SmartTrack™
Nanopharm has developed a unique proprietary in-vitro in-silico modeling platform that can demonstrate bioequivalence (BE) of generic inhaled drug products to marketed reference drugs without having to conduct a comparative clinical endpoint (CCEP) study. SmartTrack™ represents a combination of several specialized inhalation development technologies, from breath profiling to regional deposition modeling and pharmacokinetic simulations to create the world’s first non-clinical pathway that can demonstrate pharmacodynamic bioequivalence of new generic inhalation drugs. And no need for costly and time consuming CCEP studies. Typical comparative clinical equivalence studies can cost as much as $30-$40 million US dollars and take many years to complete. Nanopharm’s exclusive SmartTrack™ process can shorten the overall development timeline and significantly reduce costs for generic drug manufacturers. SmartTrack was developed in close collaboration with the U.S. FDA and meets regulatory requirements.
Nanopharm SmartTrack™ for Generic Inhalation Products
The inherent complexities of inhaled drugs mean it’s more challenging to demonstrate comparative bioequivalence to a marketed reference product than with other dosage forms. The interactions between API, formulation, device, and patient in an inhaled product can impact how much of the drug is delivered to the target location and how much drug is becomes bioavailable to each patient. Nanopharm has developed its SmartTrack™ platform to account for and control patient variability, ensuring that both the inhaled test and reference products are exposed to the same sets of variables. SmartTrack™ can define more sensitive and direct markers, that allow researchers to determine if differences in drug performance are due to patient or product. SmartTrack™ uses a variety of specialized and proprietary tools to demonstrate the bioequivalence of new inhaled generic products to reference products without the need for costly and time-consuming comparative clinical endpoint (CCEP) studies. And you’ll only find SmartTrack™ at Nanopharm. Your leading experts in OINDP product development services.
Breath Profiling & Simulation
Breath profiles and simulations are critical starting points to understanding the complex dynamics of patient impact on inhaled product performance. Many critical performance parameters such as emitted dose, fine particle mass and aerodynamic particle size distribution are largely determined by how the inhalation maneuver is performed by the patient. Inhalation flow profile measurements enable the monitoring and measurement of inhalation profiles of human beings interacting with the pMDI, DPI or nebulizer being studied. The associated breath profile simulations help scientists to define the variability observed between patients with various conditions. Nanopharm scientists collect inhalation or breath profiles from patients using a proprietary Inhalation Flow Profile (NIP™) device. This proprietary device enables the real-time measurement of peak inspiratory flow (PIF), total inhaled volume (IV) and time taken to reach maximum flow rate. Our NIP™ data can also be used to help with patient training during clinical trials, as well as being simulated in the laboratory during in-vitro testing to allow us to account for the impact of the patient inhalation maneuver on the product’s performance.
Realistic Aerosol Testing
Nanopharm offers the specialized capabilities to conduct realistic aerosol testing using techniques such as realistic Aerodynamic Particle Size Distribution (rAPSD) and Delivered Dose Uniformity (DDU) using simulated breathing profiles and realistic anatomical throat models, which are useful for in-vitro characterization with stronger in-vitro in-vivo correlation (IVIVC). This data can then be applied to subsequent computational models to provide more clinically relevant output simulations regarding the bioavailability of the drug in the lungs. Common test parameters studied by device type include:
Dry Powder Inhalers (DPIs)
- Particle properties.
- Mass Median Aerodynamic Diameter (MMAD)[µm].
- Geometric Standard Deviation (GSD).
- Delivered Dose (DD) [mg].
- Fine Particle Fraction (FPF) [%].
Metered-Dose Inhalers (MDIs)
- Velocity profiles.
- Droplet size changes.
- Evaporation rate of aerosols using phase doppler anemometry (PDA).
- Data used to support computational flow dynamics (CFD) modeling.
Microstructural Characterization
Nanopharm uses advanced tools to study the complex interactions between API, excipients, and device, to determine microstructural relationships within a product. Our Dissohale™ patented Q3 aerosol dose-collector is used for lung dose sample collection, achieving uniform, dose independent deposition for discriminatory analysis of microstructure. Our in-vitro release test (IVRT)/Dissolution Test can measure the combined effects of numerous physicochemical characteristics including particle/droplet size, viscosity, and microstructure arrangement of the product. It discriminates microstructural changes by controlling dissolution through diffusion-mediated transport, creating a boundary layer to account for the low levels of fluid available in the lungs for drug product dissolution. We also apply Morphologically Directed Raman Spectroscopy (MDRS) which combines high-powered optical microscopy and Raman spectroscopy for simultaneous morphology imaging comparisons and chemical analysis of multi-component formulations. MDRS is useful for directing formulation strategy, explaining changes in aerosol and dissolution properties, and ultimately helps to predict PK performance.
Regional Deposition Modeling
Nanopharm scientists apply their unique in-silico modeling tools to assess and quantify regional lung deposition of inhaled drug products. Computational fluid dynamic (CFD) simulations are performed using the in-vitro data in conjunction with a proprietary library of real patient lung geometries (HRCT scans) categorized by major disease indications that were previously generated in collaboration with our exclusive partner, Fluidda. The lung geometry library covers major disease indications including asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), cystic fibrosis (CF), and interstitial lung disease (ILD). Lung geometries captured at inspiration and expiration are used as boundary conditions for product specific computational fluid dynamics (CFD) simulations. Drug deposition models are clinically validated with 2D scintigraphy or 3D Single Photon Emission Computed Tomography (SPECT). All of this data allows our scientists to design a digital clinical study that accounts for patient-to-patient variability in numerous characteristics.
Simhalation™ - Pharmacokinetic Simulation
Nanopharm has developed a highly advanced in-silico physiological-based pharmacokinetic (PBPK) computational simulation, called Simhalation™, that can be used to predict the pharmacokinetics (PK) of an inhaled drug product. A PBPK model is a mathematical description of drug transportation from point of entry into the body to excretion. We use differential equations to mechanistically describe the organs, tissues, and other physiological features associated with the ADME (absorption, distribution, metabolism, and excretion) processes associated with PK investigations. Our PBPK models use previously generated in-vitro and in-silico data as a bridge to connect variables present in local and systemic pharmacokinetics. These data sets can come from rAPSD, Delivered Dose Uniformity (DDU), dissolution/in-vitro release testing (IVRT), Phase Doppler Anemometry (PDA) for pMDIs, and regional deposition using CFD. Our PBPK models also incorporate lung deposition data from a variety of disease state models to ensure the PBPK model accurately accounts for any variability associated with the patient. Critical parameters measured include time to reach maximum concentration of drug in body (Tmax), maximum observed concentration of drug in body (Cmax), and area under curve (AUC) which is a measure of the bioavailability of an administered drug. Our Simhalation™ PBPK simulations have demonstrated a very strong correlation between predicted PK and actual PK results measured in clinic with real patient subjects.
SmartTrack™ Alternative Regulatory Pathway for Inhaled Generics
The U.S. FDA originally introduced the concept of microstructural (Q3) equivalence to assess performance attributes of the product. Inhaled drug products must also consider patient variability, regional deposition, and aerosol dynamics as equally important to understanding the factors affecting overall inhaled drug efficacy. U.S. generic ANDA applications have, in past, required costly and time-consuming clinical studies to demonstrate bioequivalence against the reference drug. Our proprietary SmartTrack™ system has presented regulators with an alternative approach, developed exclusively for generic inhaled products. Nanopharm has been working collaboratively with the U.S. FDA to apply it’s SmartTrack™ platform to ANDA filings and pre-ANDA briefing books. We are taking the lead in advancing in-vitro in-silico models as an alternative to conducting comparative clinical endpoint (CCEP) studies, demonstrated through our public collaboration with the U.S. FDA where we have been involved in a number of their workshops and public meetings. Our SmartTrack™ approach to new generic inhalation products uniquely positions Nanopharm to be able to guide customers through this new regulatory pathway.
