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    Features

    Overcoming the Small Molecule Bioavailability Challenge

    Approximately 90% of preclinical compounds are estimated to face bioavailability challenges.

    Overcoming the Small Molecule Bioavailability Challenge
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    David Lyon, Sr. Research Fellow, Lonza Pharma & Biotech10.15.19
    The overarching social goal of the pharmaceutical industry is to bring benefit to patients as rapidly and safely as possible. However, with disease targets, active pharmaceutical ingredients (APIs) and drug delivery technologies all becoming increasingly sophisticated and complex, getting drugs to patients quickly has become more difficult. Compounds that fall into Biopharmaceutical Classification System (BCS) II/IV regions—low-solubility and permeability compounds that require more intensive delivery efforts—are becoming the rule rather than the norm. Some 90% of the preclinical compounds are now estimated to have bioavailability challenges.1

    Other shifting market factors include the rise in specialty applications for drug products in developed markets. Specialty drugs accounted for 39% of global sales in 2018, and are expected to be more than 50% of the U.S. market by 2023 (IQVIA analysis specialty segment versus traditional; MIDAS Q4 2018 data). Meanwhile, orphan drug products exceeded 50% of new compounds approved by both the U.S. Food & Drug Administration (FDA) and the European Medicines Authority (EMA) in 2018, and are expected to account for approximately two-thirds of the FDA’s forecasted approvals through 2023. Also, an increasing number of small biopharma companies are commercializing their own compounds; 58% of 2018 FDA filings were from small companies, almost twice as many as in 2011 when only 31% of filings were from the small company category (IQVIA MIDAS restricted MAT Q4 2018; FDA; Clarivate Analytics Cortellis). Establishing market position can be especially critical for small biopharma players, but these smaller companies typically have limited capabilities in-house and require both development and manufacturing partners to progress their compounds.

    These trends have amplified the need for access to bioavailability-enhancing technology and rapid development and commercialization of drug products, which can be especially critical for drug programs with orphan or break-through designations and those following the 505(b)(2) pathway. Critical aspects for meeting bioavailability challenges rapidly include: 1) the ability to rationally choose drug delivery technologies early in the development process (technology selection) and, once clinical success is demonstrated; and 2) the ability to scale that formulation to the next phase (science of scale). Minimizing company-to-company transfers is an added potential time saving; a recent Tufts study2 suggests that as much as three-to-four months can be saved in progressing a compound using a single provider of API and drug product vs. using multiple partners.

    Drug developers and patients can benefit from strategies that help overcome the bioavailability challenge quickly and effectively, as well as working with one partner to optimize a formulation, progress their compound through clinical trials and rapidly scale the drug product to launch.

    Methods to Decrease Timelines to Clinical Evaluation and Product Commercialization
    Technology Selection. The key to rapid and accurate technology selection is using tools to determine the small molecule characteristic, or “problem statement,” that is leading to poor exposure. By first understanding which limiting mechanism is at play, the best technology can be deployed without spending time and API testing different technologies. 

    For example, if a compound is determined to have poor exposure due to a slow dissolution rate, micronization can be employed to increase its dissolution in crystalline form. Conversely, if a review of a compound shows that it needs improved solubility, either a lipid formulation or an amorphous solid dispersion can be utilized. Pharmacokinetic modulation utilizing various controlled release mechanisms in conjunction with solubility-enhancing approaches, e.g., spray dried dispersions, may also be required for formulation refinement in meeting target product profiles.

    Utilizing in silico and in vitro formulation and testing methodologies that are highly correlated to in vivo performance3 is also important. Such R&D-derived capabilities may deliver rapid, rational formulations that are predictive of the in vivo outcome, helping biopharma partners quickly and accurately select the most effective bioavailability-enhancing technologies for candidate molecules.

    Science of Scale. While optimized technology selection strategies can lead to quicker formulation for clinical trials, it is also critical to be able to progress the formulation to higher-scale production once clinical success has been achieved. Each of the processes that can be utilized to improve bioavailability (e.g., micronized API, lipid formulations, hot-melt extrudates or spray-dried dispersions) is most effective when extensively characterized and modeled using computational fluid dynamic and heat and mass transfer models. By utilizing these models, small-scale fundamental measurements and in silico approaches, the process of choice can be scaled up more successfully.4

    First-in-Human Service Packages. To aid biopharma companies in rapidly progressing compounds to first-in-human studies, contract development and manufacturing organizations (CDMOs) have launched a range of service packages incorporating API manufacturing and drug product development. For example, SimpliFiH Solutions, a service from Lonza specifically designed to address bioavailability-challenged molecules, has been designed to progress such molecules to Phase I trials in 32 weeks or less. The SimpliFiH offering is centered on technology selection methodologies and models developed from the experience of advancing thousands of compounds through particle size reduction, solid dispersion technologies and lipid-based formulations to address dissolution rate or solubility issues.

    In addition to addressing bioavailability challenges, the service includes a continuum of optional services that can be tailored to specific molecules and drug programs—to simplify the customer experience in reaching Phase I trials. Elements include solid-state characterization, formulation and good manufacturing practice (GMP) manufacturing of Phase I drug product, development of relevant analytical methods, stability studies and documentation for IND studies. API, inclusive of highly potent API, can also be developed and supplied as part of the service package. Lonza’s network has a line-of-sight to commercial manufacturing without the need for external process transfer, reducing the need to re-develop API synthesis routes, formulations and analytical methods for each and every phase of development.

    As part of the its SimpliFiH Solutions, Lonza has worked to ensure that all aspects of the service offering are phase-appropriate, e.g., streamlined quality and commercial agreements, and aligned with the range of needs facing biopharma companies in reaching IND/IMPD studies. The ultimate goal of the service package aims to generate patient benefit by helping to accelerate clinical evaluation of new compounds, especially bioavailability-challenged molecules which dominate today’s development pipeline. 

    References
    1. Kalepu S. and Nekkanti. V., Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B 2015 (5) 442
    2. DiMasi, J.A. and Getz, K.A., Analysis of Review Times for Recent 505(b)(2) Applications. Therapeutic Innovation & Regulatory Science 2017; 51 (5): 651-656
    3. Stewart, A.M., Grass, M.E., Mudie, D.M., Morgen, M.M., Friesen, D.T., and Vodak, D.T., Development of a Biorelevant, Material-Sparing Membrane Flux Test for Rapid Screening of Bioavailability-Enhancing Drug Product Formulations. Molecular Pharmaceutics 2017 14 (6), 2032-2046
    4. Dobry, D.E., Settell, D.M., Baumann, J.M., A Model-Based Methodology for Spray-Drying Process Development. Journal of Pharmaceutical Innovation (2009) 4: 133
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