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`DRAFT GUIDANCE
`This guidance document is being distributed for comment purposes only.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`publication of the Federal Register notice announcing the availability of the draft guidance.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
`
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`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
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`Contains Nonbinding Recommendations
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`TABLE OF CONTENTS
`
`V.
`
`INTRODUCTION............................................................................................................. 1
`I.
`BACKGROUND ............................................................................................................... 2
`II.
`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
`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
`Study Batches ..............................................................................................................................25
`B.
`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
`Solution Formulation Nasal Sprays........................................................................................30
`A.
`Suspension Formulation Nasal Sprays...................................................................................30
`B.
`SMALLER CONTAINER SIZES ............................................................................... 31
`XI.
`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
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`1
`Guidance for Industry
`
`Bioavailability and Bioequivalence Studies for Nasal Aerosols
`and Nasal Sprays for Local Action
`
`This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current
`thinking on this topic. It does not create or confer any rights for or on any person and does not operate to
`bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of
`the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA
`staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call
`the appropriate number listed on the title page of this guidance.
`
`I.
`
`INTRODUCTION
`
`This guidance is intended to provide recommendations to applicants who are planning product
`quality studies to measure bioavailability (BA) and/or establish bioequivalence (BE) in support
`of new drug applications (NDAs) or abbreviated new drug applications (ANDAs) for locally
`acting drugs in nasal aerosols (metered-dose inhalers (MDIs)) and nasal sprays (metered-dose
`spray pumps). This guidance addresses BA and BE studies of prescription corticosteroids,
`antihistamines, anticholinergic drug products, and the over-the-counter (OTC) mast-cell
`stabilizer cromolyn sodium. Applicability of the guidance to other classes of intranasal drugs
`that may be developed in the future should be discussed with the appropriate CDER review
`division.
`
`This guidance does not cover studies of nasal sprays included in an applicable OTC monograph2
`or studies of (1) metered-dose products intended to deliver drug systemically via the nasal route
`or (2) drugs in nasal nonmetered dose atomizer (squeeze) bottles that require premarket
`approval.
`
`The first draft of this guidance was issued in June 1999 for comment. Because of changes made
`as a result of comments received to the docket, internal discussions, and deliberations of the
`Advisory Committee for Pharmaceutical Science, we have decided to issue the guidance once
`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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`Contains Nonbinding Recommendations
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`guidance as stand alone documents on the Internet as soon as they have been completed.
`
`FDA’s guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`II.
`
`BACKGROUND
`
`Product quality studies provide information that pertains to the identity, strength, quality, purity,
`and potency of a drug product. These studies include information on chemistry, manufacturing,
`and controls (CMC), microbiology, BE and certain aspects of BA. A BE study is normally used
`to compare a test product (T) to a reference product (R): the to-be-marketed product is compared
`to a pivotal clinical trial material, and a generic product is compared to a reference listed drug. A
`BE study thus provides information on product quality. BA studies for ensuring product quality
`relate to the release of the active ingredient or active moiety from the drug product (Williams et
`al., 2000). BA studies may also address biopharmaceutical and clinical pharmacology issues,
`such as absorption, distribution, and elimination of the active ingredient and its metabolites and
`dose proportionality. These latter BA/PK studies provide information beyond product quality BA
`characterization and would also be included in the Human Pharmacokinetics section (Item 6) of
`an NDA. These latter studies are not the subject of this guidance. Rather, this guidance discusses
`studies that focus on product performance (i.e., release of a drug substance from a drug product).
`Subsequent references to BA studies in this guidance refer only to BA studies for ensuring
`product quality.
`
`This guidance should be used with other, more general CMC and BA and BE guidances available
`from CDER.3 Product quality information is different from, yet complementary to, the clinical
`safety and efficacy information that supports approval of an NDA. For information on the type of
`safety and efficacy studies that may be requested for a new active ingredient/active moiety
`intended for local action in the nose, or for a new product such as a nasal aerosol that may include
`an active ingredient/active moiety previously approved in a nasal spray, we recommend
`appropriate CDER review staff be consulted.
`
`Note: Detailed CMC information relevant to nasal aerosols and nasals sprays is presented in the
`final guidance Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products
`Chemistry, Manufacturing, and Controls Documentation.4 The document provides
`complementary information on the BA/BE testing methods recommended in this guidance.
`
`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 Agency’s thinking on this topic.
`
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`A.
`
`BA and BE Data
`
`Bioavailability is defined at 21 CFR 320.1 as “the rate and extent to which the active ingredient or
`active moiety is absorbed from a drug product and becomes available at the site of action. For
`drug products that are not intended to be absorbed into the bloodstream, bioavailability may be
`assessed by measurements intended to reflect the rate and extent to which the active ingredient or
`active moiety becomes available at the site of action.” Bioequivalence is defined as “the absence
`of a significant difference in the rate and extent to which the active ingredient or active moiety in
`pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug
`action when administered at the same molar dose under similar conditions in an appropriately
`designed study.” BA and BE are closely related, and the same approach used to measure BA in an
`NDA can generally be followed in establishing BE for an NDA or ANDA. Although BA may be
`comparative, establishing BE specifically involves a comparison of the BA of one product with
`the BA of another product. BE is usually established using (1) a criterion to allow the
`comparison, based on means and/or variances for BA measures, (2) a confidence interval for the
`criterion, and (3) a BE limit (goalpost) for the criterion.
`
`BA and BE data must be provided in accordance with the regulations.5 BA and BE can be
`established using in vivo (pharmacokinetic (PK), pharmacodynamic (PD), or clinical) and in
`vitro studies, or, in certain cases, using in vitro studies alone.6 BA and BE assessments for
`locally acting nasal aerosols and sprays are complicated because delivery to the sites of action
`does not occur primarily after systemic absorption. Droplets and/or drug particles are deposited
`topically. The drug is then absorbed and becomes available at local sites of action. A drug
`administered nasally and intended for local action has the potential to produce systemic activity,
`although plasma levels do not in general reflect the amount of drug reaching nasal sites of
`action. Systemic exposure following nasal administration can occur either from drug absorbed
`into the systemic circulation from the nasal mucosa, or after ingestion and absorption from the
`gastrointestinal tract (Daley-Yates et al., 2001). For these reasons, BA and BE studies generally
`would consider both local delivery and systemic exposure or systemic absorption.
`
`1.
`
`Local Delivery BA/BE Concepts
`
`For local delivery, BA is a function of several factors, including release of the drug
`substance from the drug product and availability to local sites of action. Release of the
`drug from the drug product produces droplet or drug particle sizes and distribution
`patterns within the nose that are dependent upon the drug substance, formulation, and
`device characteristics. Availability to local sites of action is usually a function of droplet
`or drug particle sizes and distribution patterns, as well as drug dissolution in the case of
`suspension products, absorption across mucosal barriers to nasal receptors, and rate of
`removal from the nose. From a product quality perspective, the critical issues are release
`of drug substance from drug product and delivery to the mucosa. Other factors are of
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`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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`
`lesser importance.
`
`A critical question in assessing product quality BA and BE is the extent to which one can
`rely on in vitro methods alone, or upon in vitro methods plus clinical endpoints, to
`measure (benchmark) BA and/or establish BE. In vitro methods are less variable
`(Newman et al., 1995; Borgstrom et al., 1996; Suman et al., 2002), easier to control, and
`more likely to detect differences between products if they exist, but the clinical relevance
`of these tests, or the magnitude of the differences in the tests, can not always be clearly
`established. Clinical endpoints may be highly variable (Welch et al., 1991; Meltzer et al.,
`1998) and relatively insensitive to dose differences over an eightfold or higher dose range
`(Advisory Committee for Pharmaceutical Science, 2001), thus insensitive in detecting
`potential differences between products. However, clinical studies can unequivocally
`establish effectiveness of the drug product.
`
`In this guidance, the recommended approach for solution formulations of locally acting
`nasal drug products, both aerosols and sprays, is to rely on in vitro methods to assess BA.
`To establish BE, the recommended approach relies on (1) qualitative and quantitative
`sameness of formulation of test and reference products, (2) comparability in container
`and closure systems, and (3) in vitro methods that demonstrate equivalent performance.
`This approach is based on the premise that in vitro studies would be more sensitive
`indicators of drug delivery to nasal sites of action than would be clinical studies. For
`solution formulations, see Section IV.B.1.
`
`The recommended approach for establishing BA and BE of suspension formulations of
`locally acting nasal drug products, both aerosols and sprays, is to conduct in vivo studies
`in addition to in vitro studies.7 As with the solution formulation aerosols and sprays, to
`establish BE, the approach also relies on qualitative and quantitative sameness of
`formulation of test and reference products and comparability in container and closure
`systems. We recommend that in vitro studies be coupled with a clinical study for BA, or
`a BE study with a clinical endpoint (Section VI), to determine the delivery of drug
`substance to nasal sites of action. In vivo studies are recommended because of an
`inability at the present time to adequately characterize drug particle size distribution
`(PSD) in aerosols and sprays (Sections V.B.3, 4). Drug PSD in suspension formulations
`has the potential to influence the rate and extent of drug availability to nasal sites of
`action and to the systemic circulation.
`
`2.
`
`Systemic Exposure and Systemic Absorption BA/BE Concepts
`
`Locally acting drugs are intended to produce their effects upon delivery to nasal sites of
`action without relying on systemic absorption. Although systemic absorption may
`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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`consequences of systemic absorption (e.g., hypothalamic-pituitary-adrenal (HPA) axis
`suppression by corticosteroids) are generally undesirable. In the absence of validated in
`vitro methodology for characterizing drug PSD for suspension products and when
`measurable plasma levels can be obtained, this guidance recommends PK studies to
`measure systemic exposure BA or to establish systemic exposure BE (see Section VII).
`For suspension products that do not produce sufficient plasma concentrations to allow
`assessment of systemic exposure, clinical studies or BE studies with a pharmacodynamic
`or clinical endpoint are recommended to measure systemic absorption BA and establish
`systemic absorption BE, respectively (Section VIII). For a schematic representation of
`recommended studies, see Appendix A: Decision Tree.
`
`B.
`
`CMC and In Vitro BA Tests (Noncomparative) Versus BE Tests
`(Comparative)
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`Particle size, morphic form, and state of solvation of an active ingredient have the potential to
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`affect the BA of a drug product as a result of different solubilities and/or rates of dissolution.
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`196 We recommend for an ANDA of a suspension formulation, data demonstrating comparable PSD
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`and morphic form of the drug particles, size and number of drug aggregates in the dosage form,
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`and hydrous or solvate form of the active drug in the dosage form to the reference listed drug, be
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`provided, where possible. Where impossible, the rationale for not providing this full set of
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`comparative data is requested. For suspension formulations marketed in more than one strength,
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`we recommend that the drug substance in each strength product be micronized under identical
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`parameters, and the PSD of the resultant bulk drug used in each product strength be identical.
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`
`Generally, CMC tests help characterize the identity, strength, quality, purity, and potency of the
`drug product and assist in setting specifications (tests, methods, acceptance criteria) to allow
`batch release. These tests have a different purpose than do BA/BE tests, which focus on the
`release of the drug substance from the drug product. Some of the in vitro BA/BE tests described
`in this guidance may be the same as CMC tests for characterization and/or batch release. CMC
`and in vitro BA tests have acceptance criteria. In vitro BE tests have BE limits. A specification
`(test, method, acceptance criterion) for a CMC test for batch release or an in vitro BA test is
`usually based on general or specific manufacturing experience. For example, a CMC test such as
`dose content uniformity has acceptance criteria based on repeated manufacturing of batches. In
`contrast, BE tests have limits that are not usually based on manufacturing experience, but are
`part of equivalence comparisons between test and reference products. BE limits may be based
`on a priori judgments and may be scaled to the variability of the reference product (see
`Appendices C, E). When conducted premarket for an NDA, some of the in vitro BA tests
`described in this guidance can be noncomparative and serve primarily to document (benchmark)
`the product quality BA of a pioneer product.
`
`III.
`
`FORMULATION AND CONTAINER AND CLOSURE SYSTEM
`
`A.
`
`Formulation
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`Container and Closure System
`
`B.
`
`Nasal aerosols usually consist of the formulation, container, valve, actuator, dust cap, associated
`accessories, and protective packaging, which together constitute the drug product. Similarly,
`nasal sprays usually consist of the formulation, container, pump, actuator, protection cap, and
`protective packaging, which together constitute the drug product.
`
`IV.
`
`DOCUMENTATION OF BA AND BE
`
`A.
`
`NDAs
`
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`For nasal aerosols and nasal sprays approved under an ANDA, we recommend BE be
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`documented on the basis of validated in vitro and vivo tests, or, in the case of solutions, validated
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`in vitro tests alone may be appropriate. Assurance of equivalence on the basis of in vitro tests is
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`greatest when the test product uses the same brand and model of devices (particularly the
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`215 metering valve or pump and the actuator) as used in the reference product. If this is infeasible,
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`we recommend that valve, pump, and actuator designs be as close as possible in all critical
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`dimensions to those of the reference product. We recommend that metering chamber volumes and
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`actuator orifice diameters be the same. For a nasal spray, spray characteristics can be affected by
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`features of the pump design, including the precompression mechanism, actuator design, including
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`specific geometry of the orifice (Kublic and Vidgren 1998), and the design of the swirl chamber.
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`The external dimensions of the test actuator are expected to ensure comparable depth of nasal
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`insertion to the reference actuator. A test product is expected to attain prime within the labeled
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`number of actuations for the reference product. We recommend you consider the volume of
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`components of the device that must be filled to deliver an actuation, including the internal
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`diameter and length of the diptube because this volume can influence the number of actuations
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`required to prime a spray pump.
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`For product quality, we recommend that in vitro BA studies be provided in NDAs for solution
`and suspension products, and in vivo BA studies be provided for suspension products. These
`data are useful as a benchmark to characterize the in vitro performance, and for suspensions, the
`in vivo performance of the product. Where the formulation and/or method of manufacture of the
`pivotal clinical trial product changes in terms of physicochemical characteristics of the drug
`substance, the excipients, or the device characteristics, BE data using in vitro tests (for solution
`and suspension products) and in vivo tests (for suspension products) may be useful in certain
`circumstances to ensure that the to-be-marketed product (T) is comparable to very similar
`clinical trial batches and/or to batches used for stability testing (R) (Section V.A.1). We
`recommend sponsors discuss the usefulness of these BE approaches with the appropriate CDER
`review staff.
`
`B.
`
`ANDAs
`
`For product equivalency, we recommend that the drug concentration in the test and reference
`product formulations not differ by more than ±5 percent. In addition, we recommend that the
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`inactive ingredients in the test product formulation be qualitatively (Q1)8 the same and
`quantitatively (Q2) essentially the same as the inactive ingredients in the formulation of the
`reference listed drug, and the container and closure recommendations of Section III be followed.
`Quantitatively essentially the same has been determined by CDER to mean that the
`concentration or amount of the inactive ingredient(s) in the test product would not differ by more
`than ±5 percent of the concentration or amount in the reference listed drug. We recommend a
`side-by-side Q1 and Q2 comparison of the compositions of the test and reference listed drug
`formulations be provided. Please also provide a side-by-side comparison of the components of
`the container and closure system, listing brand and model, dimensions of critical components
`(Section IIIB), and engineering drawings if possible.
`
`1.
`
`Solution Formulations
`
`We believe in vitro tests alone can be relied on to document BE for nasal solution
`formulation products intended for local action. This approach is based on an
`understanding that for solution products, equivalent in vitro performance and adherence
`to Q1 and Q2 recommendations and to container and closure recommendations will
`ensure comparable delivery to the nasal mucosa and to the respiratory and
`gastrointestinal tracts. Suggested methodology and validation approaches for the
`recommended tests are provided in Section V. Suggested statistical methods to allow
`comparisons will be discussed in the appendices to this document. When in vitro data
`fail to meet acceptance criteria, the applicant is encouraged to modify the test product to
`attain equivalent in vitro performance. Because of insensitivity to potential differences
`between T and R, in vivo studies would not be sufficient in the face of failed in vitro
`studies.
`
`2.
`
`Suspension Formulations with PK Systemic Exposure Data
`
`To document BE for suspension formulation products intended for local action, we
`recommend both in vitro and in vivo data be used. In vivo studies would include both a
`BE study with a clinical endpoint (local delivery) and a pharmacokinetic study (systemic
`exposure). This approach is only applicable for those suspension formulation products