Eleonore Haltner-Ukomadu

In vitro in vivo correlation to speed up generic product development.

Dr. Eleonore Haltner-Ukomadu, Managing director, Across Barriers, Germany

Fast development of generic drug products is a major issue today. The generic product should have the same quality as the originator product but the development time is kept to be much shorter. Furthermore the costs for the development should be as low as possible be-cause in contrast to the originator products more than one supplier will enter the market in a short time. Failures during the development will lead to prolonged timelines, a later market entry and higher costs.

The indispensable criteria for the approval of a generic product is the bioequivalence com-pared to the originator. On the one hand the bioequivalence is determined by the active in-gredient (API) by itself and on the other hand it is determined by the formulation (used ex-cipients). Generally the source of the API is not the same and excipients in a generic product will very often be exchanged due to the costs and/or patent issues.

The influencing parameters for the API are e.g. physico chemical characteristics, salt form or solid status because these parameters influence strongly the dissolution rate, solubility, per-meability and stability and these four parameters are the determinants of bioavailability.

The excipients used in the formulation are the next interacting factors.
During the last decades excipients have been considered as inert chemicals used as e.g. fillers or lubricants. Today it is well known that excipients are functional ingredients of a solid dosage form and that they influence the dissolution rate, solubility and stability of the API. And as mentioned before these are the determinants for bioavailability. Taking the vast ma-jority of excipients into account, the difficulty is that their influencing impact on biopharma-ceutical behavior is not described in the literature.

Modern in vitro methods are the necessary tools to understand the influence of the API characteristics and the function of special excipients in a formulation. The tools which help to understand the absorption mechanism are: solubility measurements in order to learn as much as possible about solubility in physiological conditions, the use of biodissolution measurements which are predictive for bioequivalence (BE) or bioavailability and further determination of permeability using cell culture systems. Along with literature data like published bioavailability and bioequivalence studies all these experimental parameters can help to set up an in vivo in vitro correlation.

Using such a rational process the developments of generic products can be realized by con-ducting less human studies in a shorter time. This process will also provide the knowledge of how a successful BE study should be designed in terms of the selection of individuals and accomplishment under fasted or fed state conditions. In most instances one human study will be successful. There are cases where the development of a generic product was been per-formed with success, just performing one clinical study within half a year.

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