Dissolution Testing of Immediate Relea Solid Oral Dosage Forms
U.S. Department of Health and Human Services
Food and Drug Administration
里勾外连Center for Drug Evaluation and Rearch (CDER)
August 1997
BP 1
Dissolution Testing of Immediate Relea Solid Oral Dosage Forms
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(Internet) v/cder/guidance.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
August 1997
BP 1
Table of Contents
I.INTRODUCTION (1)
II.BACKGROUND (1)
III.BIOPHARMACEUTICS CLASSIFICATION SYSTEM (2)
IV.SETTING DISSOLUTION SPECIFICATIONS (3)
A.Approaches for Setting Dissolution Specifications for a New Chemical Entity (4)
B.Approaches for Setting Dissolution Specifications for Generic Products (5)
C.Special Cas (6)
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D.Mapping or Respon Surface Methodology (7)
E.In Vivo-In Vitro Correlations (7)
F.Validation and Verification of Specifications (8)
V.DISSOLUTION PROFILE COMPARISONS (8)
A.Model Independent Approach Using a Similarity Factor (8)
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B.Model Independent Multivariate Confidence Region Procedure (10)
C.Model Dependent Approaches (10)
VI.DISSOLUTION AND SUPAC-IR (11)
VII.BIOWAIVERS (11)
要快乐A-1 REFERENCES
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This guidance has been prepared by the Immediate Relea Expert Working Group of the Biopharmaceutics 1
Coordinating Committee in the Center for Drug Evaluation and Rearch (CDER) at the Food and Drug Administration. This guidance document reprents the Agency’s current thinking on the dissolution testing of immediate relea solid oral dosage forms. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be ud if such approach satisfies the requirements of the applicable statute,regulations, or both.GUIDANCE FOR INDUSTRY 1
Dissolution Testing of Immediate Relea
Solid Oral Dosage Forms
I.INTRODUCTION
This guidance is developed for immediate relea (IR) dosage forms and is intended to provide
(1) general recommendations for dissolution testing; (2) approaches for tting dissolution specifications related to the biopharmaceutic characteristics of the drug substance; (3) statistical methods for comparing dissolution profiles; and (4) a process to help determine when dissolution testing is sufficient to grant a waiver for an in vivo bioequivalence study. This document also provides recommendations for dissolution tests to help ensure continuous drug product quality and performance after certain postapproval manufacturing changes. Summary information on dissolution methodology, apparatus, and operating conditions for dissolution testing of IR
products is provided in summary form in Appendix A. This guidance is intended to complement the SUPAC - IR guidance for industry: Immediate Relea Solid Oral Dosage Forms: Scale-up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In
Vivo Bioequivalence Documentation , with specific reference to the generation of dissolution profiles for comparative purpos.
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II.BACKGROUND
Drug absorption from a solid dosage form after oral administration depends on the relea of the drug substance from the drug product, the dissolution or solubilization of the drug under physiological conditions, and the permeability across the gastrointestinal tract. Becau of the critical nature of the first two of the steps, in vitro dissolution may be relevant to the prediction of in vivo performance. Bad on this general consideration, in vitro dissolution tests for
immediate relea solid oral dosage forms, such as tablets and capsules, are ud to (1) asss the lot-to-lot quality of a drug product; (2) guide development of new formulations;
and (3) ensure continuing product quality and performance after certain changes, such as changes in the formulation, the manufacturing process, the site of manufacture, and the scale-up of the manufacturing process.
Current knowledge about the solubility, permeability, dissolution, and pharmacokinetics of a drug pro
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duct should be considered in defining dissolution test specifications for the drug approval process. This knowledge should also be ud to ensure continued equivalence of the product, as well as to ensure the product's sameness under certain scale-up and postapproval changes.
New drug applications (NDAs) submitted to the Food and Drug Administration (FDA) contain bioavailability data and in vitro dissolution data, that, together with chemistry, manufacturing, and controls (CMC) data, characterize the quality and performance of the drug product. In vitro dissolution data are generally obtained from batches that have been ud in pivotal clinical and/or bioavailability studies and from other human studies conducted during product development. Acceptable bioequivalence data and comparable in vitro dissolution and CMC data are required for approval of abbreviated new drug applications (ANDAs) (21 CFR 314.94). The in vitro specifications for generic products should be established bad on a dissolution profile. For new drug applications, as well as generic drug applications, the dissolution specifications should be bad on acceptable clinical, bioavailability, and/or bioequivalence batches.
Once the specifications are established in an NDA, the dissolution specifications for batch-to-batch quality assurance are published in the United States Pharmacopeia (USP) as compendial standards, which become the official specifications for all subquent IR products with the same active ingredie
nts. In general, the compendial dissolution standards are single-point dissolution tests, not profiles.
III.BIOPHARMACEUTICS CLASSIFICATION SYSTEM
Bad on drug solubility and permeability, the following Biopharmaceutics Classification System (BCS) is recommended in the literature (Amidon 1995):
Ca 1:High Solubility - High Permeability Drugs
Ca 2:Low Solubility - High Permeability Drugs
Ca 3:High Solubility - Low Permeability Drugs
Ca 4:Low Solubility - Low Permeability Drugs
This classification can be ud as a basis for tting in vitro dissolution specifications and can also provide a basis for predicting the likelihood of achieving a successful in vivo-in vitro correlation (IVIVC). The solubility of a drug is determined by dissolving the highest unit do of the drug in 250 mL of buffer adjusted between pH 1.0 and 8.0. A drug substance is considered highly soluble when t
he do/solubility volume of solution are less than or equal to 250 mL. High-permeability drugs are generally tho with an extent of absorption that is greater than 90% in the abnce of
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