Mylan

Quality Assessment of

Inhalation Products –

Industry Perspective

Focus on MDI/DPI

Products

S. Wayne Talton

May 17, 2016

This presentation reflects the views of

the speaker and does not reflect official

Mylan opinion or policy.

2

Overview

• FDA Guidelines for MDIs and DPIs

– 1998 MDI/DPI guidance

– Product specific BE guidances

• Device Development and Guidelines

• Current Formatting Challenges in preparing a MDI/DPI

ANDA

– Device

– Pharmaceutical Development

– QbR

• Post approval changes

3

DPIs – Complex development program

Device

Development

Formulation

Development

Complex development program

Establish

bioequivalence

with reference

product

Product

Development

4

FDA Guidelines for MDI/DPI Products

2003 2013 2016 1998

1998

MDI/DPI

guidance

Fluticasone Propionate;

Salmeterol Xinafoate –

Inhalation Powder

• Beclomethasone dipropionate

• Ciclesonide

• Fluticasone furoate; Vilanterol trifenatate -

Inhalation powder

• Indacaterol maleate Inhalation Powder

• Fluticasone furoate Inhalation Powder

• Mometasone furoate

• Formoterol fumarate; Mometasone furoate

Integration of Dose-

Counting Mechanisms

into MDI Drug Products

• Budesonide; Formoterol

fumarate dihydrate

• Formoterol fumarate

• Levalbuterol tartrate

• Ipratropium bromide

2015

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Guidance for Industry; Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products

MDI/DPIs are complex products consisting of formulation

and device

Guidance covers the critical features that should be considered

when developing the product and documentation for a NDA/ANDA:

Components API and Excipients and their Specification

Manufacturers/method of manufacturing, IPCs and Packaging

Specification of Drug Product

Container closure system CCS (device and packaging) Clinical efficacy linked to design, reproducibility

and performance of CCS

Stability

Drug Product Characterisation studies

Describes studies to be conducted on commercial product

Labelling considerations

Highlights the requirement to demonstrate reproducibility of dose and

particle size distribution through the product shelf life

6

CDER:

Revised

Draft due in

2016

• Current guidance is prescriptive (pros and cons)

• Pre-dates cGMPs for 21st Century

Planned update – an opportunity

• To embed ICH Q 8 & 9 into MDI/DPI development

• Provide principles, rather than specifics, that allow

flexibility across the diverse range of MDI/DPI

products.

Guidance for Industry; Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products

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MDI/DPI Product Specific BE Guidance

• Fluticasone propionate/Salmeterol xinafoate (FP/SX) inhalation powder (Sept

2013)

• Budesonide; Formoterol fumarate dihydrate inhalation aerosol, metered (2015)

• Formoterol fumarate inhalation powder (2015)

• Levalbuterol tartrate inhalation aerosol, metered (2015)

• Ipratropium bromide inhalation aerosol, metered (2015)

• Beclomethasone dipropionate inhalation aerosol, metered (Jan 2016)

• Formoterol fumarate; Mometasone furoate inhalation aerosol, metered (Jan 2016)

• Ciclesonide inhalation aerosol, metered (Jan 2016)

• Mometasone furoate inhalation aerosol, metered (April 2016) • Fluticasone furoate; Vilanterol trifenatate - Inhalation powder (Apr 2016)

• Indacaterol maleate Inhalation Powder (April 2016)

• Fluticasone furoate Inhalation Powder (April 2016)

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Product Specific BE Guidance Fluticasone Furoate; Vilanterol Trifenatate DPI

In Vitro Studies

DPI

Equivalence of SAC

& APSD

PK BE studies

Equivalence based

on AUC and Cmax

CE Study

Equivalence based

on T/R ratio for

primary endpoints

Formulation design

Q1/Q2 equivalence

Device Design

Recommends device

characteristics

& Robustness

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MDI/DPI Device guidances

• No ‘stand alone’ device specific MDI/DPI guidance

• Device development strategy should incorporate guidance and requirements

from multiple sources as well as global requirements as applicable

– Guidance for Industry; Container Closure Systems for Packaging Human Drugs and

Biologics, 1999

– ISO standards

• ISO13485; quality management systems

• ISO 20072; Design Verification Testing

• ISO 10993 biocompatability

– 21 CFR 820.30; Design Controls

• D&D Planning

• D&D Inputs

• D&D Outputs

• D&D Reviews

• D&D Verification

• D&D Validation

• D&D Change Control

– The above is summarised in FDA guidance –

‘Design control for medical device manufacturers’

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Device Development

Medical Device

Validation

Verification

Design Review

Risk Management

User Needs Design

Input Design Process

Design Output

Prototype

Filing

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Preparing a MDI/DPI ANDA – Formatting

Challenges; Device

• Location of Device information within eCTD structure

– Container closure information split between two sections

• P.2.4 The suitability of the container closure system

• P.7 Container closure Description, specifications and methods

– Inconsistent approach across industry- where to include total package of device

information generated during development

• P.2.4, P.7 or Regional section

– Recently issued eCTD conformance guidance (October 2015)

• Provides further clarity on FDA expectations

• If referencing a Type III DMF, what is the right balance of information to

include in the ANDA?

• Ensure device information is clearly presented to aid review

– Difference in formats across companies

– Risk that reviewers think information is missing

– Does ‘one size fits all’ structure work?

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Preparing a MDI/DPI ANDA – Formatting

Challenges: Pharmaceutical Development

Design Highly

Complex Quality

Inhaled Product

Understand RLD

Product Performance

Develop Robust

Manufacturing process

• Product specific BE

guidance

• USP MDI/DPI

monograph criteria

• Sets the criteria that

drive development

of test product

• Impact of process on

product performance

• Scalability of

manufacturing process

• Meet standard criteria for

Pharm. Dev. plus

• MDI/DPI guidance

• Device design

requirements and

guidance

• Technically challenging and

time consuming to develop

and test

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Preparing a MDI/DPI ANDA – Formatting

Challenges: Pharmaceutical Development

3.2.P.2 Pharmaceutical development - complex and lengthy

compared to a more standard ANDA P2 section

• Requires expansion to standard eCTD P2 structure

– E.g. extensive RLD information

• Useful FDA examples available to aid preparation of P2

– Quality by design for ANDAs; An example for Immediate Release

Dosage Forms

• Industry would welcome further discussions on developing

examples for inhaled products

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Preparing a MDI/DPI ANDA – Formatting

Challenges: QbR

QbR Provides a useful framework for applicant and reviewer for Mod 2.3

– Aligned with FDA’s cGMPs for the 21st Century initiative

– Highlights to applicant critical information required for review

Only three out of 35 questions are related to container closure

• 2.3.P.2.4 Container closure system

– What specific container closure attributes are necessary to ensure

performance?

• 2.3.P.7 Container closure system

– What container closure system is proposed for packaging and storage of the

drug product?

– Has the container closure system been qualified as suitable for use with this

dosage form?

FDA have issued QbR for other dosage forms (e.g. sterile products)

– Any plans to provide further updates for other complex products?

– Does QbR need to be updated with recognition of

drug/device combination products?

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Post approval changes

• No specific guidance for MDI/DPI

– No equivalent to SUPAC

– Is it possible to provide one set of criteria that fits all products -

due to the wide variety of products?

• Comparability Protocol Guidance

Re-issued in April 2016

– Could this be used as a mechanism to provide product specific

change management plan?

• Would welcome the opportunity to engage with the FDA

on a framework for post approval changes

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Conclusion

• MDI/DPI are complex products

– Useful guidance and emerging guidance to aid development

– Complex product = complex ANDA

• Welcome update of the MDI/DPI guidance

– Opportunity to:

• Incorporate elements of QbD & quality risk management

• Provide guiding principles rather than prescriptive requirements

• Allow flexibility to cover wide range of product/devices

• Opportunities

– Working with Agency on developing new guidances as well

as other science initiatives for inhaled products

– Develop framework for post approval changes

– Two way engagement during the development lifecycle

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Acknowledgments

• Michelle Lee Bourner, Head of Regulatory Science, Respiratory,

Mylan Global Respiratory Group, Sandwich, UK

• Zena Smith, Senior Director, Regulatory CMC, Mylan Global

Respiratory Group, Sandwich, UK

• Roisin Wallace, Head of Global Device Development, Mylan, Dublin,

Ireland

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Thank You