Leveraging Modeling and Simulation to Enhance the Efficiency of Bioequivalence Approaches for Generic Drugs: Highlights from the 2023 Generic Drug Science and Research Initiatives Public Workshop.

The 2023 Generic Drug Science and Research Initiative Public Workshop organized by the U.S. Food and Drug Administration (FDA) discussed the research needs to improve and enhance bioequivalence (BE) approaches for generic drug development. FDA takes such research needs and panel discussions into account to develop its Generic Drug User Fee Amendments III (GDUFA III) Science and Research Initiatives specific to generics. During the five workshop sessions, presentations and panel discussions focused on identifying and addressing scientific gaps and research needs related to nitrosamine impurity issues, BE assessment for oral products, innovative BE approaches for long-acting injectable products, alternative BE approaches for orally inhaled products, and advanced BE methods for topical products. Specifically, this report highlights the discussions on how to improve BE assessment for developing generic drug products based on research priorities for leveraging quantitative methods and modeling, as well as artificial intelligence/machine learning (AI/ML).

Use of the Same Model or Modeling Strategy Across Multiple Submissions: Focus on Complex Drug Products.

Evidence shows that there is an increasing use of modeling and simulation to support product development and approval for complex generic drug products in the USA, which includes the use of mechanistic modeling and model-integrated evidence (MIE). The potential for model reuse was the subject of a workshop session summarized in this review, where the session included presentations and a panel discussion from members of the U.S. Food and Drug Administration (FDA), academia, and the generic drug product industry. Concepts such as platform performance assessment and MIE standardization were introduced to provide potential frameworks for model reuse related to mechanistic models and MIE, respectively. The capability of models to capture formulation and product differences was explored, and challenges with model validation were addressed for drug product classes including topical, orally inhaled, ophthalmic, and long-acting injectable drug products. An emphasis was placed on the need for communication between FDA and the generic drug industry to continue to foster maturation of modeling and simulation that may support complex generic drug product development and approval, via meetings and published guidance from FDA. The workshop session provided a snapshot of the current state of modeling and simulation for complex generic drug products and offered opportunities to explore the use of such models across multiple drug products.

CFD-DEM investigation of the effects of aperture size for a capsule-based dry powder inhaler.

Capsule based dry powder inhalers (DPIs) often require piercing of the capsule before inhalation, and the characteristics of the apertures (punctured holes) affect air flow and the release of powders from the capsule. This work develops a numerical model based on the two-way coupling of computational fluid dynamics and discrete element method (CFD-DEM) to investigate the effect of aperture size on powder dispersion in the Aerolizer® device loaded with only carrier particles (lactose). Powders (carrier particles) in the size range 60-140 µm (d50: 90 µm and span: 0.66) were initialized in a capsule which had a circular aperture at each end. Boundary conditions corresponding to an air flow rate of 45 L/min were specified at each inlet to the mixing chamber (i.e., a total flow rate 90 L/min), and a capsule spin speed of âˆ¼ 4050 rpm. The velocity magnitudes inside the capsule were considerably lower than those in the mixing chamber in the vicinity of the rotating capsule, with the exception of the capsules featuring 2.5 mm and 4 mm apertures. Larger apertures reduced the capsule emptying time and increased the particle evacuation velocity; the fluid drag force on the particles issuing from the capsule peaked for an aperture of 1.3 mm. Inside the capsule, particle-particle (PP) collisions were more frequent than particle-wall (PW) collisions due to high concentration of powder, but PP collisions had smaller (median) impact energy than PW collisions. Larger apertures resulted in fewer collisions in the capsule with higher PW and virtually unchanged PP collision energies. Outside the capsule (i.e., in the inhaler mixing chamber), PW collisions occurred more frequently than PP collisions with median collision energies typically two orders of magnitude higher than inside the capsule. Larger apertures resulted in more collisions with slightly reduced collision energy, but this effect plateaued for aperture sizes larger than 1.3 mm. Powder dispersion, expressed as the fine particle fraction (FPF) of the powder, was predicted using an empirical equation based on carrier PW collisions. Therefore, consistent with the model prediction of the effect of aperture sizes on the chamber collision frequency, FPF increased with aperture size but plateaued beyond 1.3 mm.

The role of capsule aperture size on the dispersion of carrier-based formulation at different air flowrates.

The effect of capsule aperture size on the aerosol performance of lactose blend formulation was studied using Foradil® (containing 12 µg of formoterol fumarate (FF1) and 24 mg of lactose) dispersed with a powder inhaler Aerolizer® at increasing air flowrates. Apertures sizes of 0.4, 1.0, 1.5, 2.5, and 4.0 mm were introduced at the opposite ends of the capsule. The formulation was dispersed into a Next Generation Impactor (NGI) at 30, 60 and 90 L/min, with the fine particle fractions (FPFrec and FPFem) measured by chemical assay of FF and lactose using high-performance liquid chromatography. Particle size distribution (PSD) of FF particles dispersed in wet media was also characterized by laser diffraction. FPFrec showed a stronger dependency on the flowrate than the capsule aperture size. The most efficient dispersion was achieved at 90 L/min. At a given flowrate, FPFem remained broadly constant across different aperture sizes. The laser diffraction studies demonstrated the presence of large agglomerates.

Transport and deposition of beclomethasone dipropionate drug aerosols with varying ethanol concentration in severe asthmatic subjects.

This study aims to assess the effects of varying an ethanol co-solvent on the deposition of drug particles in severe asthmatic subjects with distinct airway structures and lung functions using computational fluid dynamics. The subjects were selected from two quantitative computed tomography imaging-based severe asthmatic clusters, differentiated by airway constriction in the left lower lobe. Drug aerosols were assumed to be generated from a pressurized metered-dose inhaler (MDI). The aerosolized droplet sizes were varied by increasing the ethanol co-solvent concentration in the MDI solution. The MDI formulation consists of 1,1,2,2-tetrafluoroethane (HFA-134a), ethanol, and beclomethasone dipropionate (BDP) as the active pharmaceutical ingredient. Since HFA-134a and ethanol are volatile, both substances evaporate rapidly under ambient conditions and trigger condensation of water vapor, increasing the size of aerosols that are predominantly composed of water and BDP. The average deposition fraction in intra-thoracic airways for severe asthmatic subjects with (or without) airway constriction increased from 37%±12 to 53.2%±9.4 (or from 20.7%± 4.6 to 34.7%±6.6) when the ethanol concentration was increased from 1 to 10%wt/wt. However, when the ethanol concentration was further increased from 10 to 20%wt/wt, the deposition fraction decreased. This indicates the importance of selecting appropriate co-solvent amounts during drug formulation development for the treatment of patients with narrowed airway disease. For severe asthmatic subjects with airway narrowing, the inhaled aerosol may benefit from a low hygroscopic effect by reducing ethanol concentration to penetrate the peripheral region effectively. These results could potentially inform the selection of co-solvent amounts for inhalation therapies in a cluster-specific manner.

Computational Model of In Vivo Corneal Pharmacokinetics and Pharmacodynamics of Topically Administered Ophthalmic Drug Products.

INTRODUCTION: Although the eye is directly accessible on the surface of the human body, drug delivery can be extremely challenging due to the presence of multiple protective barriers in eye tissues. Researchers have developed complex formulation strategies to overcome these barriers to ophthalmic drug delivery. Current development strategies rely heavily on in vitro experiments and animal testing to predict human pharmacokinetics (PK) and pharmacodynamics (PD). OBJECTIVE: The primary objective of the study was to develop a high-fidelity PK/PD model of the anterior eye for topical application of ophthalmic drug products. METHODS: Here, we present a physiologically-based in silico approach to predicting PK and PD in rabbits after topical administration of ophthalmic products. A first-principles based approach was used to describe timolol dissolution, transport, and distribution, including consideration of ionized transport, following topical instillation of a timolol suspension. RESULTS: Using literature transport and response parameters, the computational model described well the concentration-time and response-time profiles in rabbit. Comparison of validated rabbit model results and extrapolated human model results demonstrate observable differences in the distribution of timolol at multiple time points. CONCLUSION: This modeling framework provides a tool for model-based prediction of PK in eye tissues and PD after topical ophthalmic drug administration to the eyes.

Establishing quantitative relationships between changes in nasal spray in vitro metrics and drug delivery to the posterior nasal region.

Nasal sprays are typically characterized using in vitro spray metrics such as spray cone angle and droplet size distribution. It is currently not clear how these in vitro metrics correlate with regional nasal deposition, and these relationships could help explain the impact of product differences. In this study, the effects of changes in spray cone angle, spray velocity, spray ovality and droplet size distribution on regional nasal deposition were analyzed using a validated computational fluid dynamics model in recently developed adult characteristic nasal airway anatomies. The impact of the spray on the surrounding air phase was included. Results indicated that changes in spray cone angle largely influenced the nasal posterior deposition (PD) of the drug. Changes in the plume ovality and characteristic droplet size moderately influenced PD, but the results were dependent on the insertion conditions and nasal geometry. Changes in spray velocity and uniformity constant of the droplet size distribution had only minimal influence on PD. The rank order of metrics having the greatest to least impact on PD was cone angle ≫ plume ovality ≫ characteristic droplet size ≫ velocity ≫ size distribution uniformity constant. Overall, results from this study established quantitative relationships for predicting expected changes in PD.

Mechanistic modeling of ophthalmic, nasal, injectable, and implant generic drug products: A workshop summary report.

For approval, a proposed generic drug product must demonstrate it is bioequivalent (BE) to the reference listed drug product. For locally acting drug products, conventional BE approaches may not be feasible because measurements in local tissues at the sites of action are often impractical, unethical, or cost-prohibitive. Mechanistic modeling approaches, such as physiologically-based pharmacokinetic (PBPK) modeling, may integrate information from drug product properties and human physiology to predict drug concentrations in these local tissues. This may allow clinical relevance determination of critical drug product attributes for BE assessment during the development of generic drug products. In this regard, the Office of Generic Drugs of the US Food and Drug Administration has recently established scientific research programs to accelerate the development and assessment of generic products by utilizing model-integrated alternative BE approaches. This report summarizes the presentations and panel discussion from a public workshop that provided research updates and information on the current state of the use of PBPK modeling approaches to support generic product development for ophthalmic, injectable, nasal, and implant drug products.

Regulatory utility of mechanistic modeling to support alternative bioequivalence approaches: A workshop overview.

On September 30 and October 1, 2021, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics cosponsored a live virtual workshop titled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches." The overall aims of the workshop included (i) engaging the generic drug industry and other involved stakeholders regarding how mechanistic modeling and simulation can support their product development and regulatory submissions; (ii) sharing the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (iii) establishing a consensus on best practices for using mechanistic modeling approaches, such as physiologically based pharmacokinetic modeling and computational fluid dynamics modeling, for BE assessment; and (iv) introducing the concept of a Model Master File to improve model sharing between model developers, industry, and the FDA. More than 1500 people registered for the workshop. Based on a postworkshop survey, the majority of participants reported that their fundamental scientific understanding of mechanistic models was enhanced, there was greater consensus on model validation and verification, and regulatory expectations for mechanistic modeling submitted in abbreviated new drug applications were clarified by the workshop.

Mechanistic modeling of generic orally inhaled drug products: A workshop summary report.

In silico mechanistic modeling approaches have been designed by various stakeholders with the goal of supporting development and approval of generic orally inhaled drug products in the United States. This review summarizes the presentations and panel discussion that comprised a workshop session concentrated on the use of in silico models to predict various outcomes following orally inhaled drug product administration, including the status of such models and how model credibility may be effectively established.

Clinical Ocular Exposure Extrapolation for Ophthalmic Solutions Using PBPK Modeling and Simulation.

BACKGROUND: The development of generic ophthalmic drug products is challenging due to the complexity of the ocular system, and a lack of sensitive testing to evaluate the interplay of physiology with ophthalmic formulations. While measurements of drug concentration at the site of action in humans are typically sparse, these measurements are more easily obtained in rabbits. The purpose of this study is to demonstrate the utility of an ocular physiologically based pharmacokinetic (PBPK) model for translation of ocular exposure from rabbit to human. METHOD: The Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® v9.8.2 was used to build PBPK models for levofloxacin (Lev), moxifloxacin (Mox), and gatifloxacin (Gat) ophthalmic solutions. in the rabbit eye. The models were subsequently used to predict Lev, Mox, and Gat exposure after ocular solution administrations in humans. Drug-specific parameters were used as fitted and validated in the rabbit OCAT model. The physiological parameters were scaled to match human ocular physiology. RESULTS: OCAT model simulations for rabbit well described the observed concentrations in the eye compartments following Lev, Mox, and Gat solution administrations of different doses and various administration schedules. The clinical ocular exposure following ocular administration of Lev, Mox, and Gat solutions at different doses and various administration schedules was well predicted. CONCLUSION: Even though additional case studies for different types of active pharmaceutical ingredients (APIs) and formulations will be needed, the current study represents an important step in the validation of the extrapolation method to predict human ocular exposure for ophthalmic drug products using PBPK models.

Scientific and regulatory activities initiated by the U.S. Food and drug administration to foster approvals of generic dry powder inhalers: Bioequivalence perspective.

Regulatory science for generic dry powder inhalers (DPIs) in the United States (U.S.) has evolved over the last decade. In 2013, the U.S. Food and Drug Administration (FDA) published the draft product-specific guidance (PSG) for fluticasone propionate and salmeterol xinafoate inhalation powder. This was the first PSG for a DPI available in the U.S., which provided details on a weight-of-evidence approach for establishing bioequivalence (BE). A variety of research activities including in vivo and in vitro studies were used to support these recommendations, which have led to the first approval of a generic DPI in the U.S. for fluticasone propionate and salmeterol xinafoate inhalation powder in January of 2019. This review describes the scientific and regulatory activities that have been initiated by FDA to support the current BE recommendations for DPIs that led to the first generic DPI approvals, as well as research with novel in vitro and in silico methods that may potentially facilitate generic DPI development and approval.

Scientific and regulatory activities initiated by the U.S. food and drug administration to foster approvals of generic dry powder inhalers: Quality perspective.

Regulatory science for generic dry powder inhalation products worldwide has evolved over the last decade. The revised draft guidance Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - Quality Considerations [1] (Revision 1, April 2018) that FDA issued summarizes product considerations and potential critical quality attributes (CQAs). This guidance emphasizes the need to apply the principles of quality by design (QbD) and elements of pharmaceutical development discussed in the International Conference for Harmonisation of (ICH) guidelines. Research studies related to quality were used to support guidance recommendations, which preceded the first approval of a generic DPI product in the U.S. This review outlines scientific and regulatory hurdles that need to be surmounted to successfully bring a generic DPI to the market. The goal of this review focuses on relevant issues and various challenges pertaining to CMC topics of the generic DPI quality attributes. Furthermore, this review provides recommendations to abbreviated new drug application (ANDA) applicants to expedite generic approvals.

Anatomically realistic nasal replicas capturing the range of nasal spray drug delivery in adults.

To improve the relationships between commonly conducted in vitro studies for locally-acting nasal spray drug products with in vivo regional deposition, this study developed a set of in vitro adult nasal geometries that captured the range of nasal drug delivery to the region posterior to internal nasal valve (INV), also known as posterior delivery (PD), and evaluated their performance with existing in vivo data. The PD of fluticasone propionate (FP) and fluticasone furoate (FF) in 40 nasal cavities was statistically analyzed to identify three airway models representing the low, mean, and high PD in adults. The models were also externally validated by comparing the in vitro nasal deposition from a different drug product (mometasone furoate (MF)) with the relevant in vivo data. The three selected geometries represented the low, mean, and high PD with multiple nasal sprays. They were verified in terms of reproducibility of in vitro data and validated by showing a reasonable agreement with preexisting in vivo MF PD despite differences in administration and defining the regions. The three models are envisioned to potentially facilitate the development of locally-acting nasal sprays and provide a better understanding of how in vitro metrics relate to in vivo regional nasal deposition.

Considerations for the Forced Expiratory Volume in 1 Second-Based Comparative Clinical Endpoint Bioequivalence Studies for Orally Inhaled Drug Products.

Herein, we present the US Food and Drug Administration (FDA) Office of Research and Standards' current thinking, challenges, and opportunities for comparative clinical endpoint bioequivalence (BE) studies of orally inhaled drug products (OIDPs). Given the product-associated complexities of OIDPs, the FDA currently uses an aggregate weight-of-evidence approach to demonstrate that a generic OIDP is bioequivalent to its reference listed drug. The approach utilizes comparative clinical endpoint BE or pharmacodynamic BE studies, pharmacokinetic BE studies, and in vitro BE studies to demonstrate equivalence, in addition to formulation sameness and device similarity. For the comparative clinical endpoint BE studies, metrics based on forced expiratory volume in the first second (FEV1 ) are often the recommended clinical endpoints. However, the use of FEV1 can pose a challenge due to its large variability and a relatively flat dose-response relationship for most OIDPs. The utility of applying dose-scale analysis was also investigated by the FDA but often not recommended, due to either flat dose-response relationships or insufficient clinical study data. As a potential way to reduce sample size, we found adapting covariate analysis only explained a limited portion of the variation based on further investigation. The FDA continues to develop alternative methods to make BE assessment of OIDPs more cost- and time-efficient. Prospective generic drug applicants and academia are encouraged to participate in this effort by proposing new approaches in pre-abbreviated new drug application meeting requests and collaborating in the form of grants and contracts under the Generic Drug User Fee Amendments (GDUFA) Regulatory Science and Research Program.

Effect of inflow conditioning for dry powder inhalers.

The transport of pharmaceutical dry powder inside an optically accessible inhaler-like device is studied using both macro- and microscopic high-speed imaging. The investigation aims to systematically study the effect of inflow modifications on the dispersion characteristics of agglomerates inside a dry powder inhaler (DPI) geometry. An inhaler device was designed with geometrical features akin to commercial inhalers used in the current market and research oriented inhalers such as the Twincer®: two offset inlet channels (one with a powder pocket), a clockwise swirling chamber and a single outlet channel. At the device outlet, a vacuum pump was fitted with an actuator and calibrated to achieve a steady state inhalation with a peak flowrate of 85 and 125 L/min. Airflow conditions at the intake of the device were strategically perturbed in order to induce powder fluidisation and dispersion using turbulence grids and through physically obstructing channel streams in order to achieve changes in flow behaviour (e.g., flow separation). Complete fluidisation of the powder bed was observed with image processing enabling statistics on de-agglomerated fragment size and velocity. A range of behaviour was noted including local turbulence through introduction of a grid, bimodal fragment size behaviour for cohesive mannitol powder, as well as introduction of low velocity zones in the device through flow splitting. The geometry enables simple systematic study of inflow conditions into a DPI-like device with the data being useful for study of a given powder formulation (mannitol) and validation of computational models.

A quasi-3D model of the whole lung: airway extension to the tracheobronchial limit using the constrained constructive optimization and alveolar modeling, using a sac-trumpet model.

Existing computational models used for simulating the flow and species transport in the human airways are zero-dimensional (0D) compartmental, three-dimensional (3D) computational fluid dynamics (CFD), or the recently developed quasi-3D (Q3D) models. Unlike compartmental models, the full CFD and Q3D models are physiologically and anatomically consistent in the mouth and the upper airways, since the starting point of these models is the mouth-lung surface geometry, typically created from computed tomography (CT) scans. However, the current resolution of CT scans limits the airway detection between the 3rd-4th and 7th-9th generations. Consequently, CFD and the Q3D models developed using these scans are generally limited to these generations. In this study, we developed a method to extend the conducting airways from the end of the truncated Q3D lung to the tracheobronchial (TB) limit. We grew the lung generations within the closed lung lobes using the modified constrained constructive optimization, creating an aerodynamically optimized network aiming to produce equal pressure at the distal ends of the terminal segments. This resulted in a TB volume and lateral area of ∼165 cc and ∼2000 cm2, respectively. We created a "sac-trumpet" model at each of the TB outlets to represent the alveoli. The volumes of the airways and the individual alveolar generations match the anatomical values by design: with the functional residual capacity at 2611 cc. Lateral surface areas were scaled to match the physiological values. These generated Q3D whole lung models can be efficiently used for conducting multiple breathing cycles of drug transport and deposition simulations.

In vitro evaluation of regional nasal drug delivery using multiple anatomical nasal replicas of adult human subjects and two nasal sprays.

Quantifying drug delivery to the site of action using locally-acting nasal suspension sprays is a challenging but important step toward understanding bioequivalence (BE) between test and reference products. The main objective of this study was to investigate the in vitro deposition pattern of two common but different locally-acting nasal suspension sprays using multiple nasal cavities. Twenty anatomically accurate nasal replicas were developed from high-resolution sinonasal computed tomography scans of adults with healthy nasal airways. The airways were segmented into two regions of anterior and posterior to the internal nasal valve. Both sides of the septum were considered separately; hence, 40 nasal cavities were studied. The positioning of the spray nozzle in all 40 cavities was characterized by the head angle, coronal angle, and the insertion depth. Despite using a controlled protocol to minimize the anterior losses, a wide range of variability in posterior drug delivery was observed. The observed intersubject variability using this in vitro method may have important implications for understanding BE of locally-acting nasal suspension sprays.

Assessment and Validation of a Hygroscopic Growth Model with Different Water Activity Estimation Methods.

Hygroscopic growth models are currently of interest as aids for targeting the deposition of inhaled drug particles in preferred areas of the lung that will maximize their pharmaceutical effect. Mathematical models derived to estimate hygroscopic growth over time have been previously developed but have not been thoroughly validated. For this study, model validation involved a comparison of modeled values to measured values when the growing droplet had reached equilibrium. A second validation process utilized a novel system to measure the growth of a droplet on a microscope coverslip relative to modeled values when the droplet is undergoing the initial rapid growth phase. Various methods currently used to estimate the water activity of the growing droplet, which influences the droplet growth rate, were also compared. Results indicated that a form of the hygroscopic growth model that utilizes coupled-differential equations to estimate droplet diameter and temperature over time was valid throughout droplet growth until it reached its equilibrium size. Accuracy was enhanced with the use of a polynomial expression to estimate water activity relative to the use of a simplified estimate of water activity based on Raoult's Law. Model accuracy was also improved when constraining the film of salt solution surrounding the dissolving salt core at saturation.