In Vitro Studies , Dissolution Studies to Determine Bioequivalence and Bioavailability of a Drug
Under certain circumstances, product quality BA and BE can be documented using in vitro approaches (21 CFR 320.24(b)(5) and 21 CFR 320.22(d)(3)). For highly soluble, highly permeable, rapidly dissolving, and orally administered drug products, documentation of BE using an in vitro approach (dissolution studies) is appropriate based on the biopharmaceutics classification system.(see Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System ) This approach may also be suitable under some circumstances in assessing BE during the IND period, for NDA and ANDA submissions, and in the presence of certain postapproval changes to approved NDAs and ANDAs. In addition, in vitro approaches to documenting BE for nonbioproblem drugs approved before 1962 remain appropriate (21 CFR 320.33).

Dissolution testing is also used to assess batch-to-batch quality, where the dissolution tests, with defined procedures and acceptance criteria, are used to allow batch release. FDA recommend that dissolution testing is also used to
(1) provide process control and quality assurance, and
(2) assess whether further BE studies relative to minor postapproval changes be conducted, where dissolution can function as a signal of bioinequivalence. In vitro dissolution characterization is encouraged for all product formulations investigated (including prototype formulations),
particularly if in vivo absorption characteristics are being defined for the different product formulations. Such efforts may enable the establishment of an in vitro-in vivo correlation.

When an in vitro-in vivo correlation or association is available (21 CFR 320.24(b)(1)(ii)), the in vitro test can serve not only as a quality control specification for the manufacturing process, but also as an indicator of how the product will perform in vivo.  recommendations on the development of dissolution methodology, setting specifications, and the regulatory applications of dissolution testing:

(1) Dissolution Testing of Immediate Release Solid Oral Dosage Forms; and
(2) Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations.

FDA recommend that the following information generally be included in the dissolution method development report for solid oral dosage forms:
For an NDA:
* The pH solubility profile of the drug substance
* Dissolution profiles generated at different agitation speeds (e.g., 100 to 150 revolutions per minute (rpm) for U.S. Pharmacopeia (USP) Apparatus I (basket), or 50 to 100 rpm for USP Apparatus II (paddle))

* Dissolution profiles generated on all strengths in at least three dissolution media (e.g.,pH 1.2, 4.5, and 6.8 buffer). Water can be used as an additional medium. If the drug being considered is poorly soluble, appropriate concentrations of surfactants are recommended.
It is recommended that the sponsor select the agitation speed and medium that provide adequate discriminating ability, taking into account all the available in vitro and in vivo data.
For ANDAs:
* For immediate-release drug products, FDA recommend that the appropriate USP method be submitted. If there is no USP method available, FDA recommend that the FDA method for the reference listed drug be used. If the USP and/or FDA methods are not available, FDA recommend that the dissolution method development report described above be submitted.
* For modified-release products, dissolution profiles using the appropriate USP method (if available) can be submitted. If there is no USP method available, FDA recommend that the FDA method for the reference listed drug be used. In addition, FDA recommend that profiles using at least three other dissolution media (e.g., pH 1.2, 4.5, and 6.8 buffer) and water be submitted.
It is recommended that dissolution data from three batches for both NDAs and ANDAs be used to set dissolution specifications for modified-release dosage forms, including extendedrelease dosage forms.

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