Scientific Considerations for Development of Generic …€¦ · Scientific Considerations for...

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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

Transcript of Scientific Considerations for Development of Generic …€¦ · Scientific Considerations for...

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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

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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

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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

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Resistance and Flow characteristics

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Cyclohaler

Slope = Resistance

Increasing velocity

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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.

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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

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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

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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

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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

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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.