§ 320.22
`
`process, including a change in product
`formulation or dosage strength, beyond
`the variations provided for in the ap-
`proved application.
`(2) A change in the labeling to pro-
`vide for a new indication for use of the
`drug product, if clinical studies are re-
`quired to support the new indication
`for use.
`(3) A change in the labeling to pro-
`vide for a new dosage regimen or for an
`additional dosage regimen for a special
`patient population, e.g., infants, if clin-
`ical studies are required to support the
`new or additional dosage regimen.
`(d) FDA may approve a full new drug
`application, or a supplemental applica-
`tion proposing any of the changes set
`forth in paragraph (c) of this section,
`that does not contain evidence of in
`vivo bioavailability or information to
`permit waiver of the requirement for in
`vivo bioavailability data, if all of the
`following conditions are met.
`(1) The application is otherwise ap-
`provable.
`(2) The application agrees to submit,
`within the time specified by FDA, ei-
`ther:
`(i) Evidence measuring the in vivo
`bioavailability and demonstrating the
`in vivo bioequivalence of the drug
`product that is the subject of the appli-
`cation; or
`(ii)
`Information to permit FDA to
`waive measurement of in vivo bio-
`availability.
`(e) Evidence measuring the in vivo
`bioavailability and demonstrating the
`in vivo bioequivalence of a drug prod-
`uct shall be obtained using one of the
`approaches
`for
`determining
`bio-
`availability set forth in § 320.24.
`(f) Information
`to permit FDA
`to
`waive the submission of evidence meas-
`uring the in vivo bioavailability or
`demonstrating the in vivo bioequiva-
`lence shall meet the criteria set forth
`in § 320.22.
`(g) Any person holding an approved
`full or abbreviated new drug applica-
`tion shall submit to FDA a supple-
`mental application containing new evi-
`dence measuring
`the
`in vivo bio-
`availability or demonstrating the in
`vivo bioequivalence of the drug product
`that is the subject of the application if
`notified by FDA that:
`
`21 CFR Ch. 1 (4-1-05 Edition)
`
`(1) There are data demonstrating
`that the dosage regimen in the labeling
`is based on incorrect assumptions or
`facts regarding the pharmacokinetics
`of the drug product and that following
`this dosage regimen could potentially
`result in subtherapeutic or toxic levels;
`or
`
`(2) There are data measuring signifi-
`cant
`intra-batch and batch-to-batch
`variability, e.g., plus or minus 25 per-
`cent, in the bioavailability of the drug
`product.
`(h) The requirements of this section
`regarding the submission of evidence
`measuring the in vivo bioavailability
`or demonstrating
`in vivo bio-
`the
`equivalence apply only to a full or ab-
`breviated new drug application or a
`supplemental application for a finished
`dosage formulation.
`[57 FR 17998, Apr. 28, 1992, as amended at 67
`FR 77672, Dec. 19, 2002]
`
`§ 320.22 Criteria for waiver of evidence
`of in vivo bioavailability or bio-
`equivalence.
`(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 bio-
`availability 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 sec-
`tion, 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-evi-
`dent. 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 bioequiva-
`lence may be considered self-evident
`based on other data in the application
`if the product meets one of the fol-
`lowing criteria:
`
`Par Pharm., Inc.
`Exhibit 1047
`Page 001
`
`

`

`Food and Drug Administration, HHS
`
`(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 in-
`active ingredients
`in the same con-
`centration 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 ingre-
`dient 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 absorp-
`tion of the active drug ingredient or
`active moiety for products that are
`systemically absorbed, or that may sig-
`nificantly affect systemic or
`local
`availability for products intended to
`act locally.
`(c) FDA shall waive the requirement
`for the submission of evidence meas-
`uring the in vivo bioavailability or
`demonstrating the in vivo bioequiva-
`lence of a solid oral dosage form (other
`than a delayed release or extended re-
`lease 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 prod-
`uct in
`the Approved Drug Products
`
`§ 320.22
`
`with Therapeutic Equivalence Evalua-
`tions List, and rated the drug product
`as having a known or potential bio-
`equivalence problem. A drug product so
`rated reflects a determination by FDA
`that an in vivo bioequivalence study is
`required.
`(d) For certain drug products, bio-
`availability may be measured or bio-
`equivalence may be demonstrated by
`evidence obtained in vitro in lieu of in
`vivo data. FDA shall waive the require-
`ment for the submission of evidence
`obtained
`in vivo measuring the bio-
`availability or demonstrating the bio-
`equivalence of the drug product if the
`drug product meets one of the fol-
`lowing criteria:
`(1) [Reserved]
`(2) The drug product is
`in the same
`a
`different
`dosage
`form, but
`in
`strength, and is proportionally similar
`in its active and inactive ingredients to
`another drug product for which the
`same manufacturer has obtained ap-
`proval and the conditions
`in para-
`graphs (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 ap-
`propriate
`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 ex-
`tended 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 reformu-
`lated product that is identical, except
`for a different color, flavor, or preserv-
`ative that could not affect the bio-
`availability of the reformulated prod-
`uct, to another drug product for which
`the same manufacturer has obtained
`app )val and the following conditions
`are met:
`(i) The bioavailability of the other
`product has been measured; and
`(ii) Both drug products meet an ap-
`propriate
`in vitro test approved by
`FDA.
`
`Par Pharm., Inc.
`Exhibit 1047
`Page 002
`
`

`

`§ 320.23
`
`21 CFR Ch. 1 (4-1-05 Edition)
`
`(e) FDA, for good cause, may waive a
`requirement for the submission of evi-
`dence of in vivo bioavailability or bio-
`equivalence
`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 bio-
`availability 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 dif-
`ference between the drug product and a
`listed drug may affect
`the bio-
`availability or bioequivalence of the
`drug product.
`[57 FR 17998, Apr. 28, 1992, as amended at 67
`FR 77673, Dec. 19, 2002]
`
`§ 320.23 Basis for measuring in vivo
`bioavailability or demonstrating
`bioequivalence.
`(a)(1) The in vivo bioavailability of a
`drug product is measured if the prod-
`uct's rate and extent of absorption, as
`determined by comparison of measured
`parameters, e.g., concentration of the
`active drug ingredient in
`the blood,
`urinary excretion rates, or pharma-
`cological effects, do not indicate a sig-
`nificant difference from the reference
`material's rate and extent of absorp-
`tion. For drug products that are not in-
`tended to be absorbed into the blood-
`stream, bioavailability may be as-
`sessed by measurements intended to re-
`flect the rate and extent to which the
`active ingredient or active moiety be-
`comes available at the site of action.
`(2) Statistical techniques used shall
`be of sufficient sensitivity to detect
`differences in rate and extent of ab-
`sorption that are not attributable to
`subject variability.
`(3) A drug product that differs from
`the reference material in its rate of ab-
`sorption, but not in its extent of ab-
`sorption, may be considered to be bio-
`available if the difference in the rate of
`absorption
`is
`intentional,
`is appro-
`priately reflected in the labeling, is not
`essential to the attainment of effective
`body drug concentrations on chronic
`use, and is considered medically insig-
`nificant for the drug product.
`
`(b) Two drug products will be consid-
`ered bioequivalent drug products
`if
`they are pharmaceutical equivalents or
`pharmaceutical
`alternatives whose
`rate and extent of absorption do not
`show a significant difference when ad-
`ministered at the same molar dose of
`the active moiety under similar experi-
`mental conditions, either single dose or
`multiple dose. Some pharmaceutical
`equivalents or pharmaceutical alter-
`natives may be equivalent in the ex-
`tent of their absorption but not in
`their rate of absorption and yet may be
`considered bioequivalent because such
`differences in the rate of absorption are
`intentional and are reflected in the la-
`beling, are not essential to the attain-
`ment of effective body drug concentra-
`tions on chronic use, and are consid-
`ered medically
`insignificant for the
`particular drug product studied.
`[57 FR 17999, Apr. 28, 1992, as amended at 67
`FR 77673, Dec. 19, 2002]
`
`§ 320.24 Types of evidence to measure
`bioavailability or establish bio-
`equivalence.
`(a) Bioavailability may be measured
`or bioequivalence may
`be
`dem-
`onstrated by several in vivo and in
`vitro methods. FDA may require
`in
`vivo or in vitro testing, or both, to
`measure the bioavailability of a drug
`product or establish the bioequivalence
`of specific drug products. Information
`on bioequivalence
`requirements
`for
`specific products is included in the cur-
`rent edition of FDA's publication "Ap-
`proved Drug Products with Thera-
`peutic Equivalence Evaluations" and
`any current supplement to the publica-
`tion. The selection of the method used
`to meet an in vivo or in vitro testing
`requirement depends upon the purpose
`of the study, the analytical methods
`available, and the nature of the drug
`product. Applicants shall conduct bio-
`availability and bioequivalence testing
`using the most accurate, sensitive, and
`reproducible approach available among
`those set forth in paragraph (b) of this
`section. The method used must be ca-
`pable of measuring bioavailability or
`establishing bioequivalence, as appro-
`priate, for the product being tested.
`
`Par Pharm., Inc.
`Exhibit 1047
`Page 003
`
`