Relative Bioavailability Risk Assessment: A Systematic Approach to Assessing In Vivo Risk Associated With CM&C-Related Changes

Abstract

Relative bioavailability (RBA) studies are often carried out to bridge changes made between drug products used for clinical studies. In this work, we describe the development of a risk assessment (RA) tool that comprehensively and objectively assesses the risk of noncomparable in vivo performance associated with Chemistry, Manufacturing, and Controls (CM&C)-related changes. The RA tool is based on a risk grid that provides a quantitative context to facilitate discussions to determine the need for an in vivo RBA study. Relevant regulatory guidances and the required in vitro and in silico absorption modeling data, on which the RA is based, are discussed. In addition, an analysis of previously executed RBA studies at Eli Lilly and Company over a period of several years is presented. The risk grid incorporates individual risk factors for a given study and provides a recommendation on the risk associated with bypassing an RBA study. The outcome of an RA results in one of 3 possible risk zones; lower tier risk, intermediate tier risk, and upper tier risk. In cases where the outcome from the RA falls into the intermediate tier risk zone, further in depth data analysis is required.

Metoclopramide-OROS Dispersible Tablets Optimized Formula Bioavailability Study

“…The RBA study also referred as a pilot pharmacokinetics study was used by the drug development sponsor to assess potential in vivo performance differences between dosage forms. The data obtained from the RBA study allow the sponsor to move forward in clinical development with a new dosage form [17], [18], [19], [20]. The RBA of FCL-6 (147%) also showed the higher value compare with the RBA value of metoclopramide nasal spray dosage form (62.3%) that mentioned by Li et al study [21].…”

Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

“…We systematically searched the literature in PubMed (19), Cochrane Library (20), and Google Scholar (21) for potentially relevant studies that assessed relative BA and BE studies in a pediatric population. To collate the largest possible datasets, different search keywords were identified from the literature such as: "bioequivalence" (22); "relative bioavailability" (16); "failed bioequivalence" (23); "lack of bioequivalence" (24); "bioinequivalence" (25), and "nonbioequivalent" (26). In this paper, we used the term "bioinequivalence" to describe cases where the BE criteria were not met and to encompass lack of BE, failed BE, or non-bioequivalent.…”

“…For instance, several reports showed changes in the Biopharmaceutics Classification System (BCS) class for the same drug substance in pediatric compared to adult populations (11)(12)(13)(14)(15). A number of risk factors linked to bioinequivalence have been identified from the literature, some examples include: physiological factors (absorption-distribution-metabolism-excretion, ADME effects) (16), formulation effects (10), disease progression and other disease-related effects (17), and poor study design (18).…”

Challenges and Strategies for Solubility Measurements and Dissolution Method Development for Amorphous Solid Dispersion Formulations

“…Additionally, absorption of the drug in vivo will actively lower the drug concentration resulting in a relatively lower precipitation risk. To more closely mimic the in vivo conditions, non-standardized dissolution systems are frequently employed during development to inform about their biopharmaceutical risk of the formulation (39). In order of increasing complexity, these systems include the use of biorelevant media, use of pH shift testing, and/or use of multi-compartments such as artificial stomach duodenum (ASD) model (40), BioGIT (41), Gastrointestinal Simulator (42,43), GastroDuo (44), and TIM-1 (45).…”