§ 316.52 Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. [65 FR 56480, Sept. 19, 2000] 21 CFR Ch. I (4–1–12 Edition) PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Subpart A—General Provisions § 316.52 Availability for public disclo- sure of data and information in re- quests and applications. (a) FDA will not publicly disclose the existence of a request for orphan-drug designation under section 526 of the act prior to final FDA action on the re- quest unless the existence of the re- quest has been previously publicly dis- closed or acknowledged. (b) Whether or not the existence of a pending request for designation has been publicly disclosed or acknowl- edged, no data or information in the re- quest are available for public disclo- sure prior to final FDA action on the request. (c) Upon final FDA action on a re- quest for designation, FDA will deter- mine the public availability of data and information in the request in ac- cordance with part 20 and § 314.430 of this chapter and other applicable stat- utes and regulations. (d) In accordance with § 316.28, FDA will make a cumulative list of all or- phan drug designations available to the public and update such list monthly. (e) FDA will not publicly disclose the existence of a pending marketing appli- cation for a designated orphan drug for the use for which the drug was des- ignated unless the existence of the ap- plication has been previously publicly disclosed or acknowledged. (f) FDA will determine the public availability of data and information contained in pending and approved marketing applications for a des- ignated orphan drug for the use for which the drug was designated in ac- cordance with part 20 and § 314.430 of this chapter and other applicable stat- utes and regulations. Sec. 320.1 Definitions. Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products 320.21 Requirements for submission of bio- availability and bioequivalence data. 320.22 Criteria for waiver of evidence of in vivo bioavailability or bioequivalence. 320.23 Basis for measuring in vivo bio- availability or demonstrating bioequiva- lence. 320.24 Types of evidence to measure bio- availability or establish bioequivalence. 320.25 Guidelines for the conduct of an in vivo bioavailability study. 320.26 Guidelines on the design of a single- dose in vivo bioavailability or bioequiva- lence study. 320.27 Guidelines on the design of a mul- tiple-dose in vivo bioavailability study. 320.28 Correlation of bioavailability with an acute pharmacological effect or clinical evidence. 320.29 Analytical methods for an in vivo bioavailability or bioequivalence study. 320.30 Inquiries regarding bioavailability and bioequivalence requirements and re- view of protocols by the Food and Drug Administration. 320.31 Applicability of requirements regard- ing an ‘‘Investigational New Drug Appli- cation.’’ 320.32 Procedures for establishing or amend- ing a bioequivalence requirement. 320.33 Criteria and evidence to assess actual or potential bioequivalence problems. 320.34 Requirements for batch testing and certification by the Food and Drug Ad- ministration. 320.35 Requirements for in vitro testing of each batch. 320.36 Requirements for maintenance of records of bioequivalence testing. 320.38 Retention of bioavailability samples. 320.63 Retention of bioequivalence samples. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371. Subpart A—General Provisions § 320.1 Definitions. (a) Bioavailability means 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 190 Food and Drug Administration, HHS § 320.21 into the bloodstream, bioavailability may be assessed by measurements in- tended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. (b) Drug product means a finished dos- age form, e.g., tablet, capsule, or solu- tion, that contains the active drug in- gredient, generally, but not nec- essarily, in association with inactive ingredients. (c) Pharmaceutical equivalents means drug products in identical dosage forms that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified release dosage forms that re- quire a reservoir or overage or such forms as prefilled syringes where resid- ual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing pe- riod; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other ap- plicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uni- formity, disintegration times, and/or dissolution rates. (d) Pharmaceutical alternatives means drug products that contain the iden- tical therapeutic moiety, or its pre- cursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates. (e) Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingre- dient or active moiety in pharma- ceutical 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. Where there is an intentional difference in rate (e.g., in certain ex- tended release dosage forms), certain pharmaceutical equivalents or alter- natives may be considered bioequiva- lent if there is no significant difference in the extent to which the active ingre- dient or moiety from each product be- comes available at the site of drug ac- tion. This applies only if the difference in the rate at which the active ingre- dient or moiety becomes available at the site of drug action is intentional and is reflected in the proposed label- ing, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medi- cally insignificant for the drug. (f) Bioequivalence requirement means a requirement imposed by the Food and Drug Administration for in vitro and/or in vivo testing of specified drug prod- ucts which must be satisfied as a condi- tion of marketing. (g) Same drug product formulation means the formulation of the drug product submitted for approval and any formulations that have minor dif- ferences in composition or method of manufacture from the formulation sub- mitted for approval, but are similar enough to be relevant to the agency’s determination of bioequivalence. [42 FR 1634, Jan. 7, 1977, as amended at 42 FR 1648, Jan. 7, 1977; 57 FR 17997, Apr. 28, 1992; 67 FR 77672, Dec. 19, 2002; 74 FR 2861, Jan. 16, 2009] Subpart B—Procedures for Deter- mining the Bioavailability or Bioequivalence of Drug Prod- ucts SOURCE: 42 FR 1648, Jan. 7, 1977, unless oth- erwise noted. § 320.21 Requirements for submission of bioavailability and bioequiva- lence data. (a) Any person submitting a full new drug application to the Food and Drug Administration (FDA) shall include in the application either: (1) Evidence measuring the in vivo bioavailability of the drug product that is the subject of the application; or (2) Information to permit FDA to waive the submission of evidence meas- uring in vivo bioavailability. (b) Any person submitting an abbre- viated new drug application to FDA shall include in the application either: (1) Evidence demonstrating that the drug product that is the subject of the 191 § 320.21 abbreviated new drug application is bioequivalent to the reference listed drug (defined in § 314.3(b) of this chap- ter). A complete study report must be submitted for the bioequivalence study upon which the applicant relies for ap- proval. For all other bioequivalence studies conducted on the same drug product formulation, the applicant must submit either a complete or sum- mary report. If a summary report of a bioequivalence study is submitted and FDA determines that there may be bio- equivalence issues or concerns with the product, FDA may require that the ap- plicant submit a complete report of the bioequivalence study to FDA; or (2) Information to show that the drug product is bioequivalent to the ref- erence listed drug which would permit FDA to waive the submission of evi- dence demonstrating in vivo bioequiva- lence as provided in paragraph (f) of this section. (c) Any person submitting a supple- mental application to FDA shall in- clude in the supplemental application the evidence or information set forth in paragraphs (a) and (b) of this section if the supplemental application pro- poses any of the following changes: (1) A change in the manufacturing site or a change in the manufacturing 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. 21 CFR Ch. I (4–1–12 Edition) (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: (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 the in vivo bio- 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; 74 FR 2862, Jan. 16, 2009] 192 Food and Drug Administration, HHS § 320.22 § 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: (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 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 dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to 193 § 320.23 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 approval 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. (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] 21 CFR Ch. I (4–1–12 Edition) § 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 194 Food and Drug Administration, HHS § 320.24 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. (b) The following in vivo and in vitro approaches, in descending order of ac- curacy, sensitivity, and reproduc- ibility, are acceptable for determining the bioavailability or bioequivalence of a drug product. (1)(i) An in vivo test in humans in which the concentration of the active ingredient or active moiety, and, when appropriate, its active metabolite(s), in whole blood, plasma, serum, or other appropriate biological fluid is meas- ured as a function of time. This ap- proach is particularly applicable to dosage forms intended to deliver the active moiety to the bloodstream for systemic distribution within the body; or (ii) An in vitro test that has been correlated with and is predictive of human in vivo bioavailability data; or (2) An in vivo test in humans in which the urinary excretion of the ac- tive moiety, and, when appropriate, its active metabolite(s), are measured as a function of time. The intervals at which measurements are taken should ordinarily be as short as possible so that the measure of the rate of elimi- nation is as accurate as possible. De- pending on the nature of the drug prod- uct, this approach may be applicable to the category of dosage forms described in paragraph (b)(1)(i) of this section. This method is not appropriate where urinary excretion is not a significant mechanism of elimination. (3) An in vivo test in humans in which an appropriate acute pharma- cological effect of the active moiety, and, when appropriate, its active me- tabolite(s), are measured as a function of time if such effect can be measured with sufficient accuracy, sensitivity, and reproducibility. This approach is applicable to the category of dosage forms described in paragraph (b)(1)(i) of this section only when appropriate methods are not available for measure- ment of the concentration of the moi- ety, and, when appropriate, its active metabolite(s), in biological fluids or ex- cretory products but a method is avail- able for the measurement of an appro- priate acute pharmacological effect. This approach may be particularly ap- plicable to dosage forms that are not intended to deliver the active moiety to the bloodstream for systemic dis- tribution. (4) Well-controlled clinical trials that establish the safety and effectiveness of the drug product, for purposes of measuring bioavailability, or appro- priately designed comparative clinical trials, for purposes of demonstrating bioequivalence. This approach is the least accurate, sensitive, and reproduc- ible of the general approaches for measuring bioavailability or dem- onstrating bioequivalence. For dosage forms intended to deliver the active moiety to the bloodstream for systemic distribution, this approach may be con- sidered acceptable only when analyt- ical methods cannot be developed to permit use of one of the approaches 195 § 320.25 outlined in paragraphs (b)(1)(i) and (b)(2) of this section, when the ap- proaches described in paragraphs (b)(1)(ii), (b)(1)(iii), and (b)(3) of this section are not available. This ap- proach may also be considered suffi- ciently accurate for measuring bio- availability or demonstrating bio- equivalence of dosage forms intended to deliver the active moiety locally, e.g., topical preparations for the skin, eye, and mucous membranes; oral dos- age forms not intended to be absorbed, e.g., an antacid or radiopaque medium; and bronchodilators administered by inhalation if the onset and duration of pharmacological activity are defined. (5) A currently available in vitro test acceptable to FDA (usually a dissolu- tion rate test) that ensures human in vivo bioavailability. (6) Any other approach deemed ade- quate by FDA to measure bio- availability or establish bioequiva- lence. (c) FDA may, notwithstanding prior requirements for measuring bio- availability or establishing bioequiva- lence, require in vivo testing in hu- mans of a product at any time if the agency has evidence that the product: (1) May not produce therapeutic ef- fects comparable to a pharmaceutical equivalent or alternative with which it is intended to be used interchangeably; (2) May not be bioequivalent to a pharmaceutical equivalent or alter- native with which it is intended to be used interchangeably; or (3) Has greater than anticipated po- tential toxicity related to pharmaco- kinetic or other characteristics. [57 FR 17999, Apr. 28, 1992; 57 FR 29354, July 1, 1992, as amended at 67 FR 77673, Dec. 19, 2002] § 320.25 Guidelines for the conduct of an in vivo bioavailability study. (a) Guiding principles. (1) The basic principle in an in vivo bioavailability study is that no unnecessary human re- search should be done. (2) An in vivo bioavailability study is generally done in a normal adult popu- lation under standardized conditions. In some situations, an in vivo bio- availability study in humans may pref- erably and more properly be done in suitable patients. Critically ill patients 21 CFR Ch. I (4–1–12 Edition) shall not be included in an in vivo bio- availability study unless the attending physician determines that there is a potential benefit to the patient. (b) Basic design. The basic design of an in vivo bioavailability study is de- termined by the following: (1) The scientific questions to be an- swered. (2) The nature of the reference mate- rial and the dosage form to be tested. (3) The availability of analytical methods. (4) Benefit-risk considerations in re- gard to testing in humans. (c) Comparison to a reference material. In vivo bioavailability testing of a drug product shall be in comparison to an appropriate reference material unless some other approach is more appro- priate for valid scientific reasons. (d) Previously unmarketed active drug ingredients or therapeutic moieties. (1) An in vivo bioavailability study involving a drug product containing an active drug ingredient or therapeutic moiety that has not been approved for mar- keting can be used to measure the fol- lowing pharmacokinetic data: (i) The bioavailability of the formu- lation proposed for marketing; and (ii) The essential pharmacokinetic characteristics of the active drug in- gredient or therapeutic moiety, such as the rate of absorption, the extent of ab- sorption, the half-life of the thera- peutic moiety in vivo, and the rate of excretion and/or metabolism. Dose pro- portionality of the active drug ingre- dient or the therapeutic moiety needs to be established after single-dose ad- ministration and in certain instances after multiple-dose administration. This characterization is a necessary part of the investigation of the drug to support drug labeling. (2) The reference material in such a bioavailability study should be a solu- tion or suspension containing the same quantity of the active drug ingredient or therapeutic moiety as the formula- tion proposed for marketing. (3) The reference material should be administered by the same route as the formulation proposed for marketing unless an alternative or additional 196 Food and Drug Administration, HHS § 320.25 route is necessary to answer the sci- entific question under study. For ex- ample, in the case of an active drug in- gredient or therapeutic moiety that is poorly absorbed after oral administra- tion, it may be necessary to compare the oral dosage form proposed for mar- keting with the active drug ingredient or therapeutic moiety administered in solution both orally and intravenously. (e) Ne formulations of active drug in- gredients or therapeutic moieties approved for marketing. (1) An in vivo bio- availability study involving a drug product that is a new dosage form, or a new salt or ester of an active drug in- gredient or therapeutic moiety that has been approved for marketing can be used to: (i) Measure the bioavailability of the new formulation, new dosage form, or new salt or ester relative to an appro- priate reference material; and (ii) Define the pharmacokinetic pa- rameters of the new formulation, new dosage form, or new salt or ester to es- tablish dosage recommendation. (2) The selection of the reference ma- terial(s) in such a bioavailability study depends upon the scientific questions to be answered, the data needed to es- tablish comparability to a currently marketed drug product, and the data needed to establish dosage rec- ommendations. (3) The reference material should be taken from a current batch of a drug product that is the subject of an ap- proved new drug application and that contains the same active drug ingre- dient or therapeutic moiety, if the new formulation, new dosage form, or new salt or ester is intended to be com- parable to or to meet any comparative labeling claims made in relation to the drug product that is the subject of an approved new drug application. (f) Extended release formulations. (1) The purpose of an in vivo bio- availability study involving a drug product for which an extended release claim is made is to determine if all of the following conditions are met: (i) The drug product meets the ex- tended release claims made for it. (ii) The bioavailability profile estab- lished for the drug product rules out the occurrence of any dose dumping. (iii) The drug product’s steady-state performance is equivalent to a cur- rently marketed nonextended release or extended release drug product that contains the same active drug ingre- dient or therapeutic moiety and that is subject to an approved full new drug application. (iv) The drug product’s formulation provides consistent pharmacokinetic performance between individual dosage units. (2) The reference material(s) for such a bioavailability study shall be chosen to permit an appropriate scientific evaluation of the extended release claims made for the drug product. The reference material shall be one of the following or any combination thereof: (i) A solution or suspension of the ac- tive drug ingredient or therapeutic moiety. (ii) A currently marketed noncon- trolled release drug product containing the same active drug ingredient or therapeutic moiety and administered according to the dosage recommenda- tions in the labeling of the noncon- trolled release drug product. (iii) A currently marketed extended release drug product subject to an ap- proved full new drug application con- taining the same active drug ingre- dient or therapeutic moiety and admin- istered according to the dosage rec- ommendations in the labeling proposed for the extended release drug product. (iv) A reference material other than one set forth in paragraph (f)(2) (i), (ii) or (iii) of this section that is appro- priate for valid scientific reasons. (g) Combination drug products. (1) Gen- erally, the purpose of an in vivo bio- availability study involving a combina- tion drug product is to determine if the rate and extent of absorption of each active drug ingredient or therapeutic moiety in the combination drug prod- uct is equivalent to the rate and extent of absorption of each active drug ingre- dient or therapeutic moiety adminis- tered concurrently in separate single- ingredient preparations. (2) The reference material in such a bioavailability study should be two or more currently marketed, single-ingre- dient drug products each of which con- tains one of the active drug ingredients 197 § 320.26 or therapeutic moieties in the com- bination drug product. The Food and Drug Administration may, for valid scientific reasons, specify that the ref- erence material shall be a combination drug product that is the subject of an approved new drug application. (3) The Food and Drug Administra- tion may permit a bioavailability study involving a combination drug product to determine the rate and ex- tent of absorption of selected, but not all, active drug ingredients or thera- peutic moieties in the combination drug product. The Food and Drug Ad- ministration may permit this deter- mination if the pharmacokinetics and the interactions of the active drug in- gredients or therapeutic moieties in the combination drug product are well known and the therapeutic activity of the combination drug product is gen- erally recognized to reside in only one of the active drug ingredients or thera- peutic moieties, e.g., ampicillin in an ampicillin-probenecid combination drug product. (h) Use of a placebo as the reference material. Where appropriate or where necessary to demonstrate the sensi- tivity of the test, the reference mate- rial in a bioavailability study may be a placebo if: (1) The study measures the thera- peutic or acute pharmacological effect of the active drug ingredient or thera- peutic moiety; or (2) The study is a clinical trial to es- tablish the safety and effectiveness of the drug product. (i) Standards for test drug product and reference material. (1) Both the drug product to be tested and the reference material, if it is another drug product, shall be shown to meet all compendial or other applicable standards of iden- tity, strength, quality, and purity, in- cluding potency and, where applicable, content uniformity, disintegration times, and dissolution rates. (2) Samples of the drug product to be tested shall be manufactured using the same equipment and under the same conditions as those used for full-scale production. [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] 21 CFR Ch. I (4–1–12 Edition) § 320.26 Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study. (a) Basic principles. (1) An in vivo bio- availability or bioequivalence study should be a single-dose comparison of the drug product to be tested and the appropriate reference material con- ducted in normal adults. (2) The test product and the reference material should be administered to subjects in the fasting state, unless some other approach is more appro- priate for valid scientific reasons. (b) Study design. (1) A single-dose study should be crossover in design, unless a parallel design or other design is more appropriate for valid scientific reasons, and should provide for a drug elimination period. (2) Unless some other approach is ap- propriate for valid scientific reasons, the drug elimination period should be either: (i) At least three times the half-life of the active drug ingredient or thera- peutic moiety, or its metabolite(s), measured in the blood or urine; or (ii) At least three times the half-life of decay of the acute pharmacological effect. (c) Collection of blood samples. (1) When comparison of the test product and the reference material is to be based on blood concentration time curves, unless some other approach is more appropriate for valid scientific reasons, blood samples should be taken with sufficient frequency to permit an estimate of both: (i) The peak concentration in the blood of the active drug ingredient or therapeutic moiety, or its metabo- lite(s), measured; and (ii) The total area under the curve for a time period at least three times the half-life of the active drug ingredient or therapeutic moiety, or its metabo- lite(s), measured. (2) In a study comparing oral dosage forms, the sampling times should be identical. (3) In a study comparing an intra- venous dosage form and an oral dosage form, the sampling times should be those needed to describe both: (i) The distribution and elimination phase of the intravenous dosage form; and 198 Food and Drug Administration, HHS § 320.27 (ii) The absorption and elimination phase of the oral dosage form. (4) In a study comparing drug deliv- ery systems other than oral or intra- venous dosage forms with an appro- priate reference standard, the sampling times should be based on valid sci- entific reasons. (d) Collection of urine samples. When comparison of the test product and the reference material is to be based on cu- mulative urinary excretion-time curves, unless some other approach is more appropriate for valid scientific reasons, samples of the urine should be collected with sufficient frequency to permit an estimate of the rate and ex- tent of urinary excretion of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured. (e) Measurement of an acute pharma- cological effect. (1) When comparison of the test product and the reference ma- terial is to be based on acute pharma- cological effect-time curves, measure- ments of this effect should be made with sufficient frequency to permit a reasonable estimate of the total area under the curve for a time period at least three times the half-life of decay of the pharmacological effect, unless some other approach is more appro- priate for valid scientific reasons. (2) The use of an acute pharma- cological effect to determine bio- availability may further require dem- onstration of dose-related response. In such a case, bioavailability may be de- termined by comparison of the dose-re- sponse curves as well as the total area under the acute pharmacological ef- fect-time curves for any given dose. [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] § 320.27 Guidelines on the design of a multiple-dose in vivo bioavailability study. (a) Basic principles. (1) In selected cir- cumstances it may be necessary for the test product and the reference material to be compared after repeated adminis- tration to determine steady-state lev- els of the active drug ingredient or therapeutic moiety in the body. (2) The test product and the reference material should be administered to subjects in the fasting or nonfasting state, depending upon the conditions reflected in the proposed labeling of the test product. (3) A multiple-dose study may be re- quired to determine the bioavailability of a drug product in the following cir- cumstances: (i) There is a difference in the rate of absorption but not in the extent of ab- sorption. (ii) There is excessive variability in bioavailability from subject to subject. (iii) The concentration of the active drug ingredient or therapeutic moiety, or its metabolite(s), in the blood re- sulting from a single dose is too low for accurate determination by the analyt- ical method. (iv) The drug product is an extended release dosage form. (b) Study design. (1) A multiple-dose study should be crossover in design, unless a parallel design or other design is more appropriate for valid scientific reasons, and should provide for a drug elimination period if steady-state con- ditions are not achieved. (2) A multiple-dose study is not re- quired to be of crossover design if the study is to establish dose proportion- ality under a multiple-dose regimen or to establish the pharmacokinetic pro- file of a new drug product, a new drug delivery system, or an extended release dosage form. (3) If a drug elimination period is re- quired, unless some other approach is more appropriate for valid scientific reasons, the drug elimination period should be either: (i) At least five times the half-life of the active drug ingredient or thera- peutic moiety, or its active metabo- lite(s), measured in the blood or urine; or (ii) At least five times the half-life of decay of the acute pharmacological ef- fect. (c) Achievement of steady-state condi- tions. Whenever a multiple-dose study is conducted, unless some other ap- proach is more appropriate for valid scientific reasons, sufficient doses of the test product and reference material should be administered in accordance with the labeling to achieve steady- state conditions. (d) Collection of blood or urine samples. (1) Whenever comparison of the test product and the reference material is 199 § 320.28 to be based on blood concentration- time curves at steady state, appro- priate dosage administration and sam- pling should be carried out to docu- ment attainment of steady state. (2) Whenever comparison of the test product and the reference material is to be based on cumulative urinary ex- cretion-time curves at steady state, ap- propriate dosage administration and sampling should be carried out to docu- ment attainment of steady state. (3) A more complete characterization of the blood concentration or urinary excretion rate during the absorption and elimination phases of a single dose administered at steady-state is encour- aged to permit estimation of the total area under concentration-time curves or cumulative urinary excretion-time curves and to obtain pharmacokinetic information, e.g., half-life or blood clearance, that is essential in pre- paring adequate labeling for the drug product. (e) Steady-state parameters. (1) In cer- tain instances, e.g., in a study involv- ing a new drug entity, blood clearances at steady-state obtained in a multiple- dose study should be compared to blood clearances obtained in a single-dose study to support adequate dosage rec- ommendations. (2) In a linear system, the area under the blood concentration-time curve during a dosing interval in a multiple- dose steady-state study is directly pro- portional to the fraction of the dose ab- sorbed and is equal to the cor- responding ‘‘zero to infinity’’ area under the curve for a single-dose study. Therefore, when steady-state condi- tions are achieved, a comparison of blood concentrations during a dosing interval may be used to define the frac- tion of the active drug ingredient or therapeutic moiety absorbed. (3) Other methods based on valid sci- entific reasons should be used to deter- mine the bioavailability of a drug prod- uct having dose-dependent kinetics (non-linear system). (f) Measurement of an acute pharma- cological effect. When comparison of the test product and the reference material is to be based on acute pharma- cological effect-time curves, measure- ments of this effect should be made with sufficient frequency to dem- 21 CFR Ch. I (4–1–12 Edition) onstrate a maximum effect and a lack of significant difference between the test product and the reference mate- rial. [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] § 320.28 Correlation of bioavailability with an acute pharmacological ef- fect or clinical evidence. Correlation of in vivo bioavailability data with an acute pharmacological ef- fect or clinical evidence of safety and effectiveness may be required if needed to establish the clinical significance of a special claim, e.g., in the case of an extended release preparation. [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] § 320.29 Analytical methods for an in vivo bioavailability or bioequiva- lence study. (a) The analytical method used in an in vivo bioavailability or bioequiva- lence study to measure the concentra- tion of the active drug ingredient or therapeutic moiety, or its active me- tabolite(s), in body fluids or excretory products, or the method used to meas- ure an acute pharmacological effect shall be demonstrated to be accurate and of sufficient sensitivity to meas- ure, with appropriate precision, the ac- tual concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), achieved in the body. (b) When the analytical method is not sensitive enough to measure accu- rately the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products produced by a single dose of the test product, two or more single doses may be given together to produce higher concentra- tion if the requirements of § 320.31 are met. [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] § 320.30 Inquiries regarding bio- availability and bioequivalence re- quirements and review of protocols by the Food and Drug Administra- tion. (a) The Commissioner of Food and Drugs strongly recommends that, to 200 Food and Drug Administration, HHS § 320.31 avoid the conduct of an improper study and unnecessary human research, any person planning to conduct a bio- availability or bioequivalence study submit the proposed protocol for the study to FDA for review prior to the initiation of the study. (b) FDA may review a proposed pro- tocol for a bioavailability or bioequiva- lence study and will offer advice with respect to whether the following condi- tions are met: (1) The design of the proposed bio- availability or bioequivalence study is appropriate. (2) The reference material to be used in the bioavailability or bioequivalence study is appropriate. (3) The proposed chemical and statis- tical analytical methods are adequate. (c)(1) General inquiries relating to in vivo bioavailability requirements and methodology shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Of- fice of Clinical Pharmacology, 10903 New Hampshire Ave., Silver Spring, MD 20993–0002. (2) General inquiries relating to bio- equivalence requirements and method- ology shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Divi- sion of Bioequivalence (HFD–650), 7500 Standish Pl., Rockville, MD 20855–2773. [57 FR 18000, Apr. 28, 1992, as amended at 67 FR 77674, Dec. 19, 2002; 74 FR 13114, Mar. 26, 2009] § 320.31 Applicability of requirements regarding an ‘‘Investigational New Drug Application.’’ (a) Any person planning to conduct an in vivo bioavailability or bioequiva- lence study in humans shall submit an ‘‘Investigational New Drug Applica- tion’’ (IND) if: (1) The test product contains a new chemical entity as defined in § 314.108(a) of this chapter; or (2) The study involves a radioactively labeled drug product; or (3) The study involves a cytotoxic drug product. (b) Any person planning to conduct a bioavailability or bioequivalence study in humans using a drug product that contains an already approved, non-new chemical entity shall submit an IND if the study is one of the following: (1) A single-dose study in normal sub- jects or patients where either the max- imum single or total daily dose exceeds that specified in the labeling of the drug product that is the subject of an approved new drug application or ab- breviated new drug application. (2) A multiple-dose study in normal subjects or patients where either the single or total daily dose exceeds that specified in the labeling of the drug product that is the subject of an ap- proved new drug application or abbre- viated new drug application. (3) A multiple-dose study on an ex- tended release product on which no sin- gle-dose study has been completed. (c) The provisions of parts 50, 56, and 312 of this chapter are applicable to any bioavailability or bioequivalence study in humans conducted under an IND. (d) A bioavailability or bioequiva- lence study in humans other than one described in paragraphs (a) through (c) of this section is exempt from the re- quirements of part 312 of this chapter if the following conditions are satisfied: (1) If the study is one described under § 320.38(b) or § 320.63, the person con- ducting the study, including any con- tract research organization, must re- tain reserve samples of any test article and reference standard used in the study and release the reserve samples to FDA upon request, in accordance with, and for the period specified in, § 320.38; (2) An in vivo bioavailability or bio- equivalence study in humans must be conducted in compliance with the re- quirements for institutional review set forth in part 56 of this chapter, and in- formed consent set forth in part 50 of this chapter; and (3) The person conducting the study, including any contract research orga- nization, must notify FDA and all par- ticipating investigators of any serious adverse event, as defined in § 312.32(a), observed during the conduct of the study as soon as possible but in no case later than 15 calendar days after be- coming aware of its occurrence. Each report must be submitted on FDA Form 3500A or in an electronic format 201 § 320.32 that FDA can process, review, and ar- chive. FDA will periodically issue guid- ance on how to provide the electronic submission (e.g., method of trans- mission, media, file formats, prepara- tion and organization of files). Each re- port must bear prominent identifica- tion of its contents, i.e., ‘‘bio- availability/bioequivalence safety re- port.’’ The person conducting the study, including any contract research organization, must also notify FDA of any fatal or life-threatening adverse event from the study as soon as pos- sible but in no case later than 7 cal- endar days after becoming aware of its occurrence. Each notification under this paragraph must be submitted to the Director, Office of Generic Drugs in the Center for Drug Evaluation and Re- search at FDA. Relevant followup in- formation to a bioavailability/bio- equivalence safety report must be sub- mitted as soon as the information is available and must be identified as such, i.e., ‘‘Followup bioavailability/ bioequivalence safety report.’’ Upon re- quest from FDA, the person conducting the study, including any contract re- search organization, must submit to FDA any additional data or informa- tion that the agency deems necessary, as soon as possible, but in no case later than 15 calendar days after receiving the request. [57 FR 18000, Apr. 28, 1992, as amended at 58 FR 25927, Apr. 28, 1993; 67 FR 77674, Dec. 19, 2002; 75 FR 59963, Sept. 29, 2010] § 320.32 Procedures for establishing or amending a bioequivalence require- ment. (a) The Food and Drug Administra- tion, on its own initiative or in re- sponse to a petition by an interested person, may propose and promulgate a regulation to establish a bioequiva- lence requirement for a product not subject to section 505(j) of the act if it finds there is well-documented evi- dence that specific pharmaceutical equivalents or pharmaceutical alter- natives intended to be used inter- changeably for the same therapeutic effect: (1) Are not bioequivalent drug prod- ucts; or 21 CFR Ch. I (4–1–12 Edition) (2) May not be bioequivalent drug products based on the criteria set forth in § 320.33; or (3) May not be bioequivalent drug products because they are members of a class of drug products that have close structural similarity and similar phys- icochemical or pharmacokinetic prop- erties to other drug products in the same class that FDA finds are not bio- equivalent drug products. (b) FDA shall include in a proposed rule to establish a bioequivalence re- quirement the evidence and criteria set forth in § 320.33 that are to be consid- ered in determining whether to issue the proposal. If the rulemaking is pro- posed in response to a petition, FDA shall include in the proposal a sum- mary and analysis of the relevant in- formation that was submitted in the petition as well as other available in- formation to support the establishment of a bioequivalence requirement. (c) FDA, on its own initiative or in response to a petition by an interested person, may propose and promulgate an amendment to a bioequivalence re- quirement established under this sub- part. [57 FR 18000, Apr. 28, 1992] § 320.33 Criteria and evidence to as- sess actual or potential bioequiva- lence problems. The Commissioner of Food and Drugs shall consider the following factors, when supported by well-documented evidence, to identify specific pharma- ceutical equivalents and pharma- ceutical alternatives that are not or may not be bioequivalent drug prod- ucts. (a) Evidence from well-controlled clinical trials or controlled observa- tions in patients that such drug prod- ucts do not give comparable thera- peutic effects. (b) Evidence from well-controlled bioequivalence studies that such prod- ucts are not bioequivalent drug prod- ucts. (c) Evidence that the drug products exhibit a narrow therapeutic ratio, e.g., there is less than a 2-fold dif- ference in median lethal dose (LD50) 202 Food and Drug Administration, HHS § 320.34 and median effective dose (ED50) val- ues, or have less than a 2-fold dif- ference in the minimum toxic con- centrations and minimum effective concentrations in the blood, and safe and effective use of the drug products requires careful dosage titration and patient monitoring. (d) Competent medical determination that a lack of bioequivalence would have a serious adverse effect in the treatment or prevention of a serious disease or condition. (e) Physicochemical evidence that: (1) The active drug ingredient has a low solubility in water, e.g., less than 5 milligrams per 1 milliliter, or, if dis- solution in the stomach is critical to absorption, the volume of gastric fluids required to dissolve the recommended dose far exceeds the volume of fluids present in the stomach (taken to be 100 milliliters for adults and prorated for infants and children). (2) The dissolution rate of one or more such products is slow, e.g., less than 50 percent in 30 minutes when tested using either a general method specified in an official compendium or a paddle method at 50 revolutions per minute in 900 milliliters of distilled or deionized water at 37 C, or differs sig- nificantly from that of an appropriate reference material such as an identical drug product that is the subject of an approved full new drug application. (3) The particle size and/or surface area of the active drug ingredient is critical in determining its bio- availability. (4) Certain physical structural char- acteristics of the active drug ingre- dient, e.g., polymorphic forms, con- forms, solvates, complexes, and crystal modifications, dissolve poorly and this poor dissolution may affect absorption. (5) Such drug products have a high ratio of excipients to active ingredi- ents, e.g., greater than 5 to 1. (6) Specific inactive ingredients, e.g., hydrophilic or hydrophobic excipients and lubricants, either may be required for absorption of the active drug ingre- dient or therapeutic moiety or, alter- natively, if present, may interfere with such absorption. (f) Pharmacokinetic evidence that: (1) The active drug ingredient, thera- peutic moiety, or its precursor is ab- sorbed in large part in a particular seg- ment of the gastrointestinal tract or is absorbed from a localized site. (2) The degree of absorption of the ac- tive drug ingredient, therapeutic moi- ety, or its precursor is poor, e.g., less than 50 percent, ordinarily in compari- son to an intravenous dose, even when it is administered in pure form, e.g., in solution. (3) There is rapid metabolism of the therapeutic moiety in the intestinal wall or liver during the process of ab- sorption (first-class metabolism) so the therapeutic effect and/or toxicity of such drug product is determined by the rate as well as the degree of absorp- tion. (4) The therapeutic moiety is rapidly metabolized or excreted so that rapid dissolution and absorption are required for effectiveness. (5) The active drug ingredient or therapeutic moiety is unstable in spe- cific portions of the gastrointestinal tract and requires special coatings or formulations, e.g., buffers, enteric coatings, and film coatings, to assure adequate absorption. (6) The drug product is subject to dose dependent kinetics in or near the therapeutic range, and the rate and ex- tent of absorption are important to bioequivalence. [42 FR 1635, Jan. 7, 1977. Redesignated and amended at 57 FR 18001, Apr. 28, 1992] § 320.34 Requirements for batch test- ing and certification by the Food and Drug Administration. (a) If the Commissioner determines that individual batch testing by the Food and Drug Administration is nec- essary to assure that all batches of the same drug product meet an appropriate in vitro test, he shall include in the bioequivalence requirement a require- ment for manufacturers to submit sam- ples of each batch to the Food and Drug Administration and to withhold distribution of the batch until notified by the Food and Drug Administration that the batch may be introduced into interstate commerce. (b) The Commissioner will ordinarily terminate a requirement for a manu- facturer to submit samples for batch testing on a finding that the manufac- turer has produced four consecutive 203 § 320.35 batches that were tested by the Food and Drug Administration and found to meet the bioequivalence requirement, unless the public health requires that batch testing be extended to additional batches. [42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992] § 320.35 Requirements for in vitro test- ing of each batch. If a bioequivalence requirement specifies a currently available in vitro test or an in vitro bioequivalence standard comparing the drug product to a reference standard, the manufac- turer shall conduct the test on a sam- ple of each batch of the drug product to assure batch-to-batch uniformity. [42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992] § 320.36 Requirements for mainte- nance of records of bioequivalence testing. (a) All records of in vivo or in vitro tests conducted on any marketed batch of a drug product to assure that the product meets a bioequivalence re- quirement shall be maintained by the manufacturer for at least 2 years after the expiration date of the batch and submitted to the Food and Drug Ad- ministration on request. (b) Any person who contracts with another party to conduct a bioequiva- lence study from which the data are in- tended to be submitted to FDA as part of an application submitted under part 314 of this chapter shall obtain from the person conducting the study suffi- cient accurate financial information to allow the submission of complete and accurate financial certifications or dis- closure statements required under part 54 of this chapter and shall maintain that information and all records relat- ing to the compensation given for that study and all other financial interest information required under part 54 of this chapter for 2 years after the date of approval of the application. The per- son maintaining these records shall, upon request for any properly author- ized officer or employee of the Food and Drug Administration, at reason- able time, permit such officer or em- 21 CFR Ch. I (4–1–12 Edition) ployee to have access to and copy and verify these records. [42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992, as amended at 63 FR 5252, Feb. 2, 1998] § 320.38 Retention of bioavailability samples. (a) The applicant of an application or supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bio- availability testing was performed under contract, the contract research organization shall retain an appro- priately identified reserve sample of the drug product for which the appli- cant is seeking approval (test article) and of the reference standard used to perform an in vivo bioavailability study in accordance with and for the studies described in paragraph (b) of this section that is representative of each sample of the test article and ref- erence standard provided by the appli- cant for the testing. (b) Reserve samples shall be retained for the following test articles and ref- erence standards and for the studies de- scribed: (1) If the formulation of the test arti- cle is the same as the formulation(s) used in the clinical studies dem- onstrating substantial evidence of safe- ty and effectiveness for the test arti- cle’s claimed indications, a reserve sample of the test article used to con- duct an in vivo bioavailability study comparing the test article to a ref- erence oral solution, suspension, or in- jection. (2) If the formulation of the test arti- cle differs from the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and ef- fectiveness for the test article’s claimed indications, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to the formulation(s) (ref- erence standard) used in the clinical studies. (3) For a new formulation, new dos- age form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for mar- keting, a reserve sample of the test ar- ticle and of the reference standard used 204 Food and Drug Administration, HHS § 320.63 to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference standard) that contains the same active drug in- gredient or therapeutic moiety. (c) Each reserve sample shall consist of a sufficient quantity to permit FDA to perform five times all of the release tests required in the application or supplemental application. (d) Each reserve sample shall be ade- quately identified so that the reserve sample can be positively identified as having come from the same sample as used in the specific bioavailability study. (e) Each reserve sample shall be stored under conditions consistent with product labeling and in an area segregated from the area where testing is conducted and with access limited to authorized personnel. Each reserve sample shall be retained for a period of at least 5 years following the date on which the application or supplemental application is approved, or, if such ap- plication or supplemental application is not approved, at least 5 years fol- lowing the date of completion of the bioavailability study in which the sam- ple from which the reserve sample was obtained was used. (f) Authorized FDA personnel will or- dinarily collect reserve samples di- rectly from the applicant or contract research organization at the storage site during a preapproval inspection. If authorized FDA personnel are unable to collect samples, FDA may require the applicant or contract research or- ganization to submit the reserve sam- ples to the place identified in the agen- cy’s request. If FDA has not collected or requested delivery of a reserve sam- ple, or if FDA has not collected or re- quested delivery of any portion of a re- serve sample, the applicant or contract research organization shall retain the sample or remaining sample for the 5- year period specified in paragraph (e) of this section. (g) Upon release of the reserve sam- ples to FDA, the applicant or contract research organization shall provide a written assurance that, to the best knowledge and belief of the individual executing the assurance, the reserve samples came from the same samples as used in the specific bioavailability or bioequivalence study identified by the agency. The assurance shall be exe- cuted by an individual authorized to act for the applicant or contract re- search organization in releasing the re- serve samples to FDA. (h) A contract research organization may contract with an appropriate, independent third party to provide storage of reserve samples provided that the sponsor of the study has been notified in writing of the name and ad- dress of the facility at which the re- serve samples will be stored. (i) If a contract research organization conducting a bioavailability or bio- equivalence study that requires reserve sample retention under this section or § 320.63 goes out of business, it shall transfer its reserve samples to an ap- propriate, independent third party, and shall notify in writing the sponsor of the study of the transfer and provide the study sponsor with the name and address of the facility to which the re- serve samples have been transferred. [58 FR 25927, Apr. 28, 1993, as amended at 64 FR 402, Jan. 5, 1999] § 320.63 Retention of bioequivalence samples. The applicant of an abbreviated ap- plication or a supplemental application submitted under section 505 of the Fed- eral Food, Drug, and Cosmetic Act, or, if bioequivalence testing was per- formed under contract, the contract re- search organization shall retain re- serve samples of any test article and reference standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the ab- breviated application or supplemental application. The applicant or contract research organization shall retain the reserve samples in accordance with, and for the period specified in, § 320.38 and shall release the reserve samples to FDA upon request in accordance with § 320.38. [58 FR 25928, Apr. 28, 1993, as amended at 64 FR 402, Jan. 5, 1999] 205 Pt. 328 PART 328—OVER-THE-COUNTER DRUG PRODUCTS INTENDED FOR ORAL INGESTION THAT CONTAIN ALCOHOL Subpart A—General Provisions Sec. 328.1 Scope. 328.3 Definitions. Subpart B—Ingredients 328.10 Alcohol. Subpart C—Labeling 328.50 Principal display panel of all OTC drug products intended for oral ingestion that contain alcohol. AUTHORITY: Secs. 201, 301, 501, 502, 503, 505, 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371). SOURCE: 60 FR 13595, Mar. 13, 1995, unless otherwise noted. EDITORIAL NOTE: Nomenclature changes to part 328 appear at 69 FR 13717, Mar. 24, 2004. Subpart A—General Provisions § 328.1 Scope. Reference in this part to regulatory sections of the Code of Federal Regula- tions are to chapter I of title 21 unless otherwise noted. § 328.3 Definitions. As used in this part: (a) Alcohol means the substance known as ethanol, ethyl alcohol, or Al- cohol, USP. (b) Inactive ingredient means any com- ponent of a product other than an ac- tive ingredient as defined in § 210.3(b)(7) of this chapter. Subpart B—Ingredients § 328.10 Alcohol. (a) Any over-the-counter (OTC) drug product intended for oral ingestion shall not contain alcohol as an inactive ingredient in concentrations that ex- ceed those established in this part, un- less a specific exemption, as provided in paragraph (e) or (f) of this section, has been approved. (b) For any OTC drug product in- tended for oral ingestion and labeled for use by adults and children 12 years 21 CFR Ch. I (4–1–12 Edition) of age and over, the amount of alcohol in the product shall not exceed 10 per- cent. (c) For any OTC drug product in- tended for oral ingestion and labeled for use by children 6 to under 12 years of age, the amount of alcohol in the product shall not exceed 5 percent. (d) For any OTC drug product in- tended for oral ingestion and labeled for use by children under 6 years of age, the amount of alcohol in the prod- uct shall not exceed 0.5 percent. (e) The Food and Drug Administra- tion will grant an exemption from paragraphs (b), (c), and (d) of this sec- tion where appropriate, upon petition under the provisions of § 10.30 of this chapter. Appropriate cause, such as a specific solubility or manufacturing problem, must be adequately docu- mented in the petition. Decisions with respect to requests for exemption shall be maintained in a permanent file for public review by the Division of Dock- ets Management (HFA–305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. (f) Ipecac syrup is exempt from the provisions of paragraph (d) of this sec- tion. (g) The following drugs are tempo- rarily exempt from the provisions of paragraphs (b), (c), and (d) of this sec- tion: (1) Aromatic Cascara Fluidextract. (2) Cascara Sagrada Fluidextract. (3) Orally ingested homeopathic drug products. [60 FR 13595, Mar. 13, 1995, as amended at 61 FR 58630, Nov. 18, 1996; 68 FR 24879, May 9, 2003] Subpart C—Labeling § 328.50 Principal display panel of all OTC drug products intended for oral ingestion that contain alcohol. (a) The amount (percentage) of alco- hol present in a product shall be stated in terms of percent volume of absolute alcohol at 60 F (15.56 C) in accordance with § 201.10(d)(2) of this chapter. (b) A statement expressing the amount (percentage) of alcohol present in a product shall appear prominently and conspicuously on the ‘‘principal display panel,’’ as defined in § 201.60 of 206