This presentation guides ANDA preparation for Orally Inhaled and Nasal Drug Products. It gives a few in vitro models mimicking inhalation.

1. Prof. (Dr.) Bhaswat S. Chakraborty
Emeritus Professor, Institute of Pharmacy, Nirma University
Former Sr.VP &Chair, R&D, Cadila Pharmaceuticals
Former Director, Biopharmaceutics, Biovail, Toronto
Former Sr. Efficacy & Safety Reviewer, TPD (Canadian FDA),
Ottawa
Respiratory Studies: right
approach in designs

2. Orally Inhaled And Nasal Drug Products
(OINDPs)
Performance of orally inhaled and nasal drug products
(OINDPs) is governed by complex interactions
between device, formulation, and patient factors
Because existing in vitro methods have limited
predictability of these interactions, both development
and BE demonstration of generic OINDPs is
For this reason, even though there is a current, clear
regulatory pathway utilizing the weight-of-evidence
approach for BE assessment of OINDPs, the OGD is
exploring new methods to make development and BE
assessment of OINDPs more cost and time-effective in
the future:
© 2019 Prof. Bhaswat Chakraborty 2

3. Research for BE of OINDPs
1) Identification of formulation and device variables which are
important for successful development of generic OINDPs
2) Development of clinically relevant in vitro tools for
prediction of in vivo regional drug deposition and dissolution
from OINDPs
3) Development of computational fluid dynamic (CFD) and
physiology-based pharmacokinetic (PBPK) models for
prediction of the fate of drugs delivered through OINDPs and
to assess their applicability in generic OINDP development
programs
4) Identification, validation and standardization of novel
techniques that may have the potential to reduce the burden
of current BE requirements for generic OINDPs
© 2019 Prof. Bhaswat Chakraborty 3

4. Research for BE of OINDPs..
Advanced in vitro/in silico methods such as CFD modelling
and clinically relevant in vitro dissolution and deposition tests
are being used to understand and predict performance of
OIDNPs in a realistic way
These clinically relevant in vitro methods have shown good in
vivo predictability of regional nasal and lung drug deposition
and dissolution AND
Local and systemic drug bioavailability of OIDNPs
See next slides
© 2019 Prof. Bhaswat Chakraborty 4

5. Model Simulations
Model simulations gives insight to the understanding of the
absorption of inhaled corticosteroids (ICS) and will support
and facilitate development of PSGs for generic drug
development
In support of these objectives, droplet size distributions
(DSDs) from three commercial nasal sprays were
determined at three different actuation pressures using laser
diffraction
Computational fluid dynamics (CFD) models of the nasal
passages of healthy and rhinitic subjects were developed to
simulate the transport and deposition of droplets
© 2019 Prof. Bhaswat Chakraborty 5

6. Model Simulations..
CFD simulation results for the three nasal sprays were used as
model inputs to simulate absorption of the corticosteroids
fluticasone propionate and budesonide
The PBPK models included the effects of mucociliary
clearance, drug dissolution, diffusion through nasal epithelial
layers, binding kinetics to the glucocorticoid receptor, liver
metabolism, and systemic clearance
The PBPK models can be used to determine which
physicochemical properties of the ICS affect the absorption
and systemic bioavailability
Also data from a CFD model of a human nasal cavity also
indicated that local delivery of several ICSs may not be
sensitive to actuation force when assessed across the range
normally seen within a clinical setting
© 2019 Prof. Bhaswat Chakraborty 6

7. Computational fluid dynamics (CFD) model
© 2019 Prof. Bhaswat Chakraborty
A B
(A) CFD predictions of the droplet deposition pattern of fluticasone propionate nasal
spray at a typical actuation pressure in a healthy adult nasal model. (B): PBPK model
simulations of the dissolution and absorption of fluticasone propionate (FP) and
budesonide (BUD) in the nasal mucosa [Figures are courtesy of Applied Research
Associates].
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8. Lung Models Combining CFD with PBPK
Modelling
© 2019 Prof. Bhaswat Chakraborty
A B
Integrated computational framework for pulmonary drug delivery and PBPK-
PD simulation.
[Figures are courtesy of CFD Research Corporation]
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9. Predicted Inhaled Plasma Concentrations
© 2019 Prof. Bhaswat Chakraborty
The predicted inhaled plasma PK values for momentasone furoate (left),
budesonide (center) and fluticasone propionate (right) simulations is shown
in comparison with experimental data [Figures are courtesy of CFD Research
Corporation]
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10. Predicted Inhaled Plasma Concentrations
© 2019 Prof. Bhaswat Chakraborty
The FDA explored various realistic mouth throat models that
are currently used by industry and academia to compare their
in vivo predictability
The experimental setup and inhalation profiles for a test dry
powder inhaler are shown in next two slides
The test dry powder inhaler’s in vitro performance may be
dependent on both the mouth-throat geometric size and the
inhalation profile
The studies have also evaluated the developed method using
a metered dose inhaler and a soft mist inhaler
This method, by incorporating both airway geometry and
inhalation profiles, allows assessment of aerodynamic particle
size distribution in a clinically relevant manner
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11. Predicted Inhaled Profiles
© 2019 Prof. Bhaswat Chakraborty
Left (a): Experimental setup to measure total lung dose in vitro and its aerodynamic
particle size distributions for drug aerosols delivered from an inhaler. The side inlet of
the Nephele Mixing Inlet (NMI) is also connected to a breath simulator and
compressed air source. Right (b): Inhalation profiles for the test inhaler
representative of subjects trained at fast inhalation condition
[Figures are courtesy of Dr. Michael Hindle, Virginia Commonwealth University]
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12. Dissolution Method 1
© 2019 Prof. Bhaswat Chakraborty
Left Selected Transwell® system for the evaluation of the dissolution rate of inhalation
drugs. Right Differences in the dissolution rate of three model corticosteroids (Bud:
budesonide DPI; CIC: ciclesonide MDI; FP: fluticasone propionate DPI) as assessed by
the Transwell® system [Figures are courtesy of Dr. Guenther Hochhaus, University of Florida].
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13. Dissolution Method 2
© 2019 Prof. Bhaswat Chakraborty
Left Modified stage assemblies of the Andersen cascade impactor (ACI) operated at 28.3, 60
and 90 L/min of the airflow rate to collect ≤ 5.8, ≤ 6.5 and ≤ 6.5 µm ‘respirable’ drug aerosols
from inhaler products onto the 70 mm filter membrane placed under Stage 7, 6 and 5,
respectively. Right Dissolution and permeation of the ‘respirable’ aerosol drug particles in the
Transwell® dish system. The filter membrane was placed, with the deposited drug face down,
onto the donor compartment, followed by addition of 10 mL aqueous fluid to initiate aerosol drug
dissolution and permeation into the receptor fluid at 37oC and near 100% relative humidity
[Figures are courtesy of Dr. Mashahiro Sakagami, Virginia Commonwealth University].
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14. © 2019 Prof. Bhaswat Chakraborty
Superimposed data and statistical models for three MDI formulations manufactured according to a
design of experiments (DoE) approach for delivered dose (DD) at beginning of canister life and
fine particle dose < 5µm (FPD<5). The models were determined based on the formulation
parameters that were found to significantly impact the given performance metric [Figures are
courtesy of Dr. Poonam Aliyah Sheth, Recipharm Laboratories Inc.].
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15. © 2019 Prof. Bhaswat Chakraborty
Hochhaus et al. AAPS J. 2015 Sep; 17(5): 1305–1311.
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16. References
https://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/u
cm549167.htm
Santos et al. AAPS PharmSciTech. 2018 Oct;19(7):3134-3140. doi:
10.1208/s12249-018-1154-5. Epub 2018 Aug 20.
https://www.ncbi.nlm.nih.gov/pubmed/26033698
© 2019 Prof. Bhaswat Chakraborty 16

17. Ask