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In-Vitro Bioequivalence (IVBE)

Nanopharm is a pivotal player in the development of generic Orally Inhaled and Nasal Drug Products (OINDPs), including enabling the market to access medication through the launch of generic products through the provision of  In-Vitro Bioequivalence (IVBE) studies, a scientific approach to demonstrate the bioequivalence of a generic product to its Reference Listed Drug (RLD).

A critical aspect of this process involves adhering to the stringent requirements set by major regulatory agencies, such as the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA). These agencies have established clear in-vitro criteria for nasal and inhaled drug products for the core in-vitro assessment, with continued evolution of the clinical and alternative non-clinical pathways. These criteria dictate the tests that are necessary to characterize various critical performance attributes and statistically compare the reference drug to the test articles. 

To achieve this, Nanopharm has developed specialized platforms capable of assessing the key physicochemical properties of inhaled or nasal products and the associated performance with the selected drug delivery system, to ensure the API, formulation and device are also equivalent and providing drug product bioequivalence. These in-vitro tests are pivotal in allowing scientists and regulators to understand how all of the components of a complex combination product interact and transform en route from device to patient.

These largely follow the product specific guidances and include tests for delivered dose uniformity (DDU), spray pattern (SP), plume geometry (PG), particle or droplet size distribution (DSD), and aerodynamic particle size distribution (APSD), using state of the art instrumentation to allow for precision and accuracy when developing and validating the methods, as well as designing the IVBE study to meet regulatory expectations. Nanopharm can also perform the other CMC and drug product characterization studies required for your ANDA submission and ongoing GMP batch release and stability studies.

However, Nanopharm’s approach goes beyond mere compliance to the historical standards. We have pioneered advanced in-vitro and in-silico tools that are changing the entire regulatory pathway for generic products through our long-standing collaboration with regulators and innovative development of OINDP technologies. These  are integral to understanding the microstructural (Q3) properties of formulations, and how the patient affects the pharmacodynamic and pharmacokinetic performance of the product; effectively and objectively to simulate a clinical study without touching a patient. 

The implications of Nanopharm’s approach are far-reaching. By focusing on the microstructural equivalence of formulations and leveraging IVBE, Nanopharm is not only streamlining the process of demonstrating bioequivalence but also contributing to the development of optimized and stable drug product formulations. This approach paves the way for faster market access to inhaled or nasal medications, which is beneficial not only to patients but also to healthcare providers and the broader pharmaceutical industry.

Nanopharm In-Vitro Bioequivalence (IVBE)

Nanopharm uses a number of specialized tests to demonstrate the bioequivalence of nasal and inhaled drug products, including Morphologically Directed Raman Spectroscopy (MDRS) technology which was recently added to U.S. FDA guidance for nasal sprays, as well as the well established spray and device performance tests.

Nanopharm’s proprietary SmartTrack™ platform provides an in-vitro in-silico based non-clinical pathway to comparative bioequivalence for inhaled generic products.

Q3 Microstructural equivalence requires a multidimensional approach to understanding the complex interrelationships between the API, the formulation, the device, and of course, the patient.

Nasal and Inhaled Product Bioequivalence

Nanopharm utilizes its specialized tests and knowledge to demonstrate the bioequivalence of generic nasal products for nasal aerosols and nasal sprays. Studies to support generic nasal and inhaled product bioequivalence submissions can include single actuation content (SAC)/delivered dose uniformity (DDU), droplet size distribution (DSD) by laser diffraction, drug in small particles/droplets, aerodynamic particle size distribution, spray pattern, plume geometry, priming/repriming, drug particle size distribution and dissolution tests.  Characterizing, controlling, and optimizing the parameters that determine the interactions between a nasal spray’s formulation, device and patient leads to more robust nasal drug delivery products, Nanopharm can also efficiently demonstrate generic product in-vitro bioequivalence (IVBE) with reference nasal products using their specialized laboratory techniques.

Inhalation Product Alternative Bioequivalence – SmartTrack™

Nanopharm has developed a proprietary in-vitro in-silico platform, SmartTrack ™ , that can deliver an alternative non-clinical pathway to bioequivalence without the need for costly or time-consuming comparative clinical endpoint (CCEP) studies. The SmartTrack™ system can provide a holistic understanding of each inhaled drug product’s critical parameters and how it changes on its journey from device to lungs. Using breath profiles and simulations, realistic aerosol testing, microstructural characterization, regional deposition modeling and local and systemic pharmacokinetic simulations provides our scientitst with comprehensive data driven inhalation product assessments. Developed for ANDA submissions in collaboration with the U.S. FDA, Nanopharm’s SmartTrack™ is the pioneering platform for accelerating and derisking generic OINDP approvals.

Q3 Microstructural Equivalence

Inhalation and nasal spray systems are complex.  Q3 microstructural equivalence is assessed through chemical and physical attributes as well as interactions of the formulation and device as they each play a significant role in aerosolized drug delivery and generic OINDP drug performance. Q3 equivalence measures the microstructural relationships between the formulated and aerosolized forms of the product through several in-vitro techniques such as Morphologically Directed Raman Spectroscopy (MDRS), and dissolution. Nanopharm’s proprietary, patented aerosol dose collection apparatus (Dissohale™) can be used to measure the structure and permeability kinetics. Morphologically Directed Raman Spectroscopy (MDRS) is often used to provide supportive information regarding Q3 equivalence in drug particle sizes between test and reference OINDP products.  These results are compared against their dissolution behavior to establish the relationship between the two factors. These are just a few examples of how Nanopharm uses leading edge technologies to support Q3 microstructural equivalence of critical parameters for complex orally inhaled and nasal drug products (OINDPs).

Nanopharm In-Vitro Bioequivalence (IVBE)

As industry leaders in the development of generic intranasal and inhaled drug products, Nanopharm has built the specialized drug product development and cGMP analytical capabilities needed to provide the data and documentation necessary for generic product in-vitro bioequivalence (IVBE) and applicable drug product ANDA filings. Nanopharm revolutionized in-vitro in-silico bioequivalence science for the complex and multi-dimensional requirements of OINDP drug delivery forms, such as dry-powder inhalers (DPIs), metered-dose inhalers (MDIs), nasal sprays and nebulizers. In fact, Nanopharm has been working collaboratively with several major regulatory bodies, including the U.S. FDA, to advance in-vitro in-silico based alternative pathways to in-vitro bioequivalence (IVBE) that can result in clinical endpoint study biowaivers.