From the process knowledge generated through the development that includes, among other things, potential relationships between
dissolution and other quality attributes, a design space can be established, whereby drug-product performance can be ensured
through the proper control of relevant material attributes and process parameters (13). For example, drug product performance
can depend on variables such as API particle distribution, excipients, and tablet hardness. For certain changes to formulation
and processes, in vivo BE studies may not be needed. When IVIVC or IVIVR can be established, dissolution methods or related techniques (e.g., disintegration)
and acceptance criteria are established to provide continued assurance for product clinical performance.
For IR dosage forms containing BCS I or III compounds, disintegration, single-point dissolution, and other rationalized surrogate
tests are adequate to ensure drug-product performance because most process changes should have little or no impact on the
in vivo drug release. Dissolution may have little value for rapidly dissolving IR dosage forms and should be replaced by disintegration
for performance testing. Changes to the formulation and process within the design space should not impact the drug product's
in vivo performance and thus do not require in vivo BE studies. PAT or other surrogate tests may be adequate to ensure product performance or enable real-time release of the
For IR dosage forms containing BCS II or IV compounds, in vitro dissolution could be limited by API solubilization or properties of the formulation. Dissolution profiles in various pH media
should be evaluated during development. Once a correlation is established between dissolution and API physical properties
that affect solubilization such as particle-size distribution and polymorphism, controlling the physical properties or using
a disintegration test may be sufficient to ensure product performance. Although it is not realistic to clinically test all
the tablets produced during the establishment of the design space, for IR dosage forms containing BCS II compounds, IVIVC
or IVIVR could be established to link the in vitro dissolution and in vivo performance. Within the design space, changes to formulations and processes do not require in vivo BE studies if supported by IVIVC or may not require in vivo BE studies if supported by IVIVR.
With lack of IVIVC, certain changes to formulations and processes within or beyond a design space still may not require in vivo BE studies if the products demonstrate similarity of dissolution profiles in physiologically relevant pH media. For IR dosage
forms containing BCS IV compounds, changes to formulations and processes within the design space may not require in vivo BE studies because establishment of IVIVC is not expected. Changes beyond the design space, however, are more likely to require
in vivo BE studies and should be decided on a case-by-case basis.
For modified-release solid oral dosage forms, dissolution testing should be performed appropriately to establish IVIVC or
IVIVR. The established correlation or relationship should be incorporated into the product's design space. It is anticipated
that QbD principles will play an important role in modifed-release dosage forms because dissolution will likely be a critical
quality attribute for drug-product performance.
Application of dissolution in demonstrating bioequivalence
During Phase III development, formulation changes may involve API morphology, particle-size distribution, excipients, film-coating,
dose adjustment, and tablet shape. These changes may have an impact on in vivo drug release and in vitro dissolution of the dosage form, potentially impacting the bioavailability of the API. A dissolution test could be acceptable
in lieu of an in vivo BE study depending on the BCS characteristics of the drug compound and depending on changes that affect the formulation and
For IR dosage forms containing BCS I or III compounds, in vivo BE studies may not be needed for changes in formulation, manufacturing site, or scale when the product exhibits rapid dissolution
(i.e., not less than 85% dissolved within 30 min for BCS I compounds [10,14] or not less than 85% within 15 min for BCS III
compounds ), provided that the drug substance does not have a narrow therapeutic index and excipients do not significantly
affect drug absorption. Dissolution tests are typically performed in various dissolution media with a pH range of 1–6.8, similar
to physiological fluids in the human GI tract (15, 16).