BIOEQUIVALENCE CONSIDERATIONS OF TOPICAL RECTAL AND VAGINAL SUPPOSITORIES

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ABSTRACT Topical rectal and vaginal suppositories have been widely used for the localized treatment of rectum or vagina diseases and disorders over the past few decades. Despite their prevalence, the development and approval of generic topical rectal and vaginal drug products have remained challenging due to the complexity of these products and a lack of regulatory guidance on comparative product characterization-based bioequivalence (BE) assessment approaches. The main objective of the project is to develop a rational framework to mitigate the risk of potential failure modes of BE studies, for topical rectal and vaginal suppositories. The proposed research, builds upon our previous research in the development of appropriate in vitro performance testing methods as well as in vitro-in vivo correlation (IVIVC)/relationship (IVIVR) for complex dosage forms, including parenteral polymeric microspheres and ophthalmic ointments. Based on the quality-by-besign (QbD) principles, quality target product profile (QTPP) and critical quality attributes (CQA) of the topical suppositories will be defined. A risk assessment will then be conducted to identify putative formulation and manufacturing attributes that may have high likelihood to affect CQA of the target product. CANASA® (mesalamine) and Terconazole (terconazole) suppositories have been selected as model rectal and vaginal suppositories, respectively. Mesalamine and terconazole suppositories with manufacturing and material differences will be prepared and thoroughly characterized, and in vitro and ex vivo performance testing will be conducted. The commercially available mesalamine and terconazole suppository products will be studied as controls. Based upon the outcomes of these studies, the key manufacturing and material parameters that can impact product CQA will be identified. It is expected that a comprehensive understanding of CQA and their relationship to manufacturing and material differences will be provided for topical rectal and vaginal suppositories. In addition, robust, appropriate in vitro and ex vivo performance testing methods will be identified and/or developed. These will lead to the development of comparative product characterization-based BE approaches that are suitable for topical rectal and vaginal suppository drug products. The proposed research will facilitate the establishment of in vitro BE testing methods, thus helping advance the regulatory review and approval processes for topical rectal and vaginal suppository products. This will in turn help reduce the need for human studies and provide the public with high quality, affordable generic topical medications in a timely fashion.