Thermodynamic equivalence concept

Thermodynamic Equivalence Concept The Generics statute states that to establish therapeutic equivalence, there must be same levels of drug concentration at the site of action, which, in most cases is not certain and almost always not accessible. So, FDA adopted blood level studies as the surrogate test, which works well in theory but not in practice. When establishing equivalence, the concentration at the site of action should determine the blood level profile and that does not always work because the escaping tendency or chemical potential may not be the same, even though the concentration may be. To overcome this, we designed dissolution tests, which are the good indicators of the chemical potential of a dosage form. However, a single point determination, and, as a result, does correlate well with therapeutic equivalence. Dissolution is a thermodynamic property and it requires establishing conditions at which the F2 values are statistically significant at different conditions such as temperature, polarity, dielectric, electrolytes, etc., without any reference to physiologic conditions, a limiting factor. With at least two factors and at least three levels, we have a 3x3 matrix to demonstrate chemical potential and when it is matched by the test product, we can safely assume that the chemical potential at the site of administration will be the same, and therefore, the blood level profile. The method can have a significant impact on the development of complex dosage forms such as sustained or multiple release, topical and depot dosage forms.

Use of blood level studies confounds the differences in the chemical potential, are expensive to run and unnecessarily expose to healthy subject or patients. The concept is not totally new, nut its approach is different. It will take a while for many to even try; it took me years to get the FDA to open it for discussion. But now I am hopeful that we have a chance to change how generics are approved--all types and kinds.

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