(W1130-02-08) Colestipol Hydrochloride Tablets: Challenges of Formulating a Complex Active Pharmaceutical Ingredient and Product Quality Considerations

Purpose: In recent years, a shift towards the development of complex generics is seen in the generic market domain. Complex generics represent a unique challenge from a quality perspective. The major challenge lies with the demonstration of pharmaceutical equivalence and bioequivalence to the Reference Listed Drug (RLD). Colestipol Hydrochloride Tablets is considered a complex product as it contains a complex active pharmaceutical ingredient (API). Colestipol Hydrochloride, a locally acting gastrointestinal drug, is a high molecular weight anion exchange resin indicated for the reduction of low-density lipoprotein cholesterol. The draft product-specific guidance for Colestipol Hydrochloride recommends two in-vitro studies to demonstrate bioequivalence - an equilibrium binding study, and a kinetic binding study. Here, we discuss the potential quality issues encountered in the development of generic versions of Colestipol Hydrochloride Tablets and approaches recommended to resolve these issues.

Methods: The quality issues encountered with the development of generic versions of Colestipol Hydrochloride Tablets are twofold. First, as the chemical identity of the API is complex, the generic version must define and ensure that the test API is the same as the RLD’s API. Second, equivalence of physicochemical properties between the generic and RLD product must be established to ensure bioequivalence via an in-vitro approach. The API sameness can be demonstrated by showing equivalence of: (i) chemical structure and composition, and (ii) physiochemical properties between the test API and RLD. For chemical characterizations, at least three batches of the test API should be characterized. For physicochemical characterizations, side-by-side comparative testing using at least three batches of the test API and three batches of the API extracted from the RLD product should be performed. Similarly, for the demonstration of equivalence of physicochemical properties between the generic and RLD product, a minimum of three batches/lots of the generic and RLD products should be evaluated.

Results: For the chemical characterization of API, various analytical techniques employed could include but not limited to IR spectroscopy, Raman spectroscopy, ¹³C NMR, DSC, elemental analysis, XRD, and microscopy. For physicochemical characterizations, the properties evaluated could include but not limited to pH, chloride content, water absorption, total titratable amines, colestipol exchange capacity, cholate binding capacity, and bile acid binding capacity. Findings from these evaluations would demonstrate the absence of significant differences between the test and RLD API and ensure API sameness. With the demonstration of API sameness, no impact on bioequivalence is expected. For the drug product, for physicochemical characterizations, the properties evaluated could include but not limited to total titratable amines, swelling index, Colestipol exchange capacity, and particle size distribution. The findings from these comparative evaluations would demonstrate pharmaceutical equivalence.

Conclusion: For a generic product, both pharmaceutical and bioequivalence to the RLD must be demonstrated to ensure therapeutic equivalence. However, with a complex API in the formulation, the difficulty lies with the demonstration of API sameness with RLD in order to mitigate therapeutic inequivalence. Therefore, a more sophisticated planning and development process is required to address unique characteristics of this complex generic product.

Acknowledgements:Disclaimer: The contents in this abstract reflect the views of the authors and should not be construed to represent U.S. FDA’s views or policies.