Contains Nonbinding Recommendations
`
`Determining Whether
`to Submit an ANDA or
`a 505(b)(2) Application
`Guidance for Industry
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
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`
`
`May 2019
`Generics
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`AQUESTIVE EXHIBIT 1146 Page 0001
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`Contains Nonbinding Recommendations
`
`Determining Whether
`to Submit an ANDA or
`a 505(b)(2) Application
`Guidance for Industry
`
`
`
`
`
`
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`Additional copies are available from:
`Office of Communications, Division of Drug Information
`Center for Drug Evaluation and Research
`Food and Drug Administration
`10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
`Silver Spring, MD 20993-0002
`Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
`Email: druginfo@fda.hhs.gov
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`
`
`May 2019
`Generics
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`AQUESTIVE EXHIBIT 1146 Page 0002
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`Contains Nonbinding Recommendations
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`TABLE OF CONTENTS
`
`IV.
`
`
`
`
`
`I.
`INTRODUCTION............................................................................................................. 1
`BACKGROUND ............................................................................................................... 1
`II.
`III. ABBREVIATED APPROVAL PATHWAYS ................................................................ 3
`A. ANDAs ...................................................................................................................................... 3
`B. 505(b)(2) Applications ............................................................................................................. 4
`SUBMISSION THROUGH THE APPROPRIATE ABBREVIATED APPROVAL
`PATHWAY ........................................................................................................................ 5
`A. Regulatory Considerations for ANDAs and 505(b)(2) Applications ................................... 5
`1. Duplicates ........................................................................................................................... 5
`2. Petitioned ANDAs ............................................................................................................... 5
`3. Bundling .............................................................................................................................. 6
`B. Scientific Considerations for ANDAs and 505(b)(2) Applications ...................................... 7
`1. Type of Studies, Data, and Information Submitted in ANDAs ............................................ 7
`2. Active Ingredient Sameness Evaluation .............................................................................. 7
`3. Intentional Differences Between the Proposed Drug Product and the RLD ...................... 8
`4. Other Differences .............................................................................................................. 12
`V. REQUESTING ASSISTANCE FROM FDA ............................................................... 13
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`Determining Whether to Submit an ANDA or a 505(b)(2)
`Application
`Guidance for Industry1
`
`
`
`This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
`this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
`can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
`To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
`title page.
`
`
`
`
`I.
`
`This guidance is intended to serve as a foundational guidance to assist applicants in determining
`which one of the abbreviated approval pathways under the Federal Food, Drug, and Cosmetic
`Act (FD&C Act) is appropriate for the submission of a marketing application to FDA. Many
`potential drug product developers are not familiar with the different abbreviated approval
`pathways for drug products under the FD&C Act — the abbreviated approval pathways
`described in section 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C. 355(j) and 21 U.S.C.
`355(b)(2), respectively) — or the types of data and information that are permitted to support
`approval under those pathways. In order to familiarize potential drug product developers with
`these abbreviated pathways, this guidance highlights criteria for submitting applications under
`the abbreviated approval pathways described in section 505(j) and 505(b)(2), identifies
`considerations to help potential applicants determine whether an application would be more
`appropriately submitted under section 505(j) or pursuant to section 505(b)(2) of the FD&C Act,
`and provides direction to potential applicants on requesting assistance from FDA in making this
`determination.
`
`In general, FDA’s guidance documents 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.
`
`The Drug Price Competition and Patent Term Restoration Act of 1984 (Public Law 98-417)
`(Hatch-Waxman Amendments) added section 505(b)(2) and 505(j) to the FD&C Act, which
`
`1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research at
`the Food and Drug Administration.
`
`
`
`INTRODUCTION
`
`BACKGROUND
`
`
`
`1
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`describes abbreviated approval pathways under the FD&C Act for drug products regulated by the
`Agency. The Hatch-Waxman Amendments reflect Congress’s efforts to balance the need to
`“make available more low cost generic drugs by establishing a generic drug approval procedure”
`with new incentives for drug development in the form of exclusivities and patent term
`extensions.2 With the passage of the Hatch-Waxman Amendments, the FD&C Act describes
`different routes for obtaining approval of two broad categories of drug applications: new drug
`applications (NDAs) and abbreviated new drug applications (ANDAs).3
`
`NDAs and ANDAs can be divided into the following four categories:4
`
`
`(1) A “stand-alone NDA” is an application submitted under section 505(b)(1) and
`approved under section 505(c) of the FD&C Act that contains full reports of
`investigations of safety and effectiveness that were conducted by or for the
`applicant or for which the applicant has a right of reference or use.
`
`
`(2) A 505(b)(2) application is an NDA submitted under section 505(b)(1) and
`approved under section 505(c) of the FD&C Act that contains full reports of
`investigations of safety and effectiveness, where at least some of the information
`required for approval comes from studies not conducted by or for the applicant
`and for which the applicant has not obtained a right of reference or use.5
`
`
`(3) An ANDA is an application submitted and approved under section 505(j) of the
`FD&C Act for a drug product that is a duplicate6 of a previously approved drug
`product. An ANDA relies on FDA’s finding that the previously approved drug
`product, i.e., the reference listed drug (RLD),7 is safe and effective. An ANDA
`generally must contain information to show that the proposed generic product (1)
`is the same as the RLD with respect to the active ingredient(s), conditions of use,
`route of administration, dosage form, strength, and labeling (with certain
`
`2 See H.R. Rep. No. 98-857, pt. 1, at 14-15 (1984), reprinted in 1984 U.S.C.C.A.N. 2647-2648.
`3 See section 505(b) and 505(j) of the FD&C Act. See generally 21 CFR part 314.
`4 See letter from Janet Woodcock to Katherine M. Sanzo, Jeffrey B. Chasnow, Stephen E. Lawton, and William R.
`Rakoczy (October 14, 2003), Docket Nos. FDA-2001-P-0369 (original Docket No. 2001P-0323/CP1 & C5), FDA-
`2002-P-0390 (original Docket No. 2002P-0447/CP1), and FDA-2003-P-0274 (original Docket No. 2003P-
`0408/CP1). (Please note that the docket numbers were changed in January 2008 after FDA transitioned to a new
`docketing system (Regulations.gov).)
`5 For more information on 505(b)(2) applications, see the draft guidance for industry Applications Covered by
`Section 505(b)(2) (December 1999). When final, this guidance will represent the FDA’s current thinking on this
`topic. For the most recent version of a guidance, check the FDA guidance web page at
`https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
`6 The term duplicate generally refers to a “drug product that has the same active ingredient(s), dosage form, strength,
`route of administration, and conditions of use as a listed drug.” See 54 FR 28872 at 28877 (July 10, 1989).
`However, the term duplicate, as used in this context, does not mean identical in all aspects to the listed drug.
`7 The RLD “is the listed drug identified by FDA as the drug product upon which an applicant relies in seeking
`approval of its ANDA.” 21 CFR 314.3(b). Because an ANDA applicant is relying upon FDA’s finding that the
`RLD is safe and effective, FDA’s practice is to designate as RLDs drug products that have been approved for safety
`and effectiveness.
`
`
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`permissible differences) and (2) is bioequivalent to the RLD. An ANDA may not
`be submitted if clinical investigations are necessary to establish the safety and
`effectiveness of the proposed drug product.
`
`
`(4) A petitioned ANDA is a type of ANDA for a drug product that differs from the
`RLD in its dosage form, route of administration, strength, or active ingredient (in
`a product with more than one active ingredient) and for which FDA has
`determined, in response to a petition submitted under section 505(j)(2)(C) of the
`FD&C Act (suitability petition), that studies are not necessary to establish the
`safety and effectiveness of the proposed drug product. A petitioned ANDA is
`generally expected to provide the same therapeutic effect as the listed drug that
`was relied on as the basis of the suitability petition.
`
`
`This guidance focuses on those applications that can be submitted as ANDAs under section
`505(j) of the FD&C Act, petitioned ANDAs under section 505(j)(2)(C) of the FD&C Act, or
`NDAs pursuant to section 505(b)(2) of the FD&C Act. This guidance does not discuss stand-
`alone NDAs.
`
` A
`
` scientific premise underlying the Hatch-Waxman Amendments is that a drug product approved
`in an ANDA under section 505(j) of the FD&C Act is presumed to be therapeutically equivalent8
`to its RLD. Products classified as therapeutically equivalent can be substituted with the full
`expectation that the substituted product will produce the same clinical effect and safety profile as
`the prescribed product when administered to patients under the conditions specified in the
`labeling.9 In contrast to an ANDA, a 505(b)(2) application allows greater flexibility as to the
`characteristics of the proposed product. A 505(b)(2) application will not necessarily be rated
`therapeutically equivalent to the listed drug it references.
`
`
`III. ABBREVIATED APPROVAL PATHWAYS
`
`
`A.
`
`ANDAs10
`
`
`As discussed in section II of this guidance, section 505(j) of the FD&C Act, together with its
`implementing regulations, generally requires that an ANDA demonstrate that the proposed
`
`8 See 21 CFR 314.3(b) (“Therapeutic equivalents are approved drug products that are pharmaceutical equivalents for
`which bioequivalence has been demonstrated, and that can be expected to have the same clinical effect and safety
`profile when administered to patients under the conditions specified in the labeling.”). See also preface to FDA’s
`Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book) (pg. vii-viii, 39th ed.),
`available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM071436.pdf.
`9 See preface to the Orange Book (pg. vii, 39th ed.).
`10 Please note that this guidance is intended to assist applicants deciding whether to submit an ANDA or a 505(b)(2)
`application but does not provide details on the content and format of or the submission process for an ANDA or a
`505(b)(2) application. For more information on the content and format of or the submission process for an ANDA,
`select the “Generics” heading on the FDA guidance web page. For information on the content and format of or the
`submission process for an NDA, select the “Clinical” and “Procedural” headings on the FDA guidance web page.
`
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`B.
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`505(b)(2) Applications
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`generic drug product and the applicable RLD are the same with respect to their active
`ingredient(s), dosage form, route of administration, strength, conditions of use, and labeling
`(with certain exceptions).11 An ANDA must also include sufficient information (1) to
`demonstrate that the proposed product is bioequivalent to the RLD12 and (2) to ensure the
`product’s identity, strength, quality, and purity. Consistent with any statutory provisions related
`to the exclusivity of and patents listed for the RLD, FDA must approve an ANDA unless there is
`insufficient evidence that these criteria are met.13 An ANDA relies on the Agency’s finding of
`safety and effectiveness for an RLD and, as a result, that ANDA may be approved without
`submission of the same type and extent of information as is required for an NDA to establish the
`safety and efficacy of the proposed product.14
`
`Also, as discussed in section II above, an ANDA may contain certain types of differences from
`an RLD (e.g., a change approved in response to a suitability petition or other permissible
`differences, such as certain differences in inactive ingredients, labeling, or container closure
`systems), as long as clinical investigations are not necessary to establish the safety or
`effectiveness of the drug product proposed in the ANDA.
`
`
`
`As discussed in section II above, an application submitted through the pathway described in
`section 505(b)(2) of the FD&C Act contains full reports of investigations of safety and
`effectiveness, where at least some of the information required for approval comes from studies
`not conducted by or for the applicant and for which the applicant has not obtained a right of
`reference or use15 (e.g., the Agency’s finding of safety and/or effectiveness for a listed drug,
`published literature). A 505(b)(2) applicant may rely on FDA’s finding of safety and/or
`effectiveness for a listed drug only to the extent that the proposed product in the 505(b)(2)
`application shares characteristics (e.g., active ingredient, dosage form, route of administration,
`strength, indication or other conditions of use) in common with the relied-upon listed drug(s).16
`The applicant is expected to establish a bridge (e.g., by using comparative bioavailability data)
`between the proposed drug product and each listed drug that the applicant seeks to rely upon to
`demonstrate that reliance on the listed drug is scientifically justified. To the extent that the listed
`drug and the drug proposed in the 505(b)(2) application differ (e.g., a product with a different
`dosage form or a product that is intentionally more bioavailable than the listed drug), the
`
`11 See section 505(j)(2)(A) and 505(j)(4) of the FD&C Act and 21 CFR 314.94 and 314.127.
`12 See section 505(j)(2)(A)(iv) and 505(j)(4)(F) of the FD&C Act and 21 CFR 320.21(b).
`13 See section 505(j)(2)(A) and 505(j)(4) of the FD&C Act and 21 CFR 314.94, 314.105, and 314.127.
`14 See section 505(j)(2)(A) of the FD&C Act.
`15 See 21 CFR 314.3(b) (“Right of reference or use is the authority to rely upon, and otherwise use, an investigation
`for the purposes of obtaining approval of an NDA, including the ability to make available the underlying raw data
`from the investigation for FDA audit, if necessary.”).
`16 A drug product in a 505(b)(2) application may not necessarily be bioequivalent, pharmaceutically equivalent,
`and/or therapeutically equivalent to the listed drug(s) relied upon. Generally, pharmaceutical equivalents are
`products that contain the same active ingredient(s), dosage form, route of administration, and strength. See 21 CFR
`314.3.
`
`
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`505(b)(2) application must include sufficient data to support those differences.17 If FDA has
`approved one or more pharmaceutically equivalent products in one or more NDAs before the
`date of the submission of the original 505(b)(2) application, the applicant must identify one such
`pharmaceutically equivalent product as a listed drug (or an additional listed drug) relied upon but
`need not provide a scientific bridge to that product unless it is scientifically necessary to support
`approval.18
`
`
`IV.
`
`SUBMISSION THROUGH THE APPROPRIATE ABBREVIATED APPROVAL
`PATHWAY
`
`
`
`
`
`A.
`
`Regulatory Considerations for ANDAs and 505(b)(2) Applications
`
`1.
`
`Duplicates
`
`FDA generally will refuse to file a 505(b)(2) application for a drug that is a duplicate of a listed
`drug and eligible for approval under section 505(j) of the FD&C Act.19
`
`If FDA approves a pharmaceutical equivalent to a proposed product before a 505(b)(2)
`application is submitted, such that the proposed product would be a duplicate of that
`pharmaceutically equivalent drug product and eligible for approval under section 505(j) of the
`FD&C Act, FDA will refuse to file the application as a 505(b)(2) application. However, if FDA
`approves a duplicate drug product after a 505(b)(2) application is submitted but before the
`505(b)(2) application is approved, that application would remain eligible for approval as a
`505(b)(2) application, and FDA would not require the applicant of the pending 505(b)(2)
`application to withdraw the application and submit an ANDA.
`
`
`2.
`
`Petitioned ANDAs
`
`
`As noted in section II of this guidance, certain differences between an RLD and a proposed
`generic drug product may be permitted in an ANDA if these differences are the subject of an
`approved suitability petition.20 An applicant may submit a suitability petition to FDA requesting
`permission to submit an ANDA for a generic drug product that differs from an RLD in its route
`of administration, dosage form, or strength or that has one different active ingredient in a fixed-
`combination drug product.21 An ANDA citing a suitability petition that is pending or has been
`
`17 See 21 CFR 314.54(a). See also letter from Janet Woodcock to Katherine M. Sanzo, Jeffrey B. Chasnow, Stephen
`E. Lawton, and William R. Rakoczy (October 14, 2003), supra note 4.
`18 See 21 CFR 314.50(i)(1)(i)(C), 314.54(a)(1)(iii) and (vi), and 314.125(b)(19). See also 81 FR 69580 at 69620-21
`(October 6, 2016).
`19 21 CFR 314.101(d)(9) (noting that FDA may refuse to file an NDA if the “NDA is submitted as a 505(b)(2)
`application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the
`[FD&C] Act”).
`20 See 21 CFR 314.93.
`21 See section 505(j)(2)(C) of the FD&C Act and 21 CFR 314.93.
`
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`denied will not be received for review because the application lacks a legal basis for the
`submission.22
`
`FDA will approve a suitability petition unless, among other things, (1) it determines that the
`safety and effectiveness of the proposed change from the RLD cannot be adequately evaluated
`without data from investigations that exceed what may be required for an ANDA23 or (2) the
`petition is for a drug product for which a pharmaceutical equivalent has been approved in an
`NDA, including, for example, a 505(b)(2) application that referenced the same listed drug named
`in the suitability petition.24 In the latter case, the ANDA applicant should instead refer to the
`approved pharmaceutical equivalent designated by the Agency as the RLD as the basis for
`submission of its ANDA. After approval of an NDA for a drug product that is a pharmaceutical
`equivalent to the drug product described in the suitability petition, the approved suitability
`petition (and listed drug described therein) may no longer be used as the basis for an ANDA
`submission by applicants with pending ANDAs or by prospective ANDA applicants for that
`petitioned drug product.25 In this scenario, an applicant with a pending ANDA will be required
`to submit a new ANDA that both identifies the pharmaceutically equivalent product as the RLD
`and complies with applicable regulatory requirements.26
`
`
`
`
`In some circumstances, an applicant may seek approval for multiple drug products containing the
`same active ingredient(s) when some of these products would qualify for approval under the
`section 505(j) pathway and some would qualify for approval under the 505(b)(2) pathway. In
`these circumstances, FDA has permitted an applicant to submit a single 505(b)(2) application for
`all such multiple drug products that are permitted to be bundled in a single NDA.27 For example,
`an applicant seeking approval for multiple strengths of a product, only some of which are
`included in the Orange Book as listed drugs, would not have to submit both an ANDA for the
`strengths listed in the Orange Book and a 505(b)(2) application for the new strengths; instead,
`the applicant may submit one 505(b)(2) application for all of the proposed strengths.
`
`
`3.
`
`Bundling
`
`
`22 See Manual of Policies and Procedures 5240.5 Rev. 1 ANDA Suitability Petitions, which is available on the CDER
`Manual of Policies & Procedures (MAPP) web page at https://www.fda.gov/about-fda/center-drug-evaluation-and-
`research/cder-manual-policies-procedures-mapp. See also the guidance for industry ANDA Submissions—Content
`and Format of Abbreviated New Drug Applications (September 2018) at 8-9.
`23 See section 505(j)(2)(A) and 505(j)(2)(C) of the FD&C Act and 21 CFR 314.93(e)(1)(i).
`24 21 CFR 314.93(e)(1)(vi). See also 21 CFR 314.93(b).
`25 21 CFR 314.93(f)(2).
`26 See ibid. See also 81 FR 69580 at 69621-22 (October 6, 2016).
`27 See the guidance for industry Submitting Separate Marketing Applications and Clinical Data for Purposes of
`Assessing User Fees (December 2004).
`
`
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`Scientific Considerations for ANDAs and 505(b)(2) Applications
`
`Type of Studies, Data, and Information Submitted in ANDAs
`
`B.
`
`1.
`
`
`Although ANDAs and certain 505(b)(2) applications rely on the Agency’s finding of safety and
`effectiveness for a listed drug, there may be differences in the types of studies, data, and
`information that may be necessary to support the approval of drug products proposed in ANDAs
`compared to 505(b)(2) applications. 505(b)(2) applicants have significant flexibility in the types
`of studies, data, and information they may submit in a 505(b)(2) NDA to support the
`requirements for NDA approval. The types of studies that may be submitted in a 505(b)(2) NDA
`may include clinical investigations to establish the safety and/or effectiveness of a product.
`Generally, ANDA applicants also have significant flexibility in the types of studies, data, and
`information they may submit in an ANDA to support the requirements for ANDA approval, so
`long as clinical investigations are not submitted to establish the safety or effectiveness of a
`product. For example, FDA has accepted limited confirmatory studies appropriate for petitioned
`ANDAs28 in an original ANDA, and FDA has reviewed pharmacodynamic data in determining
`active ingredient sameness.29 The precise scope and type of information necessary for approval
`will vary and may be the subject of discussion between the applicant and FDA during the drug
`development process.30
`
`If a clinical investigation (i.e., any experiment other than a bioavailability study in which a drug
`is administered or dispensed to, or used on, human subjects)31 is necessary to demonstrate the
`safety or effectiveness of a proposed drug product, generally this type of study goes beyond the
`scope of information that may be relied upon as necessary for approval in an ANDA. We
`recommend that a prospective ANDA applicant considering submission of an application that
`may require data that could be considered outside of the scope of the ANDA pathway contact the
`Office of Generic Drugs (OGD) prior to submission of an application to inform which type of
`application is appropriate.32
`
`
`2.
`
`Active Ingredient Sameness Evaluation
`
`
`As stated in sections II. and III.A of this guidance, section 505(j) of the FD&C Act generally
`requires that a proposed generic drug product demonstrate that it is the same as the RLD with
`
`
`28 See 54 FR 28872 at 28880 (July 10, 1989) and 57 FR 17950 at 17958 (April 28, 1992).
`29 See, for example, the draft product-specific guidance for Enoxaparin Sodium injections, which includes
`equivalence of the in vivo pharmacodynamic profile as one of the five criteria for demonstrating active ingredient
`sameness of the test and reference products. When final, this product-specific guidance will represent the FDA’s
`current thinking on this topic. For the most recent version of a product-specific guidance, check the Product-
`Specific Guidances for Generic Drug Development web page at
`https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm
`30 See section V of this guidance for information about requesting assistance from FDA.
`31 21 CFR 314.108(a).
`32 See section V of this guidance for information about requesting assistance from OGD.
`
`
`
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`respect to active ingredient(s).33 If the active ingredient in an applicant’s proposed drug product
`cannot be demonstrated to be the same as the active ingredient in the RLD by using the
`information and data that may be submitted in connection with an ANDA, the drug product
`should not be submitted for approval in an ANDA.
`
`FDA has broad discretion to determine whether an ANDA applicant has submitted information
`sufficient for the Agency to reasonably conclude that the proposed drug product’s active
`ingredient is the same as the active ingredient in the RLD.34 That is, the statutory provisions
`outlining the contents of an ANDA do not describe the type or amount of information that an
`ANDA applicant must submit to demonstrate that the active ingredient in the proposed generic
`drug product is the same as the active ingredient in the RLD. In addition, in the preamble to the
`final rule to implement the Hatch-Waxman Amendments, FDA specifically rejected the adoption
`of requirements that active ingredients “exhibit the same physical and chemical characteristics
`[as the RLD], that no additional residues or impurities can result from the different manufacture
`or synthesis process, and that the stereochemical characteristics and solid state forms of the drug
`have not been altered.”35 Instead, FDA has adopted a more flexible approach.36
`
`In some instances, current limitations of scientific understanding and technology may preclude
`approval of an ANDA with the data permitted for submission in an ANDA, including, for
`example, with respect to establishing active ingredient sameness of a given product. As
`scientific understanding and technology evolve, though, FDA may be able to receive, review,
`and approve ANDAs where it previously lacked the scientific basis to do so. We therefore
`recommend that a prospective ANDA applicant with questions about determining active
`ingredient sameness contact OGD prior to submission of the application.37
`
`
`3.
`
`Intentional Differences Between the Proposed Drug Product and the RLD
`
`
`
`a.
`
`Differences in formulation
`
`
`Although section 505(j) of the FD&C Act generally requires that the active ingredient(s) in a
`proposed ANDA be the same as the active ingredient(s) in the RLD, certain differences in
`inactive ingredients are permissible. An ANDA must include information regarding the identity
`and quantity of all active and inactive ingredients of the proposed drug product (i.e., the
`formulation) and a characterization of any permitted differences between the formulations of the
`proposed drug product and the RLD, along with a justification demonstrating that the safety and
`
`
`33 See section 505(j)(2)(A)(ii) and 505(j)(4)(C) of the FD&C Act.
`34 See generally Serono Laboratories, Inc. v. Shalala, 158 F.3d 1313 (D.C. Cir. 1998).
`35 57 FR 17950 at 17958-59 (April 28, 1992).
`36 Ibid. at 17959. See also letter from Janet Woodcock to J. Michael Nicholas (April 16, 2015), Docket No. FDA-
`2015-P-1050.
`37 See section V of this guidance for information about requesting assistance from OGD.
`
`
`
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`Contains Nonbinding Recommendations
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`effectiveness of the proposed drug product is not adversely affected by these differences.38 For
`products for certain routes of administration, the types of changes to inactive ingredients that are
`permissible in an ANDA have been limited by regulation.39 For example, in order to qualify for
`submission as an ANDA:
`
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`• Parenteral drug products generally must contain the same inactive ingredients and in the
`same concentrations as the RLD.40 However, specific qualitative and quantitative
`changes from the RLD formulation are permitted in an ANDA for a parenteral drug
`product for certain inactive ingredients (i.e., preservatives, buffers, and antioxidants) that
`are considered exception excipients.41 All other inactive ingredients in a proposed
`parenteral drug product must be qualitatively and quantitatively the same (Q1/Q2 same)
`as the RLD.42
`
`• Ophthalmic drug products generally must be Q1/Q2 same as the RLD with respect to all
`of their inactive ingredients.43 However, an ANDA for an ophthalmic drug product may
`contain differences from the RLD with respect to certain inactive ingredients (i.e.,
`preservatives, buffers, substances to adjust tonicity, or thickening agents), which are
`considered exception excipients.44 To note, for certain ophthalmic drug products,
`however, FDA has determined that, as a scientific matter, qualitative or quantitative
`deviations from the RLD in exception excipients may necessitate the need to conduct an
`
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`38 21 CFR 314.94(a)(9)(ii). See also 21 CFR 314.94(a)(5) for active ingredient identity and 21 CFR314.94(a)(6) for
`active ingredient strengths.
`39 See 21 CFR 314.94(a)(9)(iii) and (iv).
`40 21 CFR 314.94(a)(9)(iii).
`41 Ibid. (“However, an applicant may seek approval of a [parenteral] drug product that differs from the reference
`listed drug in preservative, buffer, or antioxidant provided that the applicant identifies and characterizes the
`differences and provides information demonstrating that the differences do not affect the safety or efficacy of the
`proposed drug product.”).
`42 See 21 CFR 314.94(a)(9)(iii). When an ANDA applicant seeks approval for a parenteral formulation that is the
`same as that previously marketed by the innovator, FDA has determined that, in appropriate circumstances, pursuant
`to 21 CFR 314.99(b), it may waive the requirement in the regulation that the inactive ingredients in a parenteral drug
`product approved under an ANDA be the same as those in the RLD (except for preservatives, buffers, and
`antioxidants), as long as the statutory requirement regarding safety of inactive ingredients has been met. See section
`505(j)(4)(H) of the FD&C Act. In determining whether to grant such a waiver, the