Current Challenges and Future Regulatory Directions in In Vitro Dissolution

Abstract

In vitro dissolution is well established as a quality control technique to monitor the batch-to-batch quality and performance of a drug product. Dissolution is routinely used by most pharmaceutical firms to guide the development of new formulations and to monitor product quality after scale-up of batch size, and after changes in formulation, manufacturing process, equipment, and site of manufacture. The results of in vitro dissolution testing are used to demonstrate the continued equivalence of the product.

One of the biggest challenges facing the regulatory agencies and the pharmaceutical industry is to explore and validate the relationship between in vitro dissolution and in vivo bioavailability. It is important to recognize the strengths and limitations of dissolution in circumstances where it is used to make assumptions about in vivo performance.

There are several unresolved critical issues related to dissolution testing. Some of these issues are as follows:

1. 1.

In what situations does a multipoint or multimedia dissolution test better reflect in vivo bioavailability?

2.

When does a dissolution profile provide more information than a single time point dissolution test?

3.

What methodologies exist to compare different dissolution profiles? and

4.

What type of dissolution test method works best for chewable tablets, implants, and relatively insoluble drug products?

In order to best assure the bioavailability of a drug product, some of the optimal approaches are as follows. For immediate release products, critical manufacturing variables should be identified and a “mapping” approach should be used as a basis for dissolution specifications. For extended release products, the goal should be to develop an in vitro-in vivo correlation. Finally, gastrointestinal physiology and physiological factors which represent rate limiting steps in drug absorption should be considered in the development of more meaningful dissolution test methodologies. Several examples illustrating various challenges presented by dissolution data are discussed.