclusion Criteria  
1052   
1053  The BA study to characterize systemic exposure can be one of the same PK studies conducted to 
1054  address clinical pharmacology and biopharmaceutics questions of regulatory interest.  The BA 
1055  study can be conducted in healthy subjects or allergic rhinitis (AR) patients.  Where 
1056  appropriate, the BA study would include a reference product that may be an oral or intravenous 
1057  solution, oral suspension, or other nasal product.  Consultation with the appropriate review 
1058  division is recommended regarding whether a comparative or noncomparative BA study is 
1059  appropriate. 
1060   
1061  For an NDA or an ANDA, the in vivo BE study would be conducted with a replicate or 
1062  nonreplicate randomized crossover design.  For aqueous nasal sprays, the study would be 
1063  conducted at the maximum  labeled adult dose to maximize plasma  drug levels, while avoiding 
1064  the possibility of alteration of the drug deposition pattern within the nose at higher volumes 
1065  when dosed above label claim.   The deposition pattern could be altered due to loss of drug 
1066  from  the nasal cavity at these higher volumes, due either to drainage into the nasopharynx or 
1067  externally from  the nasal cavity.  Although alteration of the deposition pattern may be less 
1068  likely for a nasal aerosol when dosed above the maximum  labeled number of actuations, the 
1069  same  study design and dose as for aqueous nasal sprays would be followed.  We  recommend 
1070  that subjects for the study be healthy, with exclusions primarily for reasons of safety.  The 
1071  study protocol would include information regarding time  interval between doses to each  nostril 
1072  and subject head position during dosing. 
1073   
1074  This guidance recommends that the PK study generally be conducted as a single-dose study. 
1075  Such studies  are more sensitive than multiple dose studies in assessing rate of  release of  the drug 
1076  substance from the drug product into the systemic circulation.  In addition, the nasally dosed 
1077  corticosteroids tend to have biologic half-lives ranging from less than one hour up to about eight 
1078  hours. For these products, when dosed either once or twice daily, systemic accumulation is 
1079  expected to be relatively low, thus a multiple  dose study may not result in a more reliable 
1080  analytical measurement.  However, there may be drugs that, due to pharmacokinetic 
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Draft  Not for Implementation 
1081  characteristics, yield higher concentrations in a multiple-dose study, enabling the drug 
1082  moiety(ies) of interest to be measured more reliably than in a single-dose study.  For these 
1083  drugs, a multiple-dose PK study would be preferred to a single-dose study. 
1084   
1085  D.  Study Measures 
1086   
1087  The following BA and BE measures are considered pivotal17  in a single-dose study: AUC (a 
0 - tlast 
1088  measure of total exposure); AUC (a measure of total exposure); and C (peak exposure).  If 
0 - 4  max  
1089  AUC cannot be determined reliably due to inability to estimate k accurately, total exposure 
0 - 4  el 
1090  would be based only on AUC .  The following BA and BE measurements and plasma  
0 - tlast
1091  concentrations provide supportive PK characterization: plasma  concentrations at each sampling 
1092  time; T ; and k .  The following BA and BE measurements are considered-pivotal for a 
max el
1093  multiple-dose study: AUC (total exposure),  where t is the dosing interval; and C (peak 
0 -t max  
1094  exposure).  T data should also be provided as supportive characterization. 
max  
1095   
1096  Statistical analysis information is provided in Appendix G. 
1097   
1098   
1099  VIII.  PD OR CLINICAL STUDIES FOR SYSTEMIC ABSORPTION   
1100   
1101  A.   General Information 
1102   
1103  As stated in Section VI.A, at present only certain corticosteroids are formulated  as suspension 
1104  products and require product quality in vivo studies.  For those suspension drug products for 
1105  which the moiety(ies) to be measured in the blood or plasma  (Section VII) are too low to allow 
1106  reliable analytical measurement for an  adequate length of time, PD or clinical endpoint studies 
1107  serve as measures of systemic absorption (Section II.A.2).  However,  PK studies as measures of 
1108  systemic exposure are preferred if at  all possible.  As stated in Section VII, if a sponsor has 
1109  convincing data based on  unsuccessful attempts to conduct the PK study a PD or clinical study 
1110  would be used in lieu of the PK study.  The BA study to characterize systemic absorption may 
1111  be one of the same  clinical studies conducted to establish the safety of the drug product.  The 
1112  study would be conducted under an authorized IND in support of a forthcoming NDA (21 CFR 
1113  314.126). 
1114   
1115  If a PD or clinical study is to be conducted (see previous paragraph), the recommended systemic 
1116  absorption BE  study design for nasal corticosteroids would be assessment of the HPA axis.  
1117  The study would be conducted at the maximum  labeled adult dose of the nasal aerosol or nasal 
1118  spray to maximize study sensitivity.  However, the study design would be based on an 
1119  understanding that the maximum  labeled dose over a 6-week period (Section VIII.C) may not 
1120  result in detectable adrenal suppression by T and R because this dose may be at or near the 
1121  bottom  of the adrenal suppression dose-response curve.  In addition to a test product placebo 
1122  (P), we recommend an active control such as prednisone be included to ensure that the study is 
1123  sufficiently sensitive to detect  a drug  effect (sensitivity  analysis).  Ensure that  the active control 
1124  dose is sufficiently large and the duration sufficiently long to produce a statistically significant 
1125  response relative to placebo, with a duration sufficiently short to minimize undue exposure or 
1126  risk to subjects.  Determination of the optimum active control dose and dosing regimen may 
  26
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Draft  Not for Implementation 
1127  call for a pilot study by the sponsor.  The pilot study may determine that an initial phase of the 
1128  6-week study period may use a matching active control placebo, with active control given over 
1129  the remainder of the study period, in an effort to reduce patient exposure to the active control. 
1130  The pilot study can also provide an estimate of the number of subjects to be included in the 
1131  pivotal study to yield a statistically significant difference in the HPA axis endpoint between the 
1132  active control and the test product placebo (i.e., the aerosol or  spray placebo).  It may also  
1133  allow estimation of the number of subjects to be included to characterize any HPA axis effects 
1134  or lack thereof and to allow conclusions about any relative effects of T versus P and R versus P  
1135  (relative assessment of the HPA axis; Appendix G.B).  Conduct of the study in allergic rhinitis 
1136  (AR) patients will allow an efficacy assessment to evaluate compliance with the study protocol  
1137  (efficacy analysis).  Therefore, AR patients, rather than  healthy, non-allergic patients are 
1138  recommended as the study population.  We also recommend that other measures of compliance 
1139  be instituted, including before and after weighing of the aerosol or spray container and diary 
1140  entry of drug use. 
1141   
1142  Because this section does not provide  specific recommendations, we recommend sponsors 
1143  submit prior to the conduct of the study a protocol for a BE study with a PD or clinical endpoint 
1144  for a specific drug product to the appropriate review division at FDA.  For an NDA, the same  
1145  adequate and well-controlled clinical trials in humans conducted under an authorized IND, used 
1146  to establish the safety and effectiveness of a drug product in support of a forthcoming NDA (21  
1147  CFR 314.126), can be used in some  cases to establish BA or, when comparative, BE (21 CFR 
1148  320.24). For an ANDA, if the maximum  single or total daily dose of the active control in the 
1149  pilot or full-scale study exceeds that specified in the labeling of the selected active control drug 
1150  product, an authorized Bio-IND will be needed.13 
 
1151   
1152  B.  Clinical Study Batches  
1153   
1154  The Agency recommends the BA batch used for the study be a pivotal clinical trial batch used in 
1155  the in vitro BA studies (Section V.A).  For BE studies for an NDA, the batches of T and R would 
1156  be batches used in in vitro testing.  For an ANDA, the batches of T and R used for the systemic 
1157  absorption study would be the same batches used for the clinical study for local delivery.  Each 
1158  of these batches would be one of the three batches used for the in vitro BE  studies.  Formulation 
1159  and device recommendations for the P are described in Section VI.B.  An active control such as 
1160  prednisone is recommended.  For blinding, matching active control placebo (identical in 
1161  appearance to the active control) is also recommended. 
1162   
1163  C.   Clinical BE Study Designs and Subject Inclusion Criteria  
1164   
1165  We recommend the study be conducted as a placebo and active-controlled, randomized, double- 
1166  blind, parallel design comparing T and R for a 6-week duration.  The study would not be 
1167  conducted as a subset of the 2-week local delivery rhinitis study (Section VI).  Subjects would be 
1168  patients with a history of AR.  The relative assessment of HPA axis suppression would be 
1169  conducted as an evaluable (per protocol) analysis.  The sensitivity analysis and efficacy analysis 
1170  would be conducted as intent-to-treat analyses.  The protocol  would specify whether placebo 
1171  responders will or  will not be excluded from  the analysis.  We recommend that subjects be 
1172  domiciled within the clinical study center during the days of HPA axis assessment.  Domiciling 
  27
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1173  the subjects during the 24-hour urine or plasma  collection periods can help to conduct the study- 
1174  related procedures reliably and completely.  T and R would be dosed at the maximum  labeled 
1175  adult dose. P would be dosed at the same  frequency and number of actuations per nostril as T 
1176  and R.  As stated above, the study would include an active control such as prednisone.  Four 
1177  study arms would be included: T, R, P, and the active control.  The randomized portion of the 
1178  study would  be conducted according to a double-blinding design (i.e., all subjects would receive 
1179  both the active control (either the active control itself or a matching placebo of the active control) 
1180  and a spray or aerosol (either active or placebo)).  The four treatment groups would be T plus 
1181  matching active control placebo, R plus matching active control placebo, P plus matching active 
1182  control placebo, and P plus active control.  The matching active control placebo would be dosed 
1183  on days when the active control is not taken, including the placebo run-in period.  We  
1184  recommend the number of centers conducting the HPA assessment be kept to a minimum  to avoid 
1185  center-to-center variability.  A double-dummy  design is not recommended for aqueous nasal 
1186  sprays, as explained in Section VI.C.  However, study blinding is a critical consideration, and we 
1187  recommend a description of how the T, R and P products are to be masked  be carefully described 
1188  in the study protocol.18  
1189   
1190  The expected effect for the active control would be far larger than that for the T and R products. 
1191  The sample size of the active control arm  group may therefore be smaller in size than for the 
1192  other study arms.  We recommend the sample size for the T and R study arms be sufficient to 
1193  characterize any HPA axis effects or lack thereof to allow conclusions  about any relative effects 
1194  of T versus P and R versus P, as stated  in Section VIII.A. 
1195   
1196  We recommend timed urine or plasma  samples for determination of 24-hour urinary free cortisol 
1197  (UFC) or 24-hour plasma  cortisol levels, respectively, be collected.  Collections would be made 
1198  prior to dosing (baseline) and during the last 24 hours of the 42 days of dosing (i.e., over the day 
1199  41  42 period) while the drug is being actively dosed. 
1200   
1201  D.  Clinical BE Study Endpoints  for Corticosteroids  
1202   
1203  Whether the drug is labeled for once or twice daily dosing, the endpoint can be either 24-hour 
1204  urinary free cortisol (UFC), based on a full 24-hour urine collection, or plasma  cortisol levels 
1205  collected every 4 hours over a 24-hour period, with exclusion of the middle of the night 
1206  sample.  For the UFC endpoint, urinary creatinine would also be measured to confirm  
1207  completeness of the 24-hour collection. The UFC value would not be corrected for 
1208  creatinine.  We recommend for the plasma  cortisol endpoint, both AUC(0-24) and the trough 
1209  (maximum  effect) concentration during the dosing interval should be  determined.  The 
1210  sensitivity analysis endpoint would be baseline-adjusted prior to analysis.  Raw data would 
1211  be provided for the relative assessment of HPA axis suppression.  Efficacy analysis TNSS 
1212  data would be expressed as change from baseline. 
1213   
1214  Statistical approaches for each of the analyses are provided in Appendix G.B. 
                                                 
18  A draft guidance entitled  Allergic Rhinitis: Clinical  Development  Programs for Drug  Products was issued in  
April 2000. Once finalized, this guidance will represent the agency's thinking  on  this topic. 
 
  28
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1215   
1216   
1217  IX.   NUMBER OF RESERVE SAMPLES FOR BA AND BE  TESTING  
1218   
1219  Reserve samples must be retained for BA and BE studies (21 CFR 320.38 and 320.63) conducted 
1220  in vivo or in vitro. The regulations state that each reserve sample must consist of a sufficient 
1221  quantity of samples to permit FDA to perform  five times all of  the release tests required  in the 
1222  application or supplemental application. Dose content uniformity or spray content uniformity 
1223  release tests alone usually require  30 units (canisters or bottles) per batch. Performance of other 
1224  release tests  requires additional units.  The number of  reserve sample units required for three 
1225  batches of T and R could exceed 1000 units (up to  250 units for each batch of T and R) based on 
1226  the five-times-quantity  requirement. 
1227   
1228  The Agency has determined that in lieu of the five-times-quantity  requirement, the quantity of  
1229  inhalant (nasal aerosol or nasal spray) test article (T) and reference standard (R) retained  for 
1230  testing and analyses be at least 50 units for each batch.19  For NDAs, three batches are needed for 
1231  BA studies.  Thus, we recommend at least 50 units from  each of the three batches of nasal spray 
1232  or nasal aerosol be retained. However, where the reference product is another nasal aerosol or 
1233  nasal spray, at least 50 units of that batch would also be retained. For ANDAs, at least 50 units 
1234  of each of three batches would be retained for each of T and R used in in vivo or in vitro BE 
1235  studies. For NDAs and ANDAs, if the in vivo or in vitro studies include placebo aerosols or 
1236  sprays, at least 50 units of each placebo batch would also be retained. These recommendations  
1237  apply only to nasal aerosols and nasal sprays for local action covered in this guidance and which 
1238  are marketed as multiple dose products, typically labeled to deliver  30 or more actuations per 
1239  canister or bottle. The number of reserves for nasal aerosols and nasal sprays delivering less 
1240  than 30 actuations per canister or  bottle is not addressed in this guidance. Additional information 
1241  regarding retention of BA and BE testing samples is pending.20  
1242   
1243   
1244  X.  MULTIPLE STRENGTHS  
1245   
1246  A small number of nasal sprays for local action are available in two strengths.  Current 
1247  examples are (1) ipratropium  bromide nasal spray, a solution formulation, and (2) 
1248  beclomethasone dipropionate nasal spray, a suspension formulation.  Lower strengths of a 
1249  product ordinarily would achieve the lower dose per actuation using a lower concentration 
1250  formulation, without changing the actuator and metering valve or pump (other than diptube due 
1251  to different volumes of product or other factors) used in the higher strength product.  The 
1252  following sections describe recommended BA and BE studies for low strengths of nasal sprays 
1253  for which BA or BE for the higher strengths has previously been established. Recommendations 
1254  are also  provided for cases in which  BA or BE is initially established on the low-strength 
1255  product.  No approved nasal aerosols are available in multiple strengths, thus BA and BE 
                                                 
19  Quantity of  Reserve Samples, Preamble to  final rule, Retention of Bioavailability and Bioequivalence Testing 
Samples, 58 FR 25918-26, 1993, IIC21. 
20  A draft guidance for industry entitled  Handling and  Retention of  BA and BE  Testing Samples  was issued in  August 
2002. Once finalized, it will represent the Agencys thinking on  this topic. 
  29
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1256  recommendations are not considered for these products. 
1257   
1258  A.  Solution Formulation Nasal Sprays 
1259   
1260  We recommend the BA of lower or higher strength solution formulation nasal sprays be based on 
1261  conduct of all applicable in vitro tests described in Section V.  These studies are generally 
1262  noncomparative in character. Documentation of BE between T and R products would follow the 
1263  recommendations described in Section III regarding formulation and container and closure 
1264  system. Abbreviated in vitro testing,  as follows, is recommended to document BE of the low- 
1265  strength T product to the low-strength R product, provided BE of the high-strength product has 
1266  been documented. 
1267   
1268  In vitro test  High Strength  Low Strength 
1269   
1270  Single Actuation Content  
1271  Through Container Life          B, Ea                                                            B, E  
1272  Priming and Repriming                      Yes                                         Yes 
1273  Droplet Size Distribution 
1274  by Laser Diffraction  B, E   B 
1275  Drug in Small Particles/Droplets  
1276  by Cascade Impactor   B  No   
1277  Spray Pattern   B   B 
1278  Plume Geometry   B  No  
1279  a   
Beginning (B), Middle (M), End (E) 
1280   
1281  With the exception of the reduced testing, the Agency recommends the same protocols and 
1282  acceptance criteria used to establish BE of the high-strength products be used for the low 
1283  strength products.  In vivo studies are not needed for documentation of BA or BE of solution 
1284  formulation nasal sprays.  Initial documentation of BE of the low-strength product would be 
1285  based on all applicable  in vitro tests described in Section V.  For subsequent documentation of 
1286  BE for the high-strength product, all applicable in vitro tests described above for the high- 
1287  strength product would be conducted. 
1288   
1289  B.  Suspension Formulation Nasal Sprays  
1290   
1291  We  recommend BA of lower strength suspension formulation nasal sprays be based on conduct 
1292  of all applicable in vitro tests described in Section V and systemic exposure studies, assuming 
1293  availability of bioanalytical methodology to allow measurement of systemic  concentrations.  In 
1294  the absence of this methodology, we suggest BA for systemic  absorption be documented through 
1295  pharmacodynamic or clinical studies.  
1296   
1297  BE conditions for the lower strength  product would include: 
1298   
1299  1.  Documentation of BE for the high-strength test and reference products, based on 
1300  acceptable comparative formulations and container and closure systems, 
1301  comparative in vitro data, and comparative in vivo data. 
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  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1302 
  
1303  2.  Acceptable comparative formulations and container and closure systems for the 

1304  low-strength test and reference products. 

1305 
  
1306  3.  Acceptable comparative studies for low-strength test and reference products for 

1307  all applicable in vitro tests in Section  V. 

1308 
  
1309  4.  Proportionally similar Single Actuation Content Through Container Life between 
 
1310  high- and low-dose test product and high- and low-dose reference product. 

1311 
  
1312  In vivo studies would not be needed for documentation of BE of the lower strength products. 
  
1313  For cases in which an ANDA applicant initially documents BE on the low-strength suspension 

1314  formulation product, and subsequently submits  an ANDA for the high-strength product, full in 
 
1315  vitro and in vivo documentation of BE would be provided for the high-strength product. 

1316 
  
1317 
  
1318  XI.  SMALLER CONTAINER SIZES 

1319 
  
1320  Nasal aerosols and nasal sprays may be available in two container sizes.  Current examples are: 

1321  (1) beclomethasone dipropionate nasal aerosol, a suspension formulation; (2) fluticasone 

1322  propionate nasal spray, a suspension formulation; and (3) cromolyn sodium nasal spray, a 

1323  solution formulation. Smaller container sizes of nasal aerosols would be formulated with the 

1324  same components and composition, metering valve, and actuator as the large container size that 

1325  was studied in pivotal clinical  trials (NDA) or for which BE has been documented (ANDA). 

1326  Smaller container sizes of nasal sprays would be formulated with the same  components and 

1327  composition,  pump, and actuator as the large container size that was studied in pivotal  clinical 

1328  trials (NDA) or for which BE has been documented (ANDA).   Where this is the case, no further 

1329  documentation of either BA or BE is  necessary.  However, re-establishing proper priming, 

1330  given a change in the volume of components of the device that will be filled to deliver an 

1331  actuation, may in some cases be appropriate (Section V.B.7). 

1332 
  
1333 
  
1334  REFERENCES
  
1335 
  
1336  Advisory Committee for Pharmaceutical Science Meeting, Report from the Orally Inhaled and
  
1337  Nasal Drug Products Subcommittee, Rockville, MD, Transcript,  July  19, 2001, pp. 24- 

1338  91.

1339 

 
1340  Borgstrom  L, Asking L, Beckman O, Bondesson E, Kallen A, Olsson B. Dose Variation , within 

1341  and between individuals, with different inhalation systems. Respiratory Drug Delivery V, 

1342  Interpharm  Press, Buffalo Grove, IL, 1996, pp. 19-24. 

1343 

 
1344  Daley-Yates PT, Price AC, Sisson JR, Pereira A, Dallow N. Beclomethasone dipropionate: 

1345  absolute bioavailability, pharmacokinetics and metabolism  following intravenous, oral, 

1346  intranasal and inhaled administration in man. Br J Clin Pharmacol 2001;51:400-9.

1347 

 
1348  Kublic H., Vidgren MT. Nasal Delivery Systems and Their Effect on Deposition  and Absorption. 
 
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  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1349  Advanced Drug Delivery Reviews  1998;29:157-77.
1350 
 
1351  Meltzer EO, Jalowayski AA, Orgel HA, Harris AG. Subjective and objective assessments in 

1352  patients with  seasonal allergic rhinitis: Effects of therapy with mometasone furoate nasal 

1353  spray. J Allergy Clin Immunol  1998;102:39-49.

1354 

 
1355  Newman S, Steed K, Hooper G, Kallen A, Borgstrom  L. Comparison of gamma scintigraphy and 

1356  a pharmacokinetic technique for assessing pulmonary deposition of terbutaline sulphate 

1357  delivered by pressurized metered dose inhaler. Pharm Res 1995;12:231-6.

1358 

 
1359  Suman JD, Laube BL, Lin T, Brouet G, Dalby R. Validity of in vitro tests on aqueous spray 

1360  pumps as surrogates for nasal deposition. Pharm Res 2002;19:1-6.

1361 

 
1362  Task Group on Lung Dynamics: Deposition  and Retention Models for Internal Dosimetry of the 
 
1363  Human Respiratory Tract. Health Phys 1966;12:173-207.

1364 

 
1365  Welch MJ, Bronsky EA, Grossman J, Shapiro GG, Tinkelman DG, Garcia JD, Gillen MS. 

1366  Clinical evaluation of triamcinolone acetonide nasal aerosol in children with perennial 

1367  allergic rhinitis. Annals Allergy  1991;67:493-8. 

1368 

 
1369  Williams  RL, Adams W,  Chen M-L, Hare D, Hussain A, Lesko L, Patnaik R, Shah V, FDA 

1370  Biopharmaceutics Coordinating Committee. Where are we now and where do we go next 

1371  in terms of  the scientific basis for regulation on bioavailability and bioequivalence? 

1372  Europ J Drug Metab Pharmacokinet 2000;25:7-12. 

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373   
374  TABLE 1 
375  RECOMMENDED IN  VITRO STUDIES  FOR BA AND BE OF NASAL AEROSOLS AND NASAL 
376  SPRAYS  
377   
378   
   
TEST1   BA AND BE  BE MEASURE(S) FOR  LIFESTAGE(S)  STATISTICAL EVALUATION  GUIDANCE 
STUDY MEASURE(S)   STATISTICAL  B (beginning), M (middle),  FOR BE   SECTIONS  
EVALUATION   E (end)   PBE (population  bioequivalence)  
Single Actuation  Content  Drug mass per single  Same as  previous  column  B, M, E (aerosols)  PBE  V.B.1, App. B, C 
Through Container Life   actuation   B, E (sprays)  
Droplet Size Distribution   D , D , D , span   D , span  B, E  PBE  V.B.2, App. B, C 
10 50 90 50
by Laser Diffraction   at 2  distances  
Drug in Small  Drug mass below upper  Same as  previous  column  B (sprays)  PBE modified to  be one-sided with  V.B.3, App. B, D 
Particles/Droplets by   stage   respect to the mean comparison  
Cascade Impactor  
Particle/Droplet Size   Drug mass on individual  Deposition profile  B (aerosols)  Profile analysis  V.B.3, App. B, E 
Distribution by  Cascade  accessories, stages, etc   
Impactor   profile analysis  
Drug Particle Size   Drug CMD;  Same as  previous  column  B  Not applicable  V.B.4 
Distribution by  Microscopy   extent of agglomerates  
for Suspensions  
Spray Pattern   Automated analysis:  area,   Qualitative   shape  B  PBE for area and ovality ratio   V.B.5, App. C 
ovality  ratio at 2 distances  comparison  (automated analysis)  
or  Quantitative - Same  as   or 
Manual analysis:  D ,  previous column  
ovality  ratio at 2 dismtaaxnces   Dmax  and ovality ratio manual 
analysis  
Plume Geometry   Height, width, and cone  Width and cone angle of   B  Point estimates  V.B.6 
angle of  one side view at  one side view at one delay  
one delay  time   time  
Priming and Repriming   Drug mass per single  Same as  previous  column   B (Priming)  Point estimate  relative to label   V.B.7 
actuation  at  first primed or   for Priming, and Repriming  Lifestage not specified   claim if in precursor product (R)  
reprimed actuation   if in precursor product (R)  (Repriming)   labeling  
labeling  
379  1 Although alternate test methods may be appropriate for certain  tests, if validated, we recommend sponsors planning  to use such  methods contact the appropriate reviewing division prior to use.  
  33