Dissolution testing IVIVC correlation

In vitro dissolution testing is an important tool in the development of solid drug products, as well as in batch quality controls. The aim of the test is to see that the drug is appropriately dissolved in the gastrointestinal tract and made available for absorption. It is therefore highly desirable that the in vitro tests provide data that correlate to the in vivo situation. However, attainment of IVIVC has often failed-and the concept of IVIVC has been challenged. 

A report from a 1990 ASCPT/DIA/APS/FDA-sponsored workshop entitled 7n vitro/In vivo Testing and Correlation for Oral Controlled/Modified Release Dosage Forms (1990) concluded that, while the science and technology may not always permit meaningful IVIVC, the development of an IVIVC was an important objective on a product-by-product basis. Procedures for development, evaluation, and application of an IVIVC were described. Validation of dissolution specifications by a bioequivalence study involving two batches of product with dissolution profiles at the upper and lower dissolution specifications was suggested. 

In the presence of an IVIVC, the FDA stated that If an in vitro in vivo correlation is established, the dissolution test—after proper validation—can be used as a qualifying control method with the in vivo relevance, while in case of the absence of an IVIVC, the dissolution test can be used only as quality control method. In this case, the limits are set after calculating the plasma concentration time profile using convolution techniques or other appropriate modeling techniques, and determining whether the batches with the fastest and slowest release rates allowed by the dissolution specifications result in a maximal difference of 20% in the predicted Cmax and AUC. Of course an established IVIVC may allow the setting of wider dissolution specifications than the usual 10%. This would be dependent on the predictions of the IVIVC (i.e., 20% differences in the predicted Cmax and AUC) (Fig. II). 

As denoted above, the rate-limiting step in the oral absorption of Class II drug substances is often the in vivo dissolution [23-25]. Hence, a well-designed dissolution test should be capable of providing adequate in vitro-in vivo correlation (IVIVC). 

As discussed above, the rate-limiting step in the oral absorption of Class II drug substances is likely to be the in vivo dissolution [23-25]. For Class II dissolution rate limited drugs, hence, if in vivo dissolution can be estimated in vitro, an in vitro-in vivo correlation may be established. As discussed in Section 3.5, such media have been developed, and an adequate IVIVC was shown for number of Class II drugs. However, due to the numerous in vivo parameters involved, it appears that more research is needed to develop uniform dissolution media reflecting in vivo dissolution conditions, to establish an adequate IVIVC, and to asses the risk of bioinequivalence [86, 88], In addition, the relationship between the hydrodynamics in the currently available dissolution tests and the actual in vivo situation is not adequately characterized and might interfere to obtain the correlation. 

Although it is the ultimate goal to predict in vivo formulation behavior based on in vitro dissolution testing using biorelevant media, the number of studies in which in vitro-in vivo correlations (IVIVC) have been described, is limited. Finding a correlation between in vitro dissolution testing and in vivo performance will be challenging due to the multiple factors which affect the blood concentration-time prohle. 

Attainment of IVIVC is a key aspect in the choice of dissolution test medium. However, it is not recommended to choose a test medium based only on correlation to in vivo data. The dissolution test medium should also be relevant for the physiological conditions in the GI... 

The purpose of Level A correlations is to define a direct relationship between in vitro and in vivo data so that measurement of the in vitro dissolution rate alone is sufficient to determine the biopharmaceutical fate of the dosage form. IVIVCs should be sought as early as possible during the dosage form development (a priori correlations). In some cases, formulation has been undertaken rapidly and correlations sought on the finished product from subsequent in vitro tests. The predictive power of these correlations (a posteriori correlations) is thus limited, and they require additional validation. 

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