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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
5
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
7
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)
8
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
9
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’
10
Device Development
Medical Device
Validation
Verification
Design Review
Risk Management
User Needs Design
Input Design Process
Design Output
Prototype
Filing
11
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?
12
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
13
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
14
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?
15
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
16
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
17
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