C.F.R. » Title 21 » CHAPTER I—FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES › SUBCHAPTER D—DRUGS FOR HUMAN USE › PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS › Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products

21 C.F.R. § 320.22

Criteria for waiver of evidence of in vivo bioavailability or bioequivalence

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(a) Any person submitting a full or abbreviated new drug application, or a supplemental application proposing any of the changes set forth in § 320.21(c), may request FDA to waive the requirement for the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence of the drug product that is the subject of the application. An applicant shall submit a request for waiver with the application. Except as provided in paragraph (f) of this section, FDA shall waive the requirement for the submission of evidence of in vivo bioavailability or bioequivalence if the drug product meets any of the provisions of paragraphs (b), (c), (d), or (e) of this section.

(b) For certain drug products, the in vivo bioavailability or bioequivalence of the drug product may be self-evident. FDA shall waive the requirement for the submission of evidence obtained in vivo measuring the bioavailability or demonstrating the bioequivalence of these drug products. A drug product's in vivo bioavailability or bioequivalence may be considered self-evident based on other data in the application if the product meets one of the following criteria:

(1) The drug product:

(i) Is a parenteral solution intended solely for administration by injection, or an ophthalmic or otic solution; and

(ii) Contains the same active and inactive ingredients in the same concentration as a drug product that is the subject of an approved full new drug application or abbreviated new drug application.

(2) The drug product:

(i) Is administered by inhalation as a gas, e.g., a medicinal or an inhalation anesthetic; and

(ii) Contains an active ingredient in the same dosage form as a drug product that is the subject of an approved full new drug application or abbreviated new drug application.

(3) The drug product:

(i) Is a solution for application to the skin, an oral solution, elixir, syrup, tincture, a solution for aerosolization or nebulization, a nasal solution, or similar other solubilized form; and

(ii) Contains an active drug ingredient in the same concentration and dosage form as a drug product that is the subject of an approved full new drug application or abbreviated new drug application; and

(iii) Contains no inactive ingredient or other change in formulation from the drug product that is the subject of the approved full new drug application or abbreviated new drug application that may significantly affect absorption of the active drug ingredient or active moiety for products that are systemically absorbed, or that may significantly affect systemic or local availability for products intended to act locally.

(c) FDA shall waive the requirement for the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence of a solid oral dosage form (other than a delayed release or extended release dosage form) of a drug product determined to be effective for at least one indication in a Drug Efficacy Study Implementation notice or which is identical, related, or similar to such a drug product under § 310.6 of this chapter unless FDA has evaluated the drug product under the criteria set forth in § 320.33, included the drug product in the Approved Drug Products with Therapeutic Equivalence Evaluations List, and rated the drug product as having a known or potential bioequivalence problem. A drug product so rated reflects a determination by FDA that an in vivo bioequivalence study is required.

(d) For certain drug products, bioavailability may be measured or bioequivalence may be demonstrated by evidence obtained in vitro in lieu of in vivo data. FDA shall waive the requirement for the submission of evidence obtained in vivo measuring the bioavailability or demonstrating the bioequivalence of the drug product if the drug product meets one of the following criteria:

(1) [Reserved]

(2) The drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to another drug product for which the same manufacturer has obtained approval and the conditions in paragraphs (d)(2)(i) through (d)(2)(iii) of this section are met:

(i) The bioavailability of this other drug product has been measured;

(ii) Both drug products meet an appropriate in vitro test approved by FDA; and

(iii) The applicant submits evidence showing that both drug products are proportionally similar in their active and inactive ingredients.

(iv) Paragraph (d) of this section does not apply to delayed release or extended release products.

(3) The drug product is, on the basis of scientific evidence submitted in the application, shown to meet an in vitro test that has been correlated with in vivo data.

(4) The drug product is a reformulated product that is identical, except for a different color, flavor, or preservative that could not affect the bioavailability of the reformulated product, to another drug product for which the same manufacturer has obtained approval and the following conditions are met:

(i) The bioavailability of the other product has been measured; and

(ii) Both drug products meet an appropriate in vitro test approved by FDA.

(e) FDA, for good cause, may waive a requirement for the submission of evidence of in vivo bioavailability or bioequivalence if waiver is compatible with the protection of the public health. For full new drug applications, FDA may defer a requirement for the submission of evidence of in vivo bioavailability if deferral is compatible with the protection of the public health.

(f) FDA, for good cause, may require evidence of in vivo bioavailability or bioequivalence for any drug product if the agency determines that any difference between the drug product and a listed drug may affect the bioavailability or bioequivalence of the drug product.

[57 FR 17998, Apr. 28, 1992, as amended at 67 FR 77673, Dec. 19, 2002]
Notes of Decisions
Cited in 15 cases, 1979–2013 · leading case: Viropharma Inc. v. Hamburg, 898 F. Supp. 2d 1 (D.D.C. 2012).
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Viropharma Inc. v. Hamburg, 898 F. Supp. 2d 1 (D.D.C. 2012). · cites it 10× “21 (b) establishes, a default requirement that bioequivalence be demonstrated through in vivo testing, 14 subject to the waiver criteria set forth in 21 C.F.R. § 320.22 , which permits in vitro testing in limited circumstances.”
Bristol-Myers Squibb Co. v. Shalala, 923 F. Supp. 212 (D.D.C. 1996). · cites it 6× “See 21 C.F.R. § 320.22 (d)(3); 21 C.F.R. § 10.”
Hill Dermaceuticals, Inc. v. Food & Drug Admin., 709 F.3d 44 (D.C. Cir. 2013). · cites it 2× “” 21 C.F.R. § 320.22 (b)(3). The FDA granted bioequivalence waivers for Identi’s body and scalp *47 oil under § 820.”
Fisons Corp. v. Shalala, 860 F. Supp. 859 (D.D.C. 1994). · cites it 11× “More specifically, Fisons claims that both (1) the FDA regulation permitting the waiver of certain testing for generic drug applications, 21 C.F.R. § 320.22 (b), and (2) FDA’s policy of waiving testing and approval of these generic drugs, are arbitrary, capricious, an abuse of…”
ViroPharma, Inc. v. Hamburg, 777 F. Supp. 2d 140 (D.D.C. 2011). · cites it 2× “21(b) sets forth a general requirement that bioequivalence be demonstrated through in vivo testing, unless the drug product meets one of the waiver criteria set forth in 21 C.F.R. § 320.22 . (Compl. ¶¶ 35-37.) The FDA, however, argues that there is no such “default requirement…”
United States v. Baxter Healthcare Corp., & Glaxo Specialties, Inc., a Corp., Intervenor/defendant-Appellant, 901 F.2d 1401 (7th Cir. 1990). “See 21 C.F.R. § 320.22 (b). Thus, there would seem to be no issue concerning the bioavailability of the TRC products and the FDA-approved products.”
Hill Dermaceuticals, Inc. v. U.S. Food & Drug Admin., 826 F. Supp. 2d 252 (D.D.C. 2011). · cites it 2× “” 21 C.F.R. § 320.22 (b)(3)(i)—(iii). Furthermore, each ANDA must include “the specifications necessary to ensure the identity, strength, quality, and purity of the drug substance .”
United States v. Atropine Sulfate 1.0 Mg. (Article of Drug) Dey-Dose, & Dey Labs., Inc., Claimant-Appellant, 843 F.2d 860 (5th Cir. 1988). · cites it 2× “” This is so, Dey argues, because ASI is administered by inhalation, and such being the case, 21 C.F.R. § 320.22 (b)(4) demonstrates as a matter of law that Dey’s ASI and “generic ASI” are bioequivalent.”
Pharmadyne Labs., Inc. v. Kennedy, 466 F. Supp. 100 (D.N.J. 1979). · cites it 2× “For example, an applicant may waive evidence of in vivo bioavailability data, normally required for NDA or ANDA approval, 21 C.F.R. § 320.22 , where the drug product meets a number of conditions, one of which is that the drug contains no inactive ingredient known to…”
Somerset Pharm., Inc. v. Shalala, 973 F. Supp. 443 (D. Del. 1997). · cites it 2× “21 C.F.R. § 320.22 . 1 In cases where “the in vivo bioavailability of bioequivalence of the drug product may be self-evident,” the drug application may be approved without demonstrating either bioavailability or bioequivalence.”
Schering Corp. v. Sullivan, 782 F. Supp. 645 (D.D.C. 1992). “, Exhibit 2, if 9; 21 C.F.R. § 320.22 (b)(4). Apart from its statutory challenge, Schering has not yet offered an adequate basis for challenging the support for or the application of that regulation in this case.”
United States v. Undetermined Quantities of an Article of Drug, 709 F. Supp. 511 (D.N.J. 1987). · cites it 2× “Second, G & W asserts that a triable issue exists as to whether Anucort is exempted from demonstrating bioequivalence under 21 C.F.R. § 320.22 (b)(2). This section waives the requirement for submission of evidence of bioavailability for “a topically applied preparation, e.”
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— 21 C.F.R. § 320.22(b) — 1 case
Fisons Corp. v. Shalala, 860 F. Supp. 859 (D.D.C. 1994). “More specifically, Fisons claims that both (1) the FDA regulation permitting the waiver of certain testing for generic drug applications, 21 C.F.R. § 320.22 (b), and (2) FDA’s policy of waiving testing and approval of these generic drugs, are arbitrary, capricious, an abuse of…”
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