Scientific Considerations for Development of Generic OIPs via 505(j)
Bhawana (Bavna) Saluja, Ph.D. Office of Generic Drugs March 19, 2014
IPAC-RS/UF Orlando Inhalation Conference March 19, 2014
Disclaimer
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This presentation reflects the views of the author and should not be construed to represent FDA’s views or policies
Outline
• Introduction – Orally inhaled products (OIPs) – Bioequivalence (BE) recommendations for 505(j) DPIs – Scientific challenges for generic DPI development
• OGD DPI research project – Device considerations
• Single-unit dose device • Multi-unit dose device
• Conclusions
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Orally Inhaled Products (OIPs)
• Nebulizers - Several nebulizer drug products approved via 505(j) route
• Metered dose inhalers (MDIs) - Four chlorofluorocarbon (CFC)-based MDIs approved in 1990s via 505(j) route
• Dry powder inhalers (DPIs) - No generic DPIs approved
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Device and Formulation Design
Comparative In Vitro Studies
Comparative Pharmacokinetic
Studies
Comparative Pharmacodynamic or Clinical Endpoint
Studies
Generic DPIs Chemistry,
Manufacturing, and Controls
Key Scientific Considerations of 505(j) DPIs
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Generic DPIs API(s) • Material properties • API to excipient ratio
Excipient(s) • Material properties • API to excipient ratio
Device •Resistance •Aerosolization
Manufacturing Process
•Blending/filling
Patients • Inspiratory flow rates • Compliance
Scientific Challenges
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• Diversity in design of DPIs on the US market • DPI device designs patent protected • DPI performance dependent on design variables
of formulation and device • DPI Research was initiated in 2009:
Examine the effects of device and formulation factors on in vitro performance of DPIs to
– Enhance regulatory science in the respiratory drug delivery area
– Provide an approach towards developing a generic DPI
DPI Device and Formulation Design
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• Device selection
• Computational fluid dynamics (CFD) analysis – Study the flow characteristics within the device computationally
• Modifications to a test device – Match the device resistance and aerosolization performance with the reference DPI
• In vitro characterization – Spiriva capsule and formulation (tiotropium bromide monohydrate and lactose) – New Generation Cascade Impactor (NGI) – 20, 39 (4kPa) and 55 L/min to provide a reasonable coverage of the median peak
inspiratory flows stated in the Spiriva labeling
Resistance: 0.158 cmH2O0.5/Lmin-1 Unit dose Piercing mechanism (two pins)
Resistance: 0.055 cmH2O0.5/Lmin-1 Unit dose Piercing mechanism (two pins)
Spiriva HandiHaler (Reference) Cyclohaler or Aerolizer (Test)
In Vitro Comparability – Effect of Device
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CFD Analysis of HandiHaler
• 90% of the airflow enters through the primary flow inlet
– It determines fluidization and deaggregation of the DPI formulation in the capsule chamber.
• 10% of the airflow enters through the bypass inlets.
– It affects drug deposition in mouthpiece.
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Pressure Distribution Velocity Distribution
High-velocity airflow at the primary flow inlet
High pressure region at the capsule base
Annular region of low pressure
Fluctuation in the net force experienced by a capsule results
in axial vibrations of a capsule along the y-axis
y
x
Pressure Loss & Airflow Velocity within the HandiHaler
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CFD Analysis of Cyclohaler
Airflow enters a device through air inlets on the sides of capsule cavity
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Pressure Distribution Velocity Distribution
Airflow accelerates in the device creating a cyclone which moves the capsule in a swirling motion.
Great pressure drop occurs
Key Device attribute: Air Inlets • Principal control of air flow and pressure drop • Influences the forces on the capsule and hence powder fluidization and deaggregation
Pressure Losses & Airflow Velocity within the Cyclohaler
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Modifications to Cyclohaler
Cyclohaler Mod 1
Mod 2
• Narrowing the dimension of air inlets
• Narrowing the dimension of air inlets • Extending the narrow region of the air inlets
Resistance and Flow characteristics
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Cyclohaler
Slope = Resistance
Increasing velocity
Flow Rate (L/min)
MOD 1 T/R
MOD 2 T/R
Emitted Dose 20 0.82 1.10 39 0.68 1.05 55 0.82 0.99
Impactor-Sized Mass 20 1.12 1.02 39 0.96 1.04 55 0.98 0.98
Mass Median Aerodynamic Diameter
20 0.81 1.00 39 0.95 1.00 55 0.90 0.95
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In Vitro Characterization - Test and Reference Devices
Shur et al. Effect of Device Design on the In Vitro Performance and Comparability for Capsule-Based Dry Powder Inhalers. AAPS J. 2012, 14(4):667-676.
In Vitro Comparability – Effect of Device
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• Device selection
• Computational fluid dynamics (CFD) analysis – Study the flow characteristics within the device computationally
• Modifications to a test device – Match the device resistance and aerosolization performance with the reference
DPI • In vitro characterization
– Flovent Diskus and formulation (Fluticasone propionate and lactose) – New Generation Cascade Impactor (NGI) – 30, 60 and 90 L/min to provide a reasonable coverage of the median peak
inspiratory flows stated in the Flovent Diskus labeling
Resistance: 0.078 cmH2O0.5/Lmin-1 Multi-Unit dose
Resistance: 0.089 cmH2O0.5/Lmin-1 Multi-Unit dose
Flovent Diskus (Reference) Cipla MultiHaler (Test)
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CFD Analysis of Diskus
• 93% of the airflow enters through the by-pass.
• 7% of the airflow enters through the blister pocket.
• Flow split plays a significant role in balancing the effects of fluidization and de-aggregation in the blister pocket, by-pass and the mouthpiece.
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Pressure Distribution Velocity Distribution
High-velocity airflow at the mouthpiece
Pressure loss across blister ~700 Pa
Fluidization of DPI formulation
Large pressure differential between
the airflow
Airflow velocity in the blister was
about 30 m/s
Pressure Loss & Airflow Velocity within the Diskus
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CFD Analysis of MultiHaler
• 92% of the airflow enters through the lever arm
• 8% of the airflow enters through the cartridge
• Different mechanism of accessing, fluidizing and entraining dose in comparison to Diskus
• Cartridge is perforated to actuate dose
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Pressure Distribution Velocity Distribution
Pressure loss across blister ~2500 Pa
Airflow velocity in the cartridge 60 m/s
• Pressure and velocity profiles across the MultiHaler cartridge greater than Diskus which indicates that the air-path of both devices are different.
• The process of powder fluidization and entrainment would be very different from Diskus and therefore the pharmaceutical performance of the MultiHaler may also be different to that of the Diskus.
Pressure Loss & Airflow Velocity within the MultiHaler
Modifications to MultiHaler
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Air Channel 1
Air Channel 2
MUDI MOD 1 Air Channel 1
MUDI MOD 2 Air Channel 1 and 2
Resistance and Flow Characteristics
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MultiHaler
Slope = Resistance
Increasing velocity
MOD MH 1
MOD MH 2
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Air Channel 1
Air Channel 2
CFD Velocity Profile
Modifications to MultiHaler
In Vitro Characterization - Test and Reference Devices
Flow Rate (L/min)
MOD MH 1 T/R
MOD MH 2 T/R
Emitted Dose 30 0.47 1.00 60 0.69 0.94 90 0.75 0.96
Impactor-Sized Mass 30 0.58 1.13 60 0.86 1.14 90 0.72 0.99
Mass Median Aerodynamic Diameter
30 1.02 0.93 60 0.99 0.94 90 0.92 0.96
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Conclusions • Understanding of device aerosolization
characteristics are important in achieving in vitro equivalence of DPIs
• Critical DPI device attributes (i.e., dimensions of air inlets) need to be identified
• Product (device and formulation) and process understanding is essential in developing a test DPI bioequivalent to the reference DPI
Acknowledgements
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• Office of Generic Drugs – Robert Lionberger, Ph.D.
• Office of Pharmaceutical Science – Sau (Larry) Lee, Ph.D. – Lawrence Yu, Ph.D.
• University of Bath, United Kingdom
– Robert Price, Ph.D. – Jagdeep Shur, Ph.D.