Abstract

“Biowaiver”: An Inexpensive and Time Saving Strategy in the Formulation and Development of BCS Class I and III Oral Solid Dosage Forms

Devendra Ridhurkar, Senior Scientist, Egis Pharmaceuticals

As a part of regulatory approval process, the generic formulations must have the identical pharmacokinetics with the innovator products. Pharmacokinetic similarity can be proved by conducting a bioequivalence (BE) testing of generic products against the innovator products. As oral solid formulations are commonly available in multiple strengths BE studies are generally conducted on the highest strength of the drug product and in-vivo BE study requirement can be waived for linearly proportional lower strengths. This replacement of expensive and time consuming in-vivo BE studies by in-vitro studies are called as “bio-waiver”. It is also applicable for the changes done in formulations as per scale up and post approval changes (SUPAC) guidelines after the approval of a new drug application (NDA) or abbreviated new drug application (ANDA). As a result, the cost and time of developing generic products can be significantly lowered by eliminating clinical studies and minimizing review burden on regulators. For oral solid dosage forms, bio-waiver(s) strategy can be employed using biopharmaceutics classification system (BCS), in-vitro in-vivo correlation (IVIVC), formulation proportionality, Quality by Design (QbD) space and comparative in-vitro drug release studies. Out of various strategies, one of the best strategy opted by formulation scientist to get the bio-waiver for his formulations is to develop the proportional formulations and prove the dissolution profile similarity (f2) among various strengths of oral solid formulations. Also, in-vitro in-vivo correlation (IVIVC - Level A, B, C and D) and QbD space can be applied to assess bio-waiver for BCS class I and III oral solid formulations. Another strategy includes development of in-silico absorption model to predict performance to apply bio-waiver for BCS class I and III oral solid formulations in order to show the broad range of release rates that are expected to have no impact on AUC and C_max and therefore result in bioequivalence. Among several in-vitro models developed for studying intestinal absorption, the Caco-2 human colon carcinoma cell line has been widely utilized in the in-vitro model system for the evaluation of the rate of intestinal drug absorption. Based on these strategies, if the oral solid formulations for BCS class I and III drugs could meet aforesaid criteria, the regulatory agency would grant a waiver of the expensive and time-consuming BE studies.