With the challenges associated with IVIVC, especially for IR dosage forms, IVIVR should be increasingly leveraged to support
design-space development. IVIVR can be manifested in two general cases: (1) in vivo performance can be tuned by in vitro dissolution; and (2) dissolution guarantees in vivo performance. In the former case, dissolution has been used to guide formulation and process development and is linked to
the product and process design space. The latter case may be more valuable in the future for those drug-development paradigms
in which conventional IVIVC and IVIVR are not likely or are impossible to achieve. To ensure that dissolution guarantees in vivo performance, one needs to consider the dissolution method design and drug absorption rate (ADME—absorption, distribution,
metabolism, and excretion). The dissolution at least should be mapped over the entire range of physiological pH. The method
conditions should mimic the in vivo environment where the drug is likely to be absorbed (11).
Understanding dissolution and its mechanism should be integral to any method development. BCS provides a scientific foundation
for dissolution and its role in the drug-absorption process (12). The dissolution process generally consists of disintegration
and drug-particle solubilization. Dissolution is a general test and reflects on properties of the formulation and API (see
Figure 3). In most cases for oral IR or controlled-release dosage forms, however, the rate of dissolution is controlled by
specific formulation or API properties, and these properties can be monitored by specific tests and controlled either in the
raw materials or during the manufacturing process using process analytical technology (PAT) tools. From a QbD perspective,
the dissolution test adds limited value in these cases and should be eliminated from product-release testing.
Figure 3. (FIGURES ARE COURTESY OF THE AUTHORS.)
Value of dissolution testing: Phase III clinical development
The primary objectives of Phase III development are to provide clinical supplies, generate formulation and manufacturing process
knowledge for regulatory submission and approval, and help prepare for a successful, commercial product launch. To achieve
these goals, it is necessary to optimize and finalize robust API and drug-product manufacturing processes, initiate long-term
stability studies, and conduct pivotal bioequivalence/bioavailability (BE/BA) studies bridging Phase II and III clinical supplies
and commercial product. Ideally, in vitro drug-product performance tests such as dissolution or related techniques (e.g., disintegration) should serve as a surrogate
for in vivo bioavailability and as a predictor of the product's clinical performance. Development of a dissolution method may warrant
significant and exhaustive evaluation of dissolution profiles in multiple apparatus and media. When process is controlled
within the design space, a dissolution test may not be needed for a finished-product specification or may be replaced by other
surrogate tests based on the understanding of the dissolution mechanism in Phase II clinical development. Improvements to
the dissolution test method, including replacement with an appropriate surrogate test, may occur after product commercialization.
Discussion in this section focuses on where dissolution testing can add value to Phase III development. These areas include
the use of dissolution testing for:
- Process development and optimization
- Demonstration of bioequivalence between formulations
- Performance testing of quality control.
Process development and optimization
During Phase III development, QbD approaches can be used to optimize and finalize the drug-product formulation and manufacturing
processes. Compared with conventional development approaches, QbD is primarily devoted to increasing the mechanistic understanding
of a formulation and its manufacturing processes, their relationship to product quality attributes, and ultimately, their
impact on the safety and efficacy of the product. When a QbD approach is selected, robust product formulation and manufacturing
processes should be designed to achieve desired product performance and also relate to desired clinical performance. When
the product performance can be appropriately characterized by in vitro dissolution (or a surrogate) test, the dissolution test can be a powerful tool. In the latter case, the dissolution test
may use multivariate analysis to evaluate parameters that can affect drug-product performance, thus assisting in the identification
of critical quality attributes and critical process parameters.