CFR 2009 Title21 Vol5 Part320 BABE

Pt. 320 21 CFR Ch.
I (4–1–09 Edition)
PART 320—BIOAVAILABILITY AND that are not intended to be absorbed

BIOEQUIVALENCE REQUIREMENTS into the bloodstream, bioavailability
may be assessed by measurements in-
Subpart A—General Provisions tended to reflect the rate and extent to
which the active ingredient or active
Sec. moiety becomes available at the site of
320.1 Definitions. action.
Subpart B—Procedures for Determining the (b) Drug product means a finished dos-
Bioavailability or Bioequivalence of age form, e.g., tablet, capsule, or solu-
Drug Products tion, that contains the active drug in-
gredient, generally, but not nec-
320.21 Requirements for submission of in essarily, in association with inactive
vivo bioavailability and bioequivalence ingredients.
data.
320.22 Criteria for waiver of evidence of in (c) Pharmaceutical equivalents means
vivo bioavailability or bioequivalence. drug products in identical dosage forms
320.23 Basis for measuring in vivo bio- that contain identical amounts of the
availability or demonstrating bioequiva- identical active drug ingredient, i.e.,
lence. the same salt or ester of the same
320.24 Types of evidence to measure bio- therapeutic moiety, or, in the case of
availability or establish bioequivalence.
modified release dosage forms that re-
320.25 Guidelines for the conduct of an in
vivo bioavailability study. quire a reservoir or overage or such
320.26 Guidelines on the design of a single- forms as prefilled syringes where resid-
dose in vivo bioavailability or bioequiva- ual volume may vary, that deliver
lence study. identical amounts of the active drug
320.27 Guidelines on the design of a mul- ingredient over the identical dosing pe-
tiple-dose in vivo bioavailability study. riod; do not necessarily contain the
320.28 Correlation of bioavailability with an
same inactive ingredients; and meet
acute pharmacological effect or clinical
evidence. the identical compendial or other ap-
320.29 Analytical methods for an in vivo plicable standard of identity, strength,
bioavailability or bioequivalence study. quality, and purity, including potency
320.30 Inquiries regarding bioavailability and, where applicable, content uni-
and bioequivalence requirements and re- formity, disintegration times, and/or
view of protocols by the Food and Drug dissolution rates.
Administration.
320.31 Applicability of requirements regard-
(d) Pharmaceutical alternatives means
ing an ‘‘Investigational New Drug Appli- drug products that contain the iden-
cation.’’ tical therapeutic moiety, or its pre-
320.32 Procedures for establishing or amend- cursor, but not necessarily in the same
ing a bioequivalence requirement. amount or dosage form or as the same
320.33 Criteria and evidence to assess actual salt or ester. Each such drug product
or potential bioequivalence problems. individually meets either the identical
320.34 Requirements for batch testing and
certification by the Food and Drug Ad-
or its own respective compendial or
ministration. other applicable standard of identity,
320.35 Requirements for in vitro testing of strength, quality, and purity, including
each batch. potency and, where applicable, content
320.36 Requirements for maintenance of uniformity, disintegration times and/or
records of bioequivalence testing. dissolution rates.
320.38 Retention of bioavailability samples.
(e) Bioequivalence means the absence
320.63 Retention of bioequivalence samples.
of a significant difference in the rate
AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371. and extent to which the active ingre-
dient or active moiety in pharma-
Subpart A—General Provisions ceutical equivalents or pharmaceutical
alternatives becomes available at the
§ 320.1 Definitions. site of drug action when administered
(a) Bioavailability means the rate and at the same molar dose under similar
extent to which the active ingredient conditions in an appropriately designed
or active moiety is absorbed from a study. Where there is an intentional
drug product and becomes available at difference in rate (e.g., in certain ex-
the site of action. For drug products tended release dosage forms), certain
186
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Food and Drug Administration, HHS § 320.21
pharmaceutical equivalents or alter- (1) Evidence measuring the in vivo

natives may be considered bioequiva- bioavailability of the drug product that
lent if there is no significant difference is the subject of the application; or
in the extent to which the active ingre- (2) Information to permit FDA to
dient or moiety from each product be- waive the submission of evidence meas-
comes available at the site of drug ac- uring in vivo bioavailability.
tion. This applies only if the difference (b) Any person submitting an abbre-
in the rate at which the active ingre- viated new drug application to FDA
dient or moiety becomes available at shall include in the application either:
the site of drug action is intentional (1) Evidence demonstrating that the
and is reflected in the proposed label- drug product that is the subject of the
ing, is not essential to the attainment abbreviated new drug application is
of effective body drug concentrations bioequivalent to the reference listed
on chronic use, and is considered medi- drug (defined in § 314.3(b) of this chap-
cally insignificant for the drug. ter); or
(f) Bioequivalence requirement means a (2) Information to show that the drug
requirement imposed by the Food and product is bioequivalent to the ref-
Drug Administration for in vitro and/or erence listed drug which would permit
in vivo testing of specified drug prod- FDA to waive the submission of evi-
ucts which must be satisfied as a condi- dence demonstrating in vivo bioequiva-
tion of marketing. lence as provided in paragraph (f) of
[42 FR 1634, Jan. 7, 1977, as amended at 42 FR
this section.
1648, Jan. 7, 1977; 57 FR 17997, Apr. 28, 1992; 67 (c) Any person submitting a supple-
FR 77672, Dec. 19, 2002] mental application to FDA shall in-
clude in the supplemental application
EFFECTIVE DATE NOTE: At 74 FR 2861, Jan.
16, 2009, § 320.1 was amended by adding para-
the evidence or information set forth
graph (g), effective July 15, 2009. For the con- in paragraphs (a) and (b) of this section
venience of the user, the added text is set if the supplemental application pro-
forth as follows: poses any of the following changes:
(1) A change in the manufacturing
§ 320.1 Definitions. site or a change in the manufacturing
process, including a change in product
* * * * * formulation or dosage strength, beyond
(g) Same drug product formulation means the the variations provided for in the ap-
formulation of the drug product submitted proved application.
for approval and any formulations that have (2) A change in the labeling to pro-
minor differences in composition or method vide for a new indication for use of the
of manufacture from the formulation sub- drug product, if clinical studies are re-
mitted for approval, but are similar enough quired to support the new indication
to be relevant to the agency’s determination
for use.
of bioequivalence.
(3) A change in the labeling to pro-
vide for a new dosage regimen or for an
Subpart B—Procedures for Deter- additional dosage regimen for a special
mining the Bioavailability or patient population, e.g., infants, if clin-
Bioequivalence of Drug Prod- ical studies are required to support the
ucts new or additional dosage regimen.
(d) FDA may approve a full new drug
SOURCE: 42 FR 1648, Jan. 7, 1977, unless oth- application, or a supplemental applica-
erwise noted. tion proposing any of the changes set
forth in paragraph (c) of this section,
§ 320.21 Requirements for submission that does not contain evidence of in
of in vivo bioavailability and bio- vivo bioavailability or information to
equivalence data. permit waiver of the requirement for in
(a) Any person submitting a full new vivo bioavailability data, if all of the
drug application to the Food and Drug following conditions are met.
Administration (FDA) shall include in (1) The application is otherwise ap-
the application either: provable.
187
§ 320.22 21 CFR Ch. I (4–1–09 Edition)
(2) The application agrees to submit, tive July 15, 2009. For the convenience of the
within the time specified by FDA, ei- user, the revised text is set forth as follows:
ther: § 320.21 Requirements for submission of bio-
(i) Evidence measuring the in vivo availability and bioequivalence data.
bioavailability and demonstrating the
in vivo bioequivalence of the drug * * * * *
product that is the subject of the appli-
cation; or (b) * * *
(1) Evidence demonstrating that the drug
(ii) Information to permit FDA to product that is the subject of the abbre-
waive measurement of in vivo bio- viated new drug application is bioequivalent
availability. to the reference listed drug (defined in
(e) Evidence measuring the in vivo § 314.3(b) of this chapter). A complete study
bioavailability and demonstrating the report must be submitted for the bioequiva-
in vivo bioequivalence of a drug prod- lence study upon which the applicant relies
uct shall be obtained using one of the for approval. For all other bioequivalence
studies conducted on the same drug product
approaches for determining bio-
formulation, the applicant must submit ei-
availability set forth in § 320.24. ther a complete or summary report. If a
(f) Information to permit FDA to summary report of a bioequivalence study is
waive the submission of evidence meas- submitted and FDA determines that there
uring the in vivo bioavailability or may be bioequivalence issues or concerns
demonstrating the in vivo bioequiva- with the product, FDA may require that the
lence shall meet the criteria set forth applicant submit a complete report of the
in § 320.22. bioequivalence study to FDA; or
(g) Any person holding an approved
full or abbreviated new drug applica- * * * * *
tion shall submit to FDA a supple-
mental application containing new evi- § 320.22 Criteria for waiver of evidence
of in vivo bioavailability or bio-
dence measuring the in vivo bioequivalence.
availability or demonstrating the in
vivo bioequivalence of the drug product (a) Any person submitting a full or
that is the subject of the application if abbreviated new drug application, or a
notified by FDA that: supplemental application proposing
(1) There are data demonstrating any of the changes set forth in
that the dosage regimen in the labeling § 320.21(c), may request FDA to waive
is based on incorrect assumptions or the requirement for the submission of
facts regarding the pharmacokinetics evidence measuring the in vivo bio-
of the drug product and that following availability or demonstrating the in
this dosage regimen could potentially vivo bioequivalence of the drug product
result in subtherapeutic or toxic levels; that is the subject of the application.
or An applicant shall submit a request for
(2) There are data measuring signifi- waiver with the application. Except as
cant intra-batch and batch-to-batch provided in paragraph (f) of this sec-
variability, e.g., plus or minus 25 per- tion, FDA shall waive the requirement
cent, in the bioavailability of the drug for the submission of evidence of in
product. vivo bioavailability or bioequivalence
if the drug product meets any of the
(h) The requirements of this section
provisions of paragraphs (b), (c), (d), or
regarding the submission of evidence
(e) of this section.
measuring the in vivo bioavailability
(b) For certain drug products, the in
or demonstrating the in vivo bio-
vivo bioavailability or bioequivalence
equivalence apply only to a full or ab-
of the drug product may be self-evi-
breviated new drug application or a
dent. FDA shall waive the requirement
supplemental application for a finished
for the submission of evidence obtained
dosage formulation.
in vivo measuring the bioavailability
[57 FR 17998, Apr. 28, 1992, as amended at 67 or demonstrating the bioequivalence of
FR 77672, Dec. 19, 2002] these drug products. A drug product’s
EFFECTIVE DATE NOTE: At 74 FR 2862, Jan. in vivo bioavailability or bioequiva-
16, 2009, § 320.21 was amended by revising the lence may be considered self-evident
section heading and paragraph (b)(1), effec- based on other data in the application
188
if the product meets one of the fol- forth in § 320.33, included the drug prod-
lowing criteria: uct in the Approved Drug Products
(1) The drug product: with Therapeutic Equivalence Evalua-
(i) Is a parenteral solution intended tions List, and rated the drug product
solely for administration by injection, as having a known or potential bio-
or an ophthalmic or otic solution; and equivalence problem. A drug product so
(ii) Contains the same active and in- rated reflects a determination by FDA
active ingredients in the same con- that an in vivo bioequivalence study is
centration as a drug product that is the required.
subject of an approved full new drug (d) For certain drug products, bio-
application or abbreviated new drug availability may be measured or bio-
application. equivalence may be demonstrated by
(2) The drug product: evidence obtained in vitro in lieu of in
(i) Is administered by inhalation as a vivo data. FDA shall waive the require-
gas, e.g., a medicinal or an inhalation ment for the submission of evidence
anesthetic; and obtained in vivo measuring the bio-
(ii) Contains an active ingredient in availability or demonstrating the bio-
the same dosage form as a drug product equivalence of the drug product if the
that is the subject of an approved full drug product meets one of the fol-
new drug application or abbreviated lowing criteria:
new drug application. (1) [Reserved]
(3) The drug product: (2) The drug product is in the same
(i) Is a solution for application to the dosage form, but in a different
skin, an oral solution, elixir, syrup, strength, and is proportionally similar
tincture, a solution for aerosolization in its active and inactive ingredients to
or nebulization, a nasal solution, or another drug product for which the
similar other solubilized form; and same manufacturer has obtained ap-
(ii) Contains an active drug ingre- proval and the conditions in para-
dient in the same concentration and graphs (d)(2)(i) through (d)(2)(iii) of
dosage form as a drug product that is this section are met:
the subject of an approved full new
(i) The bioavailability of this other
drug application or abbreviated new
drug product has been measured;
drug application; and
(ii) Both drug products meet an ap-
(iii) Contains no inactive ingredient
propriate in vitro test approved by
or other change in formulation from
FDA; and
the drug product that is the subject of
the approved full new drug application (iii) The applicant submits evidence
or abbreviated new drug application showing that both drug products are
that may significantly affect absorp- proportionally similar in their active
tion of the active drug ingredient or and inactive ingredients.
active moiety for products that are (iv) Paragraph (d) of this section does
systemically absorbed, or that may sig- not apply to delayed release or ex-
nificantly affect systemic or local tended release products.
availability for products intended to (3) The drug product is, on the basis
act locally. of scientific evidence submitted in the
(c) FDA shall waive the requirement application, shown to meet an in vitro
for the submission of evidence meas- test that has been correlated with in
uring the in vivo bioavailability or vivo data.
demonstrating the in vivo bioequiva- (4) The drug product is a reformu-
lence of a solid oral dosage form (other lated product that is identical, except
than a delayed release or extended re- for a different color, flavor, or preserv-
lease dosage form) of a drug product ative that could not affect the bio-
determined to be effective for at least availability of the reformulated prod-
one indication in a Drug Efficacy uct, to another drug product for which
Study Implementation notice or which the same manufacturer has obtained
is identical, related, or similar to such approval and the following conditions
a drug product under § 310.6 of this are met:
chapter unless FDA has evaluated the (i) The bioavailability of the other
drug product under the criteria set product has been measured; and
189
§ 320.23 21 CFR Ch. I (4–1–09 Edition)
(ii) Both drug products meet an ap- use, and is considered medically insig-
propriate in vitro test approved by nificant for the drug product.
FDA. (b) Two drug products will be consid-
(e) FDA, for good cause, may waive a ered bioequivalent drug products if
requirement for the submission of evi- they are pharmaceutical equivalents or
dence of in vivo bioavailability or bio- pharmaceutical alternatives whose
equivalence if waiver is compatible rate and extent of absorption do not
with the protection of the public show a significant difference when ad-
health. For full new drug applications, ministered at the same molar dose of
FDA may defer a requirement for the the active moiety under similar experi-
submission of evidence of in vivo bio- mental conditions, either single dose or
availability if deferral is compatible multiple dose. Some pharmaceutical
with the protection of the public equivalents or pharmaceutical alter-
health. natives may be equivalent in the ex-
(f) FDA, for good cause, may require tent of their absorption but not in
evidence of in vivo bioavailability or their rate of absorption and yet may be
bioequivalence for any drug product if considered bioequivalent because such
the agency determines that any dif- differences in the rate of absorption are
ference between the drug product and a intentional and are reflected in the la-
listed drug may affect the bio- beling, are not essential to the attain-
availability or bioequivalence of the ment of effective body drug concentra-
drug product. tions on chronic use, and are consid-
[57 FR 17998, Apr. 28, 1992, as amended at 67 ered medically insignificant for the
FR 77673, Dec. 19, 2002] particular drug product studied.
§ 320.23 Basis for measuring in vivo [57 FR 17999, Apr. 28, 1992, as amended at 67
bioavailability or demonstrating FR 77673, Dec. 19, 2002]
bioequivalence.
(a)(1) The in vivo bioavailability of a § 320.24 Types of evidence to measure
bioavailability or establish bio-
drug product is measured if the prod- equivalence.
uct’s rate and extent of absorption, as
determined by comparison of measured (a) Bioavailability may be measured
parameters, e.g., concentration of the or bioequivalence may be dem-
active drug ingredient in the blood, onstrated by several in vivo and in
urinary excretion rates, or pharma- vitro methods. FDA may require in
cological effects, do not indicate a sig- vivo or in vitro testing, or both, to
nificant difference from the reference measure the bioavailability of a drug
material’s rate and extent of absorp- product or establish the bioequivalence
tion. For drug products that are not in- of specific drug products. Information
tended to be absorbed into the blood- on bioequivalence requirements for
stream, bioavailability may be as- specific products is included in the cur-
sessed by measurements intended to re- rent edition of FDA’s publication ‘‘Ap-
flect the rate and extent to which the proved Drug Products with Thera-
active ingredient or active moiety be- peutic Equivalence Evaluations’’ and
comes available at the site of action. any current supplement to the publica-
(2) Statistical techniques used shall tion. The selection of the method used
be of sufficient sensitivity to detect to meet an in vivo or in vitro testing
differences in rate and extent of ab- requirement depends upon the purpose
sorption that are not attributable to of the study, the analytical methods
subject variability. available, and the nature of the drug
(3) A drug product that differs from product. Applicants shall conduct bio-
the reference material in its rate of ab- availability and bioequivalence testing
sorption, but not in its extent of ab- using the most accurate, sensitive, and
sorption, may be considered to be bio- reproducible approach available among
available if the difference in the rate of those set forth in paragraph (b) of this
absorption is intentional, is appro- section. The method used must be ca-
priately reflected in the labeling, is not pable of measuring bioavailability or
essential to the attainment of effective establishing bioequivalence, as appro-
body drug concentrations on chronic priate, for the product being tested.
190
(b) The following in vivo and in vitro to the bloodstream for systemic dis-
approaches, in descending order of ac- tribution.
curacy, sensitivity, and reproduc- (4) Well-controlled clinical trials that
ibility, are acceptable for determining establish the safety and effectiveness
the bioavailability or bioequivalence of of the drug product, for purposes of
a drug product. measuring bioavailability, or appro-
(1)(i) An in vivo test in humans in priately designed comparative clinical
which the concentration of the active trials, for purposes of demonstrating
ingredient or active moiety, and, when bioequivalence. This approach is the
appropriate, its active metabolite(s), in least accurate, sensitive, and reproduc-
whole blood, plasma, serum, or other ible of the general approaches for
appropriate biological fluid is meas- measuring bioavailability or dem-
ured as a function of time. This ap- onstrating bioequivalence. For dosage
proach is particularly applicable to forms intended to deliver the active
dosage forms intended to deliver the moiety to the bloodstream for systemic
active moiety to the bloodstream for distribution, this approach may be con-
systemic distribution within the body; sidered acceptable only when analyt-
or ical methods cannot be developed to
(ii) An in vitro test that has been permit use of one of the approaches
correlated with and is predictive of outlined in paragraphs (b)(1)(i) and
human in vivo bioavailability data; or (b)(2) of this section, when the ap-
(2) An in vivo test in humans in proaches described in paragraphs
which the urinary excretion of the ac- (b)(1)(ii), (b)(1)(iii), and (b)(3) of this
tive moiety, and, when appropriate, its section are not available. This ap-
active metabolite(s), are measured as a proach may also be considered suffi-
function of time. The intervals at ciently accurate for measuring bio-
which measurements are taken should availability or demonstrating bio-
ordinarily be as short as possible so equivalence of dosage forms intended
that the measure of the rate of elimi- to deliver the active moiety locally,
nation is as accurate as possible. De- e.g., topical preparations for the skin,
pending on the nature of the drug prod- eye, and mucous membranes; oral dos-
uct, this approach may be applicable to age forms not intended to be absorbed,
the category of dosage forms described e.g., an antacid or radiopaque medium;
in paragraph (b)(1)(i) of this section. and bronchodilators administered by
This method is not appropriate where inhalation if the onset and duration of
urinary excretion is not a significant pharmacological activity are defined.
mechanism of elimination. (5) A currently available in vitro test
(3) An in vivo test in humans in acceptable to FDA (usually a dissolu-
which an appropriate acute pharma- tion rate test) that ensures human in
cological effect of the active moiety, vivo bioavailability.
and, when appropriate, its active me- (6) Any other approach deemed ade-
tabolite(s), are measured as a function quate by FDA to measure bio-
of time if such effect can be measured availability or establish bioequiva-
with sufficient accuracy, sensitivity, lence.
and reproducibility. This approach is (c) FDA may, notwithstanding prior
applicable to the category of dosage requirements for measuring bio-
forms described in paragraph (b)(1)(i) of availability or establishing bioequiva-
this section only when appropriate lence, require in vivo testing in hu-
methods are not available for measure- mans of a product at any time if the
ment of the concentration of the moi- agency has evidence that the product:
ety, and, when appropriate, its active (1) May not produce therapeutic ef-
metabolite(s), in biological fluids or ex- fects comparable to a pharmaceutical
cretory products but a method is avail- equivalent or alternative with which it
able for the measurement of an appro- is intended to be used interchangeably;
priate acute pharmacological effect. (2) May not be bioequivalent to a
This approach may be particularly ap- pharmaceutical equivalent or alter-
plicable to dosage forms that are not native with which it is intended to be
intended to deliver the active moiety used interchangeably; or
191
§ 320.25 21 CFR Ch. I (4–1–09 Edition)
(3) Has greater than anticipated po- dient or the therapeutic moiety needs
tential toxicity related to pharmaco- to be established after single-dose ad-
kinetic or other characteristics. ministration and in certain instances
[57 FR 17999, Apr. 28, 1992; 57 FR 29354, July
after multiple-dose administration.
1, 1992, as amended at 67 FR 77673, Dec. 19, This characterization is a necessary
2002] part of the investigation of the drug to
support drug labeling.
§ 320.25 Guidelines for the conduct of (2) The reference material in such a
an in vivo bioavailability study. bioavailability study should be a solu-
(a) Guiding principles. (1) The basic tion or suspension containing the same
principle in an in vivo bioavailability quantity of the active drug ingredient
study is that no unnecessary human re- or therapeutic moiety as the formula-
search should be done. tion proposed for marketing.
(2) An in vivo bioavailability study is (3) The reference material should be
generally done in a normal adult popu- administered by the same route as the
lation under standardized conditions. formulation proposed for marketing
In some situations, an in vivo bio- unless an alternative or additional
availability study in humans may pref- route is necessary to answer the sci-
erably and more properly be done in entific question under study. For ex-
suitable patients. Critically ill patients ample, in the case of an active drug in-
shall not be included in an in vivo bio- gredient or therapeutic moiety that is
availability study unless the attending poorly absorbed after oral administra-
physician determines that there is a tion, it may be necessary to compare
potential benefit to the patient. the oral dosage form proposed for mar-
(b) Basic design. The basic design of keting with the active drug ingredient
an in vivo bioavailability study is de- or therapeutic moiety administered in
termined by the following: solution both orally and intravenously.
(1) The scientific questions to be an- (e) New formulations of active drug in-
swered. gredients or therapeutic moieties approved
(2) The nature of the reference mate- for marketing. (1) An in vivo bio-
rial and the dosage form to be tested. availability study involving a drug
(3) The availability of analytical product that is a new dosage form, or a
methods. new salt or ester of an active drug in-
(4) Benefit-risk considerations in re- gredient or therapeutic moiety that
gard to testing in humans. has been approved for marketing can
(c) Comparison to a reference material. be used to:
In vivo bioavailability testing of a drug (i) Measure the bioavailability of the
product shall be in comparison to an new formulation, new dosage form, or
appropriate reference material unless new salt or ester relative to an appro-
some other approach is more appropriate reference material; and
priate for valid scientific reasons. (ii) Define the pharmacokinetic pa-
(d) Previously unmarketed active drug rameters of the new formulation, new
ingredients or therapeutic moieties. (1) An dosage form, or new salt or ester to es-
in vivo bioavailability study involving tablish dosage recommendation.
a drug product containing an active (2) The selection of the reference ma-
drug ingredient or therapeutic moiety terial(s) in such a bioavailability study
that has not been approved for mar- depends upon the scientific questions
keting can be used to measure the fol- to be answered, the data needed to es-
lowing pharmacokinetic data: tablish comparability to a currently
(i) The bioavailability of the formu- marketed drug product, and the data
lation proposed for marketing; and needed to establish dosage rec-
(ii) The essential pharmacokinetic ommendations.
characteristics of the active drug in- (3) The reference material should be
gredient or therapeutic moiety, such as taken from a current batch of a drug
the rate of absorption, the extent of ab- product that is the subject of an ap-
sorption, the half-life of the thera- proved new drug application and that
peutic moiety in vivo, and the rate of contains the same active drug ingre-
excretion and/or metabolism. Dose pro- dient or therapeutic moiety, if the new
portionality of the active drug ingre- formulation, new dosage form, or new
192
salt or ester is intended to be com- availability study involving a combina-

parable to or to meet any comparative tion drug product is to determine if the
labeling claims made in relation to the rate and extent of absorption of each
drug product that is the subject of an active drug ingredient or therapeutic
approved new drug application. moiety in the combination drug prod-
(f) Extended release formulations. (1) uct is equivalent to the rate and extent
The purpose of an in vivo bio- of absorption of each active drug ingre-
availability study involving a drug dient or therapeutic moiety adminis-
product for which an extended release tered concurrently in separate single-
claim is made is to determine if all of ingredient preparations.
the following conditions are met: (2) The reference material in such a
(i) The drug product meets the ex- bioavailability study should be two or
tended release claims made for it. more currently marketed, single-ingre-
(ii) The bioavailability profile estab- dient drug products each of which con-
lished for the drug product rules out tains one of the active drug ingredients
the occurrence of any dose dumping. or therapeutic moieties in the com-
(iii) The drug product’s steady-state bination drug product. The Food and
performance is equivalent to a cur- Drug Administration may, for valid
rently marketed nonextended release scientific reasons, specify that the ref-
or extended release drug product that erence material shall be a combination
contains the same active drug ingre- drug product that is the subject of an
dient or therapeutic moiety and that is approved new drug application.
subject to an approved full new drug (3) The Food and Drug Administra-
application. tion may permit a bioavailability
(iv) The drug product’s formulation study involving a combination drug
provides consistent pharmacokinetic product to determine the rate and ex-
performance between individual dosage tent of absorption of selected, but not
units. all, active drug ingredients or thera-
(2) The reference material(s) for such peutic moieties in the combination
a bioavailability study shall be chosen drug product. The Food and Drug Ad-
to permit an appropriate scientific ministration may permit this deter-
evaluation of the extended release mination if the pharmacokinetics and
claims made for the drug product. The the interactions of the active drug in-
reference material shall be one of the gredients or therapeutic moieties in
following or any combination thereof: the combination drug product are well
(i) A solution or suspension of the ac- known and the therapeutic activity of
tive drug ingredient or therapeutic the combination drug product is gen-
moiety. erally recognized to reside in only one
(ii) A currently marketed noncon- of the active drug ingredients or thera-
trolled release drug product containing peutic moieties, e.g., ampicillin in an
the same active drug ingredient or ampicillin-probenecid combination
therapeutic moiety and administered drug product.
according to the dosage recommenda- (h) Use of a placebo as the reference
tions in the labeling of the noncon- material. Where appropriate or where
trolled release drug product. necessary to demonstrate the sensi-
(iii) A currently marketed extended tivity of the test, the reference mate-
release drug product subject to an ap- rial in a bioavailability study may be a
proved full new drug application con- placebo if:
taining the same active drug ingre- (1) The study measures the thera-
dient or therapeutic moiety and admin- peutic or acute pharmacological effect
istered according to the dosage rec- of the active drug ingredient or thera-
ommendations in the labeling proposed peutic moiety; or
for the extended release drug product. (2) The study is a clinical trial to es-
(iv) A reference material other than tablish the safety and effectiveness of
one set forth in paragraph (f)(2) (i), (ii) the drug product.
or (iii) of this section that is appro- (i) Standards for test drug product and
priate for valid scientific reasons. reference material. (1) Both the drug
(g) Combination drug products. (1) Gen- product to be tested and the reference
erally, the purpose of an in vivo bio- material, if it is another drug product,
193
§ 320.26 21 CFR Ch. I (4–1–09 Edition)
shall be shown to meet all compendial (ii) The total area under the curve for
or other applicable standards of iden- a time period at least three times the
tity, strength, quality, and purity, in- half-life of the active drug ingredient
cluding potency and, where applicable, or therapeutic moiety, or its metabo-
content uniformity, disintegration lite(s), measured.
times, and dissolution rates. (2) In a study comparing oral dosage
(2) Samples of the drug product to be forms, the sampling times should be
tested shall be manufactured using the identical.
same equipment and under the same (3) In a study comparing an intra-
conditions as those used for full-scale venous dosage form and an oral dosage
production. form, the sampling times should be
those needed to describe both:
[42 FR 1648, Jan. 7, 1977, as amended at 67 FR (i) The distribution and elimination
77674, Dec. 19, 2002] phase of the intravenous dosage form;
and
§ 320.26 Guidelines on the design of a
single-dose in vivo bioavailability (ii) The absorption and elimination
or bioequivalence study. phase of the oral dosage form.
(4) In a study comparing drug deliv-
(a) Basic principles. (1) An in vivo bio- ery systems other than oral or intra-
availability or bioequivalence study venous dosage forms with an appro-
should be a single-dose comparison of priate reference standard, the sampling
the drug product to be tested and the times should be based on valid sci-
appropriate reference material con- entific reasons.
ducted in normal adults. (d) Collection of urine samples. When
(2) The test product and the reference comparison of the test product and the
material should be administered to reference material is to be based on cu-
subjects in the fasting state, unless mulative urinary excretion-time
some other approach is more appro- curves, unless some other approach is
priate for valid scientific reasons. more appropriate for valid scientific
(b) Study design. (1) A single-dose reasons, samples of the urine should be
study should be crossover in design, collected with sufficient frequency to
unless a parallel design or other design permit an estimate of the rate and ex-
is more appropriate for valid scientific tent of urinary excretion of the active
reasons, and should provide for a drug drug ingredient or therapeutic moiety,
elimination period. or its metabolite(s), measured.
(2) Unless some other approach is ap- (e) Measurement of an acute pharma-
propriate for valid scientific reasons, cological effect. (1) When comparison of
the drug elimination period should be the test product and the reference ma-
either: terial is to be based on acute pharma-
(i) At least three times the half-life cological effect-time curves, measure-
of the active drug ingredient or thera- ments of this effect should be made
peutic moiety, or its metabolite(s), with sufficient frequency to permit a
measured in the blood or urine; or reasonable estimate of the total area
(ii) At least three times the half-life under the curve for a time period at
of decay of the acute pharmacological least three times the half-life of decay
effect. of the pharmacological effect, unless
(c) Collection of blood samples. (1) some other approach is more appro-
When comparison of the test product priate for valid scientific reasons.
and the reference material is to be (2) The use of an acute pharma-
based on blood concentration time cological effect to determine bio-
curves, unless some other approach is availability may further require dem-
more appropriate for valid scientific onstration of dose-related response. In
reasons, blood samples should be taken such a case, bioavailability may be de-
with sufficient frequency to permit an termined by comparison of the dose-re-
estimate of both: sponse curves as well as the total area
(i) The peak concentration in the under the acute pharmacological ef-
blood of the active drug ingredient or fect-time curves for any given dose.
therapeutic moiety, or its metabo- [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
lite(s), measured; and 77674, Dec. 19, 2002]
194
§ 320.27 Guidelines on the design of a (ii) At least five times the half-life of
multiple-dose in vivo bioavailability decay of the acute pharmacological ef-
study. fect.
(a) Basic principles. (1) In selected cir- (c) Achievement of steady-state condi-
cumstances it may be necessary for the tions. Whenever a multiple-dose study
test product and the reference material is conducted, unless some other ap-
to be compared after repeated adminis- proach is more appropriate for valid
tration to determine steady-state lev- scientific reasons, sufficient doses of
els of the active drug ingredient or the test product and reference material
therapeutic moiety in the body. should be administered in accordance
(2) The test product and the reference with the labeling to achieve steady-
material should be administered to state conditions.
subjects in the fasting or nonfasting (d) Collection of blood or urine samples.
state, depending upon the conditions (1) Whenever comparison of the test
reflected in the proposed labeling of product and the reference material is
the test product. to be based on blood concentration-
time curves at steady state, appro-
(3) A multiple-dose study may be re-
priate dosage administration and sam-
quired to determine the bioavailability
pling should be carried out to docu-
of a drug product in the following cir-
ment attainment of steady state.
cumstances:
(2) Whenever comparison of the test
(i) There is a difference in the rate of
product and the reference material is
absorption but not in the extent of ab-
to be based on cumulative urinary ex-
sorption.
cretion-time curves at steady state, ap-
(ii) There is excessive variability in propriate dosage administration and
bioavailability from subject to subject. sampling should be carried out to docu-
(iii) The concentration of the active ment attainment of steady state.
drug ingredient or therapeutic moiety, (3) A more complete characterization
or its metabolite(s), in the blood re- of the blood concentration or urinary
sulting from a single dose is too low for excretion rate during the absorption
accurate determination by the analyt- and elimination phases of a single dose
ical method. administered at steady-state is encour-
(iv) The drug product is an extended aged to permit estimation of the total
release dosage form. area under concentration-time curves
(b) Study design. (1) A multiple-dose or cumulative urinary excretion-time
study should be crossover in design, curves and to obtain pharmacokinetic
unless a parallel design or other design information, e.g., half-life or blood
is more appropriate for valid scientific clearance, that is essential in pre-
reasons, and should provide for a drug paring adequate labeling for the drug
elimination period if steady-state con- product.
ditions are not achieved. (e) Steady-state parameters. (1) In cer-
(2) A multiple-dose study is not retain instances, e.g., in a study involv-
quired to be of crossover design if the ing a new drug entity, blood clearances
study is to establish dose proportion- at steady-state obtained in a multiple-
ality under a multiple-dose regimen or dose study should be compared to blood
to establish the pharmacokinetic pro- clearances obtained in a single-dose
file of a new drug product, a new drug study to support adequate dosage rec-
delivery system, or an extended release ommendations.
dosage form. (2) In a linear system, the area under
(3) If a drug elimination period is re- the blood concentration-time curve
quired, unless some other approach is during a dosing interval in a multiple-
more appropriate for valid scientific dose steady-state study is directly pro-
reasons, the drug elimination period portional to the fraction of the dose ab-
should be either: sorbed and is equal to the cor-
(i) At least five times the half-life of responding ‘‘zero to infinity’’ area
the active drug ingredient or thera- under the curve for a single-dose study.
peutic moiety, or its active metabo- Therefore, when steady-state condi-
lite(s), measured in the blood or urine; tions are achieved, a comparison of
or blood concentrations during a dosing
195
§ 320.28 21 CFR Ch. I (4–1–09 Edition)
interval may be used to define the frac- fluids or excretory products produced
tion of the active drug ingredient or by a single dose of the test product,
therapeutic moiety absorbed. two or more single doses may be given
(3) Other methods based on valid sci- together to produce higher concentra-
entific reasons should be used to deter- tion if the requirements of § 320.31 are
mine the bioavailability of a drug prod- met.
uct having dose-dependent kinetics
(non-linear system). [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
(f) Measurement of an acute pharma- 77674, Dec. 19, 2002]
cological effect. When comparison of the
test product and the reference material § 320.30 Inquiries regarding bio-
availability and bioequivalence re-
is to be based on acute pharma-
quirements and review of protocols
cological effect-time curves, measure- by the Food and Drug Administra-
ments of this effect should be made tion.
with sufficient frequency to dem-
onstrate a maximum effect and a lack (a) The Commissioner of Food and
of significant difference between the Drugs strongly recommends that, to
test product and the reference mate- avoid the conduct of an improper study
rial. and unnecessary human research, any
person planning to conduct a bio-
[42 FR 1648, Jan. 7, 1977, as amended at 67 FR
77674, Dec. 19, 2002] availability or bioequivalence study
submit the proposed protocol for the
§ 320.28 Correlation of bioavailability study to FDA for review prior to the
with an acute pharmacological ef- initiation of the study.
fect or clinical evidence. (b) FDA may review a proposed pro-
Correlation of in vivo bioavailability tocol for a bioavailability or bioequiva-
data with an acute pharmacological ef- lence study and will offer advice with
fect or clinical evidence of safety and respect to whether the following condi-
effectiveness may be required if needed tions are met:
to establish the clinical significance of (1) The design of the proposed bio-
a special claim, e.g., in the case of an availability or bioequivalence study is
extended release preparation. appropriate.
[42 FR 1648, Jan. 7, 1977, as amended at 67 FR (2) The reference material to be used
77674, Dec. 19, 2002] in the bioavailability or bioequivalence
study is appropriate.
§ 320.29 Analytical methods for an in
vivo bioavailability or bioequiva- (3) The proposed chemical and statis-
lence study. tical analytical methods are adequate.
(a) The analytical method used in an (c)(1) General inquiries relating to in
in vivo bioavailability or bioequiva- vivo bioavailability requirements and
lence study to measure the concentra- methodology shall be submitted to the
tion of the active drug ingredient or Food and Drug Administration, Center
therapeutic moiety, or its active me- for Drug Evaluation and Research, Of-
tabolite(s), in body fluids or excretory fice of Clinical Pharmacology, 10903
products, or the method used to meas- New Hampshire Ave., Silver Spring,
ure an acute pharmacological effect MD 20993–0002.
shall be demonstrated to be accurate (2) General inquiries relating to bio-
and of sufficient sensitivity to meas- equivalence requirements and method-
ure, with appropriate precision, the ac- ology shall be submitted to the Food
tual concentration of the active drug and Drug Administration, Center for
ingredient or therapeutic moiety, or its Drug Evaluation and Research, Divi-
active metabolite(s), achieved in the sion of Bioequivalence (HFD–650), 7500
body. Standish Pl., Rockville, MD 20855–2773.
(b) When the analytical method is
not sensitive enough to measure accu- [57 FR 18000, Apr. 28, 1992, as amended at 67
rately the concentration of the active FR 77674, Dec. 19, 2002; 74 FR 13114, Mar. 26,
drug ingredient or therapeutic moiety, 2009]
or its active metabolite(s), in body
196
§ 320.31 Applicability of requirements (2) An in vivo bioavailability or bio-

regarding an ‘‘Investigational New equivalence study in humans shall be
Drug Application.’’ conducted in compliance with the re-
(a) Any person planning to conduct quirements for institutional review set
an in vivo bioavailability or bioequiva- forth in part 56 of this chapter, and in-
lence study in humans shall submit an formed consent set forth in part 50 of
‘‘Investigational New Drug Applica- this chapter.
tion’’ (IND) if:
(1) The test product contains a new [57 FR 18000, Apr. 28, 1992, as amended at 58
FR 25927, Apr. 28, 1993; 67 FR 77674, Dec. 19,
chemical entity as defined in
2002]
§ 314.108(a) of this chapter; or
(2) The study involves a radioactively § 320.32 Procedures for establishing or
labeled drug product; or amending a bioequivalence require-
(3) The study involves a cytotoxic ment.
drug product.
(b) Any person planning to conduct a (a) The Food and Drug Administra-
bioavailability or bioequivalence study tion, on its own initiative or in re-
in humans using a drug product that sponse to a petition by an interested
contains an already approved, non-new person, may propose and promulgate a
chemical entity shall submit an IND if regulation to establish a bioequiva-
the study is one of the following: lence requirement for a product not
(1) A single-dose study in normal sub- subject to section 505(j) of the act if it
jects or patients where either the max- finds there is well-documented evi-
imum single or total daily dose exceeds dence that specific pharmaceutical
that specified in the labeling of the equivalents or pharmaceutical alter-
drug product that is the subject of an natives intended to be used inter-
approved new drug application or ab- changeably for the same therapeutic
breviated new drug application. effect:
(2) A multiple-dose study in normal (1) Are not bioequivalent drug prod-
subjects or patients where either the ucts; or
single or total daily dose exceeds that
(2) May not be bioequivalent drug
specified in the labeling of the drug
product that is the subject of an ap- products based on the criteria set forth
proved new drug application or abbre- in § 320.33; or
viated new drug application. (3) May not be bioequivalent drug
(3) A multiple-dose study on an ex- products because they are members of
tended release product on which no sin- a class of drug products that have close
gle-dose study has been completed. structural similarity and similar phys-
(c) The provisions of parts 50, 56, and icochemical or pharmacokinetic prop-
312 of this chapter are applicable to erties to other drug products in the
any bioavailability or bioequivalence same class that FDA finds are not bio-
study in humans conducted under an equivalent drug products.
IND. (b) FDA shall include in a proposed
(d) A bioavailability or bioequiva- rule to establish a bioequivalence re-
lence study in humans other than one quirement the evidence and criteria set
described in paragraphs (a) through (c) forth in § 320.33 that are to be consid-
of this section is exempt from the re- ered in determining whether to issue
quirements of part 312 of this chapter if the proposal. If the rulemaking is pro-
the following conditions are satisfied: posed in response to a petition, FDA
(1) If the study is one described under
shall include in the proposal a sum-
§ 320.38(b) or § 320.63, the person con-
mary and analysis of the relevant in-
ducting the study, including any con-
formation that was submitted in the
tract research organization, shall re-
tain reserve samples of any test article petition as well as other available in-
and reference standard used in the formation to support the establishment
study and release the reserve samples of a bioequivalence requirement.
to FDA upon request, in accordance (c) FDA, on its own initiative or in
with, and for the period specified in, response to a petition by an interested
§ 320.38; and person, may propose and promulgate
197
§ 320.33 21 CFR Ch. I (4–1–09 Edition)
an amendment to a bioequivalence re- minute in 900 milliliters of distilled or

quirement established under this sub- deionized water at 37° C, or differs sig-
part. nificantly from that of an appropriate
[57 FR 18000, Apr. 28, 1992] reference material such as an identical
drug product that is the subject of an
§ 320.33 Criteria and evidence to as- approved full new drug application.
sess actual or potential bioequiva- (3) The particle size and/or surface
lence problems. area of the active drug ingredient is
The Commissioner of Food and Drugs critical in determining its bio-
shall consider the following factors, availability.
when supported by well-documented (4) Certain physical structural char-
evidence, to identify specific pharma- acteristics of the active drug ingre-
ceutical equivalents and pharma- dient, e.g., polymorphic forms, con-
ceutical alternatives that are not or forms, solvates, complexes, and crystal
may not be bioequivalent drug prod- modifications, dissolve poorly and this
ucts. poor dissolution may affect absorption.
(a) Evidence from well-controlled (5) Such drug products have a high
clinical trials or controlled observa- ratio of excipients to active ingredi-
tions in patients that such drug prod- ents, e.g., greater than 5 to 1.
ucts do not give comparable thera- (6) Specific inactive ingredients, e.g.,
peutic effects. hydrophilic or hydrophobic excipients
(b) Evidence from well-controlled and lubricants, either may be required
bioequivalence studies that such prod- for absorption of the active drug ingre-
ucts are not bioequivalent drug prod- dient or therapeutic moiety or, alter-
ucts. natively, if present, may interfere with
(c) Evidence that the drug products such absorption.
exhibit a narrow therapeutic ratio,
(f) Pharmacokinetic evidence that:
e.g., there is less than a 2-fold dif-
(1) The active drug ingredient, thera-
ference in median lethal dose (LD50)
peutic moiety, or its precursor is ab-
and median effective dose (ED50) val-
sorbed in large part in a particular seg-
ues, or have less than a 2-fold dif-
ment of the gastrointestinal tract or is
ference in the minimum toxic con-
absorbed from a localized site.
centrations and minimum effective
concentrations in the blood, and safe (2) The degree of absorption of the ac-
and effective use of the drug products tive drug ingredient, therapeutic moi-
requires careful dosage titration and ety, or its precursor is poor, e.g., less
patient monitoring. than 50 percent, ordinarily in compari-
(d) Competent medical determination son to an intravenous dose, even when
that a lack of bioequivalence would it is administered in pure form, e.g., in
have a serious adverse effect in the solution.
treatment or prevention of a serious (3) There is rapid metabolism of the
disease or condition. therapeutic moiety in the intestinal
(e) Physicochemical evidence that: wall or liver during the process of ab-
(1) The active drug ingredient has a sorption (first-class metabolism) so the
low solubility in water, e.g., less than 5 therapeutic effect and/or toxicity of
milligrams per 1 milliliter, or, if dis- such drug product is determined by the
solution in the stomach is critical to rate as well as the degree of absorp-
absorption, the volume of gastric fluids tion.
required to dissolve the recommended (4) The therapeutic moiety is rapidly
dose far exceeds the volume of fluids metabolized or excreted so that rapid
present in the stomach (taken to be 100 dissolution and absorption are required
milliliters for adults and prorated for for effectiveness.
infants and children). (5) The active drug ingredient or
(2) The dissolution rate of one or therapeutic moiety is unstable in spe-
more such products is slow, e.g., less cific portions of the gastrointestinal
than 50 percent in 30 minutes when tract and requires special coatings or
tested using either a general method formulations, e.g., buffers, enteric
specified in an official compendium or coatings, and film coatings, to assure
a paddle method at 50 revolutions per adequate absorption.
198
(6) The drug product is subject to product meets a bioequivalence re-

dose dependent kinetics in or near the quirement shall be maintained by the
therapeutic range, and the rate and ex- manufacturer for at least 2 years after
tent of absorption are important to the expiration date of the batch and
bioequivalence. submitted to the Food and Drug Ad-
ministration on request.
[42 FR 1635, Jan. 7, 1977. Redesignated and
amended at 57 FR 18001, Apr. 28, 1992]
(b) Any person who contracts with
another party to conduct a bioequiva-
§ 320.34 Requirements for batch test- lence study from which the data are in-
ing and certification by the Food tended to be submitted to FDA as part
and Drug Administration. of an application submitted under part
(a) If the Commissioner determines 314 of this chapter shall obtain from
that individual batch testing by the the person conducting the study suffi-
Food and Drug Administration is nec- cient accurate financial information to
essary to assure that all batches of the allow the submission of complete and
same drug product meet an appropriate accurate financial certifications or dis-
in vitro test, he shall include in the closure statements required under part
bioequivalence requirement a require- 54 of this chapter and shall maintain
ment for manufacturers to submit sam- that information and all records relat-
ples of each batch to the Food and ing to the compensation given for that
Drug Administration and to withhold study and all other financial interest
distribution of the batch until notified information required under part 54 of
by the Food and Drug Administration this chapter for 2 years after the date
that the batch may be introduced into of approval of the application. The per-
interstate commerce. son maintaining these records shall,
upon request for any properly author-
(b) The Commissioner will ordinarily
ized officer or employee of the Food
terminate a requirement for a manu-
and Drug Administration, at reason-
facturer to submit samples for batch
able time, permit such officer or em-
testing on a finding that the manufac-
ployee to have access to and copy and
turer has produced four consecutive
verify these records.
batches that were tested by the Food
and Drug Administration and found to [42 FR 1635, Jan. 7, 1977. Redesignated at 57
meet the bioequivalence requirement, FR 18001, Apr. 28, 1992, as amended at 63 FR
unless the public health requires that 5252, Feb. 2, 1998]
batch testing be extended to additional
§ 320.38 Retention of bioavailability
batches. samples.
[42 FR 1635, Jan. 7, 1977. Redesignated at 57 (a) The applicant of an application or
FR 18001, Apr. 28, 1992] supplemental application submitted
under section 505 of the Federal Food,
§ 320.35 Requirements for in vitro test-
ing of each batch. Drug, and Cosmetic Act, or, if bio-
availability testing was performed
If a bioequivalence requirement under contract, the contract research
specifies a currently available in vitro organization shall retain an appro-
test or an in vitro bioequivalence priately identified reserve sample of
standard comparing the drug product the drug product for which the appli-
to a reference standard, the manufac- cant is seeking approval (test article)
turer shall conduct the test on a sam- and of the reference standard used to
ple of each batch of the drug product to perform an in vivo bioavailability
assure batch-to-batch uniformity. study in accordance with and for the
[42 FR 1635, Jan. 7, 1977. Redesignated at 57 studies described in paragraph (b) of
FR 18001, Apr. 28, 1992] this section that is representative of
each sample of the test article and ref-
§ 320.36 Requirements for mainte- erence standard provided by the appli-
nance of records of bioequivalence cant for the testing.
testing. (b) Reserve samples shall be retained
(a) All records of in vivo or in vitro for the following test articles and ref-
tests conducted on any marketed batch erence standards and for the studies de-
of a drug product to assure that the scribed:
199
§ 320.38 21 CFR Ch. I (4–1–09 Edition)
(1) If the formulation of the test arti- ple from which the reserve sample was
cle is the same as the formulation(s) obtained was used.
used in the clinical studies dem- (f) Authorized FDA personnel will or-
onstrating substantial evidence of safe- dinarily collect reserve samples di-
ty and effectiveness for the test arti- rectly from the applicant or contract
cle’s claimed indications, a reserve research organization at the storage
sample of the test article used to con- site during a preapproval inspection. If
duct an in vivo bioavailability study authorized FDA personnel are unable
comparing the test article to a ref- to collect samples, FDA may require
erence oral solution, suspension, or in- the applicant or contract research or-
jection. ganization to submit the reserve sam-
(2) If the formulation of the test arti- ples to the place identified in the agen-
cle differs from the formulation(s) used cy’s request. If FDA has not collected
in the clinical studies demonstrating or requested delivery of a reserve sam-
substantial evidence of safety and ef-
ple, or if FDA has not collected or re-
fectiveness for the test article’s
quested delivery of any portion of a re-
claimed indications, a reserve sample
serve sample, the applicant or contract
of the test article and of the reference
research organization shall retain the
standard used to conduct an in vivo
sample or remaining sample for the 5-
bioequivalence study comparing the
test article to the formulation(s) (ref- year period specified in paragraph (e)
erence standard) used in the clinical of this section.
studies. (g) Upon release of the reserve sam-
(3) For a new formulation, new dos- ples to FDA, the applicant or contract
age form, or a new salt or ester of an research organization shall provide a
active drug ingredient or therapeutic written assurance that, to the best
moiety that has been approved for mar- knowledge and belief of the individual
keting, a reserve sample of the test ar- executing the assurance, the reserve
ticle and of the reference standard used samples came from the same samples
to conduct an in vivo bioequivalence as used in the specific bioavailability
study comparing the test article to a or bioequivalence study identified by
marketed product (reference standard) the agency. The assurance shall be exe-
that contains the same active drug in- cuted by an individual authorized to
gredient or therapeutic moiety. act for the applicant or contract re-
(c) Each reserve sample shall consist search organization in releasing the re-
of a sufficient quantity to permit FDA serve samples to FDA.
to perform five times all of the release (h) A contract research organization
tests required in the application or may contract with an appropriate,
supplemental application. independent third party to provide
(d) Each reserve sample shall be ade- storage of reserve samples provided
quately identified so that the reserve that the sponsor of the study has been
sample can be positively identified as notified in writing of the name and ad-
having come from the same sample as dress of the facility at which the re-
used in the specific bioavailability serve samples will be stored.
study. (i) If a contract research organization
(e) Each reserve sample shall be conducting a bioavailability or bio-
stored under conditions consistent equivalence study that requires reserve
with product labeling and in an area sample retention under this section or
segregated from the area where testing § 320.63 goes out of business, it shall
is conducted and with access limited to transfer its reserve samples to an ap-
authorized personnel. Each reserve propriate, independent third party, and
sample shall be retained for a period of
shall notify in writing the sponsor of
at least 5 years following the date on
the study of the transfer and provide
which the application or supplemental
the study sponsor with the name and
application is approved, or, if such ap-
address of the facility to which the re-
plication or supplemental application
serve samples have been transferred.
is not approved, at least 5 years fol-
lowing the date of completion of the [58 FR 25927, Apr. 28, 1993, as amended at 64
bioavailability study in which the sam- FR 402, Jan. 5, 1999]
200
§ 320.63 Retention of bioequivalence § 328.3 Definitions.

samples.
As used in this part:
The applicant of an abbreviated ap- (a) Alcohol means the substance
plication or a supplemental application known as ethanol, ethyl alcohol, or Al-
submitted under section 505 of the Fed- cohol, USP.
eral Food, Drug, and Cosmetic Act, or, (b) Inactive ingredient means any com-
if bioequivalence testing was per- ponent of a product other than an ac-
formed under contract, the contract re- tive ingredient as defined in § 210.3(b)(7)
search organization shall retain re- of this chapter.
serve samples of any test article and
reference standard used in conducting
an in vivo or in vitro bioequivalence Subpart B—Ingredients
study required for approval of the ab-
breviated application or supplemental § 328.10 Alcohol.
application. The applicant or contract (a) Any over-the-counter (OTC) drug
research organization shall retain the product intended for oral ingestion
reserve samples in accordance with, shall not contain alcohol as an inactive
and for the period specified in, § 320.38 ingredient in concentrations that ex-
and shall release the reserve samples to ceed those established in this part, un-
FDA upon request in accordance with less a specific exemption, as provided
§ 320.38. in paragraph (e) or (f) of this section,
[58 FR 25928, Apr. 28, 1993, as amended at 64 has been approved.
FR 402, Jan. 5, 1999] (b) For any OTC drug product in-
tended for oral ingestion and labeled
PART 328—OVER-THE-COUNTER for use by adults and children 12 years
of age and over, the amount of alcohol
DRUG PRODUCTS INTENDED FOR in the product shall not exceed 10 per-
ORAL INGESTION THAT CONTAIN cent.
ALCOHOL (c) For any OTC drug product in-
Subpart A—General Provisions for use by children 6 to under 12 years
Sec. of age, the amount of alcohol in the
328.1 Scope. product shall not exceed 5 percent.
328.3 Definitions. (d) For any OTC drug product in-
Subpart B—Ingredients for use by children under 6 years of
328.10 Alcohol. age, the amount of alcohol in the prod-
uct shall not exceed 0.5 percent.
Subpart C—Labeling (e) The Food and Drug Administra-
tion will grant an exemption from
328.50 Principal display panel of all OTC
drug products intended for oral ingestion
paragraphs (b), (c), and (d) of this sec-
that contain alcohol. tion where appropriate, upon petition
under the provisions of § 10.30 of this
AUTHORITY: Secs. 201, 301, 501, 502, 503, 505, chapter. Appropriate cause, such as a
701 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371).
specific solubility or manufacturing
problem, must be adequately docu-
SOURCE: 60 FR 13595, Mar. 13, 1995, unless mented in the petition. Decisions with
otherwise noted. respect to requests for exemption shall
EDITORIAL NOTE: Nomenclature changes to be maintained in a permanent file for
part 328 appear at 69 FR 13717, Mar. 24, 2004. public review by the Division of Dock-
ets Management (HFA–305), Food and
Subpart A—General Provisions Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852.
§ 328.1 Scope. (f) Ipecac syrup is exempt from the
Reference in this part to regulatory provisions of paragraph (d) of this sec-
sections of the Code of Federal Regula- tion.
tions are to chapter I of title 21 unless (g) The following drugs are tempo-
otherwise noted. rarily exempt from the provisions of
201

CFR 2009 Title21 Vol5 Part320 BABE

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CFR 2009 Title21 Vol5 Part320 BABE

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Pt. 320 21 CFR Ch.

PART 320—BIOAVAILABILITY AND that are not intended to be absorbed

pharmaceutical equivalents or alter- (1) Evidence measuring the in vivo

salt or ester is intended to be com- availability study involving a combina-

§ 320.31 Applicability of requirements (2) An in vivo bioavailability or bio-

an amendment to a bioequivalence re- minute in 900 milliliters of distilled or

(6) The drug product is subject to product meets a bioequivalence re-

§ 320.63 Retention of bioequivalence § 328.3 Definitions.

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