Accelerated formulation strategies can aid with cost and time-efficiencies in drug development. However, there are key challenges of which developers must be aware to ensure success.
Pharmaceutical Technology Europe recently spoke with a panel of experts including Vanessa Zann, Senior Drug Development Consultant, and Chris Roe, Senior Research Fellow, with Quotient Sciences to discuss the primary hurdles to accelerated formulation strategies and best practices for developers.
Q: Could you run through the primary challenges facing developers when employing accelerated formulation strategies in drug development?
A - Zann: The main challenge with accelerated formulation strategies is knowing which dosage form technology is the most appropriate to give optimum exposure in man. There is widespread acknowledgement of the lack of predictability of pre-clinical data for formulation assessments. Improvements in in-vitro and in-silico tools are emerging; however, there are still significant risks for innovator companies, particularly given continued drug delivery challenges presented by molecule chemistry. This uncertainty is magnified when batch sizes and stability packages are needed for new formulations, for testing in the clinic to even be considered.
A - Roe: Truly understanding the drivers of poor product performance is a key challenge to overcome. Using the correct techniques can provide meaningful improvements in in-vivo performance that can aid in rapidly progressing formulation efforts. At the same time, developers need to avoid the risk of trying to progress overly complex formulations, which may add unnecessary time or cost to the drug development process. While speed is critical, it shouldn’t come at the expense of sufficient product quality.
Q: Are the challenges more significant for large-molecule products versus small-molecule ones, in your opinion?
A - Zann: The challenges for large molecules are still present but different. Large molecules will typically be administered parenterally via intravenous (IV) or subcutaneous (SC) routes, hence formulation options will be more limited compared to the likes of solubility enhancement or modified release development solutions for oral small molecules. There will be less dependency of the formulation composition on its clinical performance. The challenges still remain with regard to predictability from preclinical species and also manufacturing and stability for drug products.
A - Roe: Arguably the most significant challenges for large molecules would be to achieve adequate exposure from the oral route to exert a systemic therapeutic effect, given this is often seen as the gold standard for convenience and compliance. Issues for large molecule oral formulation strategies include poor permeability and potential instability in the gastrointestinal tract, both of which need to be addressed via compound selection and/or formulation technologies. Success is possible, as evident from the recent [US Food and Drug Administration] FDA approval of Rybelsus (Novo Nordisk), an oral glucagon-like peptide (GLP)-1 agonist (1).
Q: What sort of activities can developers pursue to ensure their accelerated formulation strategies are successful?
A - Zann: For large molecules where oral delivery is required, one optimizing strategy is to formulate with penetration enhancers to increase oral absorption either through modification of the tight junctions or membrane perturbation. There are in-vitro permeability assays that can be used to assess large-molecule permeability in the presence of various formulation components that are available to increase permeability, both early and relatively rapidly within the development programme. However, these models have limitations in terms of being able to test formulated drug products that do not damage the in-vitro cell-based system.
A - Roe: For oral small molecules, having a data driven formulation strategy based on the compounds’ biopharmaceutic properties is likely to result in a greater chance of success. Employing the developability classification system (DCS) to molecules will allow a targeted formulation strategy for poorly soluble compounds that is based on whether the absorption is either limited by dissolution rate (Class IIa) or solubility (Class IIb). Where there is uncertainty (border-line case) in the classification, Quotient Sciences would recommend assessing both a particle-size reduced formulation (a DSC IIa strategy) and a solubility-enhanced formulation (DCS Iib strategy) to cover both situations to maximize the potential for success.
Source: F. Thomas, “Successfully Accelerating Formulation Strategies,” Pharmaceutical Technology Europe 34 (3) 2022.