Description
This guidance provides recommendations to sponsors and applicants2 submitting bioavailability (BA) information for drug products in investigational new drug applications (INDs), new drug applications (NDAs), and NDA supplements. This guidance contains recommendations on how to meet the BA requirements set forth in 21 CFR part 320 as they apply to dosage forms intended for oral administration. These dosage forms include tablets, capsules, solutions, suspensions, conventional (e.g., immediate-release (IR) drug products) and modified-release (MR) (e.g., extended-release (ER), delayed-release (DR)) drug products. The guidance is also applicable to non-orally administered drug products when it is appropriate to rely on systemic exposure measures to determine the BA of a drug (e.g., transdermal delivery systems and certain vaginal, rectal, and nasal drug products). The guidance provides recommendations on conducting BA studies during the investigational period for a drug intended to be submitted for approval in an NDA and bioequivalence (BE) studies during the postapproval period for certain changes to drugproducts with an approved NDA.
Scope & Applicability
Product Classes
10conventional (e.g., immediate-release (IR) drug products); new IR drug products developed via the pathway under section 505(b)(1)
acceptable criteria for demonstrating BE might need to be narrowed
Two or more active ingredients formulated as a single drug product; BA studies for the fixed combination product should include the measurement of systemic concentrations
in vivo BA studies for higher strengths might not be necessary
use of in vitro data could be acceptable for MR drug products
Capsules, Tablets, and Suspensions
considered a single formulation even though they consist of two separate layers
reference product for comparison with modified release forms
dosage forms that release the active ingredient at a time later than immediately after administration
dosage forms designed to extend or prolong the release of the active ingredient
Stakeholders
2Entity responsible for submitting applications under section 524B
Entity submitting development data and knowledge; Entity performing the work process for change
Regulatory Context
Attributes
10Generally a more sensitive method to assess differences between formulations.; BA or BE study should be conducted under fasted conditions; BA study should be conducted under fasted conditions
effect of food on the BA should be evaluated using a high-fat and high-calorie meal
geometric mean ratios and their corresponding 90 percent CIs
value greater than or equal to 50 indicates a sufficiently similar dissolution profile; f2 values assessing the similarity between the dissolution profiles
active and inactive ingredients in identical proportions between different strengths
Used if tolerability issues or serious adverse events are anticipated under fasted conditions.; BA for the test drug product should be evaluated under fed conditions
appropriate to rely on systemic exposure measures
Cmax may be more informative for safety
AUC or Cmin may correlate with efficacy
time to reach peak exposure
Identified Hazards
Hazards
1potential cause of product failure in sustained-release dosage forms
Related CFR Sections (12)
- 21CFR320.27§ 320.27 Guidelines on the design of a multiple-dose in vivo bioavailability study.
(a) Basic principles.Read full regulation →
- 21CFR320.38§ 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 bioavailability testing was performed under contract, the contract research organization shall retain an appropriately identified reserve sample of the drugRead full regulation →
- 21CFR320.63§ 320.63 Retention of bioequivalence samples.
The applicant of an abbreviated application or a supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioequivalence testing was performed under contract, the contract research organization shall retain reserve samples of any test article and referRead full regulation →
- 21CFR320.25§ 320.25 Guidelines for the conduct of an in vivo bioavailability study.
(a) Guiding principles.Read full regulation →
- 21CFR314.70§ 314.70 Supplements and other changes to an approved NDA.
(a) Changes to an approved NDA.Read full regulation →
- 21CFR320.24§ 320.24 Types of evidence to measure bioavailability or establish bioequivalence.
(a) Bioavailability may be measured or bioequivalence may be demonstrated 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 bioequivRead full regulation →
- 21CFR320.22§ 320.22 Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.
(a) Any person submitting a full or abbreviated new drug application, or a supplemental application proposing any of the changes set forth in § 320.21(c) , may request FDA to waive the requirement for the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioeqRead full regulation →
- 21CFR314.50§ 314.50 Content and format of an NDA.
NDAs and supplements to approved NDAs are required to be submitted in the form and contain the information, as appropriate for the particular submission, required under this section. Three copies of the NDA are required: An archival copy, a review copy, and a field copy. An NDA for a new chemical enRead full regulation →
- 21CFR314.3§ 314.3 Definitions.
(a) The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act apply to those terms when used in this part and part 320 of this chapter .Read full regulation →
- 21CFR320.26§ 320.26 Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.
(a) Basic principles.Read full regulation →
- 21CFR320.21§ 320.21 Requirements for submission of bioavailability and bioequivalence data.
(a) Any person submitting a full new drug application to the Food and Drug Administration (FDA) shall include in the application either:Read full regulation →
- 21CFR320.29§ 320.29 Analytical methods for an in vivo bioavailability or bioequivalence study.
(a) The analytical method used in an in vivo bioavailability or bioequivalence study to measure the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products, or the method used to measure an acute pharmacological effect shalRead full regulation →
See Also (8)
- Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use: Guidance for Industry (Status: Final)
- Final In Vivo Bioavailability-Bioequivalence Studies- Analytical (Status: Final)
- Topical Dermatologic Corticosteroids: in Vivo Bioequivalence (Status: Final)
- Bioresearch Monitoring Technical Conformance Guide (Status: Final)
- Data Integrity for In Vivo Bioavailability and Bioequivalence Studies (Status: Draft)
- Fixed-Combinations and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment or Prevention of Human Immunodeficiency Virus-One Under the President’s Emergency Plan for Acquired Immunodeficiency Syndrome Relief (Status: Draft)
- CVM GFI #171 - Demonstrating Bioequivalence for Soluble Powder Oral Dosage Form Products and Type A Medicated Articles Containing Active Pharmaceutical Ingredients Considered to Be Soluble in Aqueous Media (Status: Final)
- Statistical Approaches to Establishing Bioequivalence (Status: Draft)