Biopharmaceutics Classification System: Interview with Prof. Gordon Amidon

by Cynthia K. Brown, Managing Editor, Dissolution Technologies

Q. The Biopharmaceutic Classification System developed over a number of years, what was the initial impetus, in your mind, in developing this classification system?

A. The need for a classification system was firmly established in my mind during a sabbatical year I spent at the FDA in 1990-91, in the Biopharmaceutics and Drug Dissolution section with Jerry Skelly and Vinod Shah. The sabbatical period was set up by Dr. Carl Peck, head of CDER, to promote research within the FDA on drug regulatory standards. During that year it became clear to me that, while the FDA tried to set general regulatory standards and guideances for the industry, when it came to product regulation it was more on a product-by-product basis since the standards were too general to be useful. That lead to the question of, is it possible to compartmentalize drugs and drug products to simplify regulatory standards. In the year following that sabbatical period it appeared that solubility and permeability would be a useful method for establishing this biopharmaceutic class. Where we are today has evolved from that initial experience at the FDA.

Q. What is the most important aspect of BCS in your mind?

A. Well, there are several things. First, it is significant that the FDA is moving to an in vitro measure to ensure in vivo bioequivalence. Since all products in the United States are required to be bioequivalent to the product used to establish the clinical efficacy claim, this is an extremely important standard for maintaining drug product quality. I believe that it is most significant that the BCS has set a sound enough scientific basis where the FDA feels comfortable in moving away from an in vivo standard to an in vitro standard for ensuring bioequivalence. This makes eminent scientific sense today but is a major paradigm shift within the FDA.

Q. You mentioned dissolution standards being used as a surrogate for in vivo bioequivelence studies. Can you explain?

A. The Cmax and AUC criteria for bioequivalence are empirical. They are not mechanistic from a biopharmaceutic point of view. The drug dissolution standards, on the other hand, can be set on a mechanistic basis and the BCS places drugs in classes depending on the rate determining step controlling drug absorption. If that rate determining step is gastric emptying, which is the case for solutions and rapidly dissolving immediate release dosage forms, then plasma levels do not provide any information relative to the biopharmaceutic differences in the two products tested. Consequently, it is not scientifically necessary to perform in vivo bioequivalence studies. This class of high solubility high permeability rapidly dissolving drugs will be the first class in which the FDA will allow in vitro standards to be used to ensure bioequivalence.

Q. Do you think these standards can be evolved to other drug classes?

A. They most definitely can. However, the dissolution methodologies must be further developed. Our current dissolution methodologies have been developed more on the basis of quality control needs rather than in vivo bioequivalence needs. These quality control needs are important along with all of the other quality control measures to ensure that you are making your product to your desired specifications. However, if you change the process significantly, a major change is defined by SUPEC, than the bioequivalence question relative to the efficacy claims becomes important. An in vitro dissolution methodology that serves as a surrogate for in vivo bioequivalence will necessarily be more elaborate than a QC dissolution methodology. This in vitro bioequivalence dissolution methodology will include a variation in pH and surfactant, or surfactant concentrations, to ensure that you are meeting the same standards that you met prior to the major manufacturing change. I envision that a bioequivalence dissolution methodology will become part of the NDA submission and be used by a company to request waivers from in vivo bioequivalance studies when changes are made to a product in its lifetime.

Q. Do you see some further implications of the BCS for drug regulation?

A. I definitely see an evolution in our dissolution methodology as noted in the previous question. But, in addition, I see the BCS as leading to change in standards for bioequivalence. For example, for a high permeability drug which is well absorbed it is not important to regulate on the basis of AUC since these drugs are completely absorbed. This has implications for long half-life drugs where it may only be necessary to set bioequivalence standards around Cmax rather than Cmax and AUC. This makes eminent scientific sense, to me, and I hope that we proceed in this direction of simplifying bioequivalence standards where it is scientifically sound.