For IR dosage forms containing BCS II compounds, in vivo BE studies may not be needed to demonstrate bioequivalence once IVIVC is established because, in most cases, in vivo drug release may be the rate-limiting step in drug absorption. IVIVC is expected if in vitro dissolution is similar to the in vivo dissolution rate, unless the product dose is very high (3).
For a drug compound with pH-dependent solubility, it is still possible to demonstrate that an in vivo BE study is not necessary by performing in vitro dissolution at a higher pH (5–6.8) that is more physiologically relevant (17, 18). For example, in vivo studies may not be needed for a weak acid API that has low solubility in acid but high solubility and rapid dissolution in
a pH 6.8 medium, if drug product risk for patients is deemed acceptable. The effect of excipients on solubility and subsequent
in vivo drug absorption should be taken into consideration.
For IR dosage forms containing BCS IV compounds, in vivo BE studies are generally expected to demonstrate bioequivalence for changes to the formulation and manufacturing process.
But in some cases, bioequivalence between lower and higher strengths of a product can be demonstrated by in vitro dissolution testing instead of in vivo BE studies if the strengths are dose-proportional and if the approach is supported by linear pharmacokinetics (16, 19).
Table I summarizes the application of dissolution or surrogate tests to demonstrate when in vivo BE studies may not be needed for IR dosage forms based on BCS and QbD principles. With the increased application of BCS and
QbD approaches throughout industry, it is hoped that more scientific understanding will lead to harmonized principles regarding
formulation and manufacturing process changes that do not require in vivo BE studies and are recognized by both industry and regulatory agencies.
Table 1: Application of dissolution and surrogate tests for immediate-release dosage forms based on BCS and QbD.
Utility of dissolution as a performance test for quality control
For a drug product developed using conventional approaches, dissolution testing is an important quality control tool for monitoring
batch-to-batch consistency and for discriminating the impact of formulation or process changes on product performance. A quality
control dissolution method for a product is specific to its dosage form. The hydrodynamics and medium can be selected to ensure
batch-to-batch product consistency and be sufficiently discriminating to changes in product quality.
On the other hand, for a drug product developed using QbD approaches, dissolution may not be needed or can be replaced by
related techniques such as disintegration or another surrogate test (e.g., API particle size by near-infrared spectroscopy).
Both dissolution and surrogate test data may be collected for batches produced from process development, clinical-supply manufacture,
intentionally produced aberrant tablets (e.g., made with over-lubricated granulation or excessive compression forces), and
stability programs to justify the use of surrogate tests in lieu of dissolution for product release. Nevertheless, unless a suitable surrogate test exists, it is generally recognized that
dissolution is an effective test to monitor collective changes in a product on stability that are attributed to temperature
and relative humidity.
For a modified-release dosage form, quality-control dissolution method can be the same as or different from the dissolution
method used during IVIVC development. If the method is different, in most cases, a quality-control method takes much less
time than the development method. A correlation between the quality-control method and the development method should be established
to justify the use of a quality-control method (e.g., comparable sensitivity toward critical process parameters).