21 C.F.R. § 314.127 : Food and Drugs — FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES — DRUGS FOR HUMAN USE — APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG — FDA ACTION ON APPLICATIONS AND ABBREVIATED APPLICATIONS — Refusal to approve an ANDA

(a) FDA will refuse to approve an ANDA for a new drug under section 505(j) of the Federal Food, Drug, and Cosmetic Act for any of the following reasons, unless the requirement has been waived under §314.99:
(1) The methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug product are inadequate to ensure and preserve its identity, strength, quality, and purity.
(2) Information submitted with the ANDA is insufficient to show that each of the proposed conditions of use has been previously approved for the listed drug referred to in the ANDA.
(3)
(i) If the reference listed drug has only one active ingredient, information submitted with the ANDA is insufficient to show that the active ingredient is the same as that of the reference listed drug;
(ii) If the reference listed drug has more than one active ingredient, information submitted with the ANDA is insufficient to show that the active ingredients are the same as the active ingredients of the reference listed drug; or
(iii) If the reference listed drug has more than one active ingredient and if the ANDA is for a drug product that has an active ingredient different from the reference listed drug:
(A) Information submitted with the ANDA is insufficient to show:

( That the other active ingredients are the same as the active ingredients of the reference listed drug; or

( That the different active ingredient is an active ingredient of a listed drug or a drug that does not meet the requirements of section 201(p) of the Federal Food, Drug, and Cosmetic Act; or

(B) No petition to submit an ANDA for the drug product with the different active ingredient was approved under §314.93.
(4)
(i) If the ANDA is for a drug product whose route of administration, dosage form, or strength purports to be the same as that of the listed drug referred to in the ANDA, information submitted in the ANDA is insufficient to show that the route of administration, dosage form, or strength is the same as that of the reference listed drug; or
(ii) If the ANDA is for a drug product whose route of administration, dosage form, or strength is different from that of the listed drug referred to in the application, no petition to submit an ANDA for the drug product with the different route of administration, dosage form, or strength was approved under §314.93.
(5) If the ANDA was submitted under the approval of a petition under §314.93, the ANDA did not contain the information required by FDA with respect to the active ingredient, route of administration, dosage form, or strength that is not the same as that of the reference listed drug.
(6)
(i) Information submitted in the ANDA is insufficient to show that the drug product is bioequivalent to the listed drug referred to in the ANDA; or
(ii) If the ANDA was submitted under a petition approved under §314.93, information submitted in the ANDA is insufficient to show that the active ingredients of the drug product are of the same pharmacological or therapeutic class as those of the reference listed drug and that the drug product can be expected to have the same therapeutic effect as the reference listed drug when administered to patients for each condition of use approved for the reference listed drug.
(7) Information submitted in the ANDA is insufficient to show that the labeling proposed for the drug is the same as the labeling approved for the listed drug referred to in the ANDA except for changes required because of differences approved in a petition under §314.93 or because the drug product and the reference listed drug are produced or distributed by different manufacturers or because aspects of the listed drug's labeling are protected by patent, or by exclusivity, and such differences do not render the proposed drug product less safe or effective than the listed drug for all remaining, nonprotected conditions of use.
(8)
(i) Information submitted in the ANDA or any other information available to FDA shows that:
(A) The inactive ingredients of the drug product are unsafe for use, as described in paragraph (a)(8)(ii) of this section, under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug product; or
(B) The composition of the drug product is unsafe, as described in paragraph (a)(8)(ii) of this section, under the conditions prescribed, recommended, or suggested in the proposed labeling because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.
(ii)
(A) FDA will consider the inactive ingredients or composition of a drug product unsafe and refuse to approve an ANDA under paragraph (a)(8)(i) of this section if, on the basis of information available to the agency, there is a reasonable basis to conclude that one or more of the inactive ingredients of the proposed drug or its composition raises serious questions of safety or efficacy. From its experience with reviewing inactive ingredients, and from other information available to it, FDA may identify changes in inactive ingredients or composition that may adversely affect a drug product's safety or efficacy. The inactive ingredients or composition of a proposed drug product will be considered to raise serious questions of safety or efficacy if the product incorporates one or more of these changes. Examples of the changes that may raise serious questions of safety or efficacy include, but are not limited to, the following:

( A change in an inactive ingredient so that the product does not comply with an official compendium.

( A change in composition to include an inactive ingredient that has not been previously approved in a drug product for human use by the same route of administration.

( A change in the composition of a parenteral drug product to include an inactive ingredient that has not been previously approved in a parenteral drug product.

( A change in composition of a drug product for ophthalmic use to include an inactive ingredient that has not been previously approved in a drug for ophthalmic use.

( The use of a delivery or a modified release mechanism never before approved for the drug.

( A change in composition to include a significantly greater content of one or more inactive ingredients than previously used in the drug product.

( If the drug product is intended for topical administration, a change in the properties of the vehicle or base that might increase absorption of certain potentially toxic active ingredients thereby affecting the safety of the drug product, or a change in the lipophilic properties of a vehicle or base, e.g., a change from an oleaginous to a water soluble vehicle or base.

(B) FDA will consider an inactive ingredient in, or the composition of, a drug product intended for parenteral use to be unsafe and will refuse to approve the ANDA unless it contains the same inactive ingredients, other than preservatives, buffers, and antioxidants, in the same concentration as the listed drug, and, if it differs from the listed drug in a preservative, buffer, or antioxidant, the ANDA contains sufficient information to demonstrate that the difference does not affect the safety or efficacy of the drug product.
(C) FDA will consider an inactive ingredient in, or the composition of, a drug product intended for ophthalmic or otic use unsafe and will refuse to approve the ANDA unless it contains the same inactive ingredients, other than preservatives, buffers, substances to adjust tonicity, or thickening agents, in the same concentration as the listed drug, and if it differs from the listed drug in a preservative, buffer, substance to adjust tonicity, or thickening agent, the ANDA contains sufficient information to demonstrate that the difference does not affect the safety or efficacy of the drug product and the labeling does not claim any therapeutic advantage over or difference from the listed drug.
(9) Approval of the listed drug referred to in the ANDA has been withdrawn or suspended for grounds described in §314.150(a) or FDA has published a notice of opportunity for hearing to withdraw approval of the reference listed drug under §314.150(a).
(10) Approval of the listed drug referred to in the ANDA has been withdrawn under §314.151 or FDA has proposed to withdraw approval of the reference listed drug under §314.151(a).
(11) FDA has determined that the reference listed drug has been withdrawn from sale for safety or effectiveness reasons under §314.161, or the reference listed drug has been voluntarily withdrawn from sale and the agency has not determined whether the withdrawal is for safety or effectiveness reasons, or approval of the reference listed drug has been suspended under §314.153, or the agency has issued an initial decision proposing to suspend the reference listed drug under §314.153(a)(1).
(12) The abbreviated new drug application does not meet any other requirement under section 505(j)(2)(A) of the Federal Food, Drug, and Cosmetic Act.
(13) The abbreviated new drug application contains an untrue statement of material fact.
(14) For an ANDA submitted pursuant to an approved petition under §10.30 of this chapter and §314.93, an NDA subsequently has been approved for the change described in the approved petition.
(b) FDA may refuse to approve an ANDA for a new drug if the applicant or contract research organization that conducted a bioavailability or bioequivalence study described in §320.63 of this chapter that is contained in the ANDA refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA.

21 C.F.R. §314.127

57 FR 17991, 4/28/1992; 57 FR 29353, 7/1/1992, as amended at 58 FR 25927, 4/28/1993; 67 FR 77672, 12/19/2002; 81 FR 69658, 12/5/2016