fda ich 8,9,10
TRANSCRIPT
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Status and Implementation of ICH Q8, Q9,
and Q10 Quality GuidelinesTopic Introduction and FDA Perspective
Moheb M. Nasr, Ph.D.
Office of New Drug Quality Assessment
OPS/CDER/FDA
Pharmaceutical Science and Clinical PharmacologyAdvisory Committee Meeting
August 5, 2009
Rockville, MD
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Outline Session Introduction
Recent quality guidances and ICHactivities
Quality by Design (QbD)
OPS infrastructure improvements
FDA CMC review office activities and
initiatives Remaining challenges and gaps
Concluding comments
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Status and Implementation of ICH Q8, Q9, andQ10 Quality Guidelines - Session Introduction
FDA Perspective Moheb M. Nasr, Ph.D.
Industry Perspective Robert Baum, Ph.D.
ICH Q IWG QbD Aspects Jean M. Wyvratt, Ph.D.
ICH Q IWG PQS Aspects Swroop Sahota, Ph.D.
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21st Ce
nturyI
nitiative
FinalR
eport
CriticalPathInitiative
ONDQACMCPilotProgram
OGDQbRAnnounced
OBPPilot
Program
INITIATIVES
004 2005 2006 2007 2008 2009
ICHQ8
Finalized
ICHQ9
Finaliz
edATGuidance
Qualit
ySyst
ems
Guid
anceF
inalize
d
ICHQ1
0Fina
lized
ICHQ8
(R1)Fi
nalize
d
ICHQ11
(Conce
ptPape
r)
Proces
sValidatio
n
uidanc
eRevision
(Draf
t)
GUIDANCE
Recent Quality Guidance and Initiatives
2
P
G
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Recent ICH Quality Guidances Pharmaceutical Development (Q8 & Q8(R1))
ICH Q8 Pharmaceutical Development Describes good practices for pharmaceutical product
development
Introduces concepts of design space and flexible regulatory
approaches
ICH Q8(R1) Annex merged with original document
Includes concepts of Quality by Design and
examples of design space
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What is Quality by Design (QbD)?
Systematic approach to development
Begins with predefined objectives
Emphasizes product and process understanding
and process control Based on sound science and quality risk
management
from ICH Q8(R)
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Why QbD? Higher level of assurance of product quality for patient
o Improved product and process design and understanding
o Quality risk management in manufacturing
o Monitoring, tracking and trending of product and process
o Continual improvement
More efficient regulatory oversighto Streamline post approval manufacturing changes and regulatory
processes
Cost saving and efficiency for industryo Increase efficiency of manufacturing process
o Minimize/eliminate potential compliance actions
o Provide opportunities for continual improvemento Facilitate innovation
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How can we advance QbD?
Guidance for industry and reviewers FDA specific guidances and Internal MAPPs
International harmonized guidances (ICH)
Organizational infrastructure Systems and processes
Staffing and expertise
Implementation experience OPS review programs and pilots On-going learning
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Quality Target product profile (QTPP)
Determine critical quality attributes (CQAs)
Link raw material attributes and processparameters to CQAs and perform riskassessment
Develop a design space
Design and implement a control strategy Manage product lifecycle, including continual
improvement
Product
profile
CQAs
Risk
assessment
Design
space
Controlstrategy
Continual
Improvement
Example QbD Approach - Q8(R1)
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Recent ICH Quality Guidance (cont.) ICH Q9 Quality Risk Management
Describes a systematic process for the assessment, control,communication and review of quality risks
Applies over product lifecycle: development, manufacturing anddistribution
Includes principles and examples of tools for quality riskmanagement
ICH Q10 Pharmaceutical Quality Systems
Describes systems that facilitate establishment andmaintainence of a state of control for process performance andproduct quality
Facilitates continual improvement
Applies to drug substance and drug product throughout productlifecycle
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ProcessDevelopment
Control Strategy
Development
ContinualImprovement
Quality Risk Management Process - Q9
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GMP
Pharmaceutical
Development
Commercial
Manufacturing
Product
Discontinuation
Technology
Transfer
Investigational products
Management Responsibil it ies
Process Performance & Product Quality Monitoring System
Corrective Action / Preventive Action (CA/PA) System
Change Management SystemManagement Review
PQS
elements
Knowledge Management
Quality Risk ManagementEnablers
Pharmaceutical Quality System
(PQS) ICH Q10
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The regulatory flexibility provided with a
design space approach requires effectivechange management at the manufacturing
siteoTrack and trend product quality
o Respond to process trends before they becomeproblems
o Maintain and update models as needed
o Internally verify that process changes aresuccessful
Why Focus on Quality Systems? - Q10
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ICH Where do we go from here? ICH Q11 Drug Substance
Proposed harmonized guidance for development andmanufacture of drug substance
Guidance to includes both small molecule and
biotechnology products ICH Implementation Work Group (IWG)
Provide clarity regarding ICH quality topics and guidance
First Q&A: http://www.ich.org/LOB/media/MEDIA5290.pdf
Provide examples for implementation for training
purposes
Evaluate progress of implementation
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OPS Advances in Quality Systems OPS has taken major steps in 2009 to strength its
infrastructure, processes, and business practices Quality Management system provides framework for: Organizational planning
Conducting CMC review
Evaluating and improving work practices
Quality Implementation Program (QIP) Includes short term and longer term goals
Evaluate and fill gaps in work-related processes and availabletools
Expected outcomes Aid in implementation of QbD
Provide more consistent approaches within and between reviewoffices
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OPS Staffing
CDER is exhibiting unprecedented growth,adding nearly 800 employees in 2008
23% Growth in OPS Reviewers and Researchers
since 2005 Many new reviewers have prior experience in
pharmaceutical industry bringing a wide range of
expertise in QbD related topics
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Implementation of QbD AcrossOPS Review Programs
Office of New Drug Quality Assessment (ONDQA) Pharmaceutical Quality Assessment System (PQAS)
2005 CMC Pilot program
Office of Biotechnology Products
2008 Biotechnology Pilot Program
Office of Generic Drugs
Question Based Review (QBR)
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ONDQAs PharmaceuticalAssessment System
Introduced in 2004 as part of FDA Quality initiatives Objectives
Facilitate product innovation and continuous improvement Provide regulatory flexibility for specification setting and post-
approval changes Streamline the submission and review processes
Key Elements
More relevant information on critical quality attributes and howthey relate to clinical safety and effectiveness Critical steps and in-process controls identified and justified to
demonstrate product knowledge and process understanding Sources of variability in manufacturing identified and controlled Less documentation of data not directly relevant to scientific
evaluation of product quality
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ONDQAs CMC Pilot Program Objectives
oTo provide participating firms an opportunity to submitCMC information demonstrating QbDoTo enable FDA to implement new QbD concepts
Statuso 9 original and 2(3) supplemental NDAs acceptedo All submitted to date: 10 approved, 2 under review
(as of J uly 2009)
Common factorso Submission of design spaceo Use of risk assessment
o Proposals of regulatory flexibility under firms quality system
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Findings from CMC Pilot Program Provided valuable experience for industry and
FDA in implementing QbDo Elements of QbD in submissions
Risk assessments
Design spaces Proposals for flexible regulatory approaches
o Risk-based regulatory decisions were enabled
Learning has been incorporated into ICH Q8R Refinement of concepts still ongoing
o QbD applications within and outside of pilot program
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Recent QbD Experiences-Outside the CMC Pilot
Number of QbD meetings and applications havebeen increasing
Applications containing QbD elements, outside
of pilot (as of May 2009): 12 NDAs 18 INDs
3 supplemental NDAs New proposals have contained challengingregulatory approaches
Additional experience is helping to coalescereview approaches
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QbD in Biotechnology
Mock Case Studies ISPE PQLI, EFPIA
CMC Working Group (formerly Conformia) Novel approach to CQAs
Future workshops
Biotechnology Quality Risk Assessment CMC Strategy Forum J uly 2009
Development of platform approaches monoclonal antibodies
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OBP Pilot Program
FR Notice J uly 2, 2008
To consider quality-by-design (QbD)approaches to unit operations in supplements
(10) as well as original applications (5)To explore the use of protocols submitted under
(21 CF 314.70(e) and 601.12(e))
5 applications accepted (3 full BLA, 2Supplements)
more under consideration
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OGD & QbD Generic Drug Quality Assessment
OGD has developed a question-based review (QBR) forquality evaluation of generic drug applications based on QbD concepts and principles focused on product and process design and understanding
Implementation progress greater than 90% of ANDA submissions contain QBR OGD CMC leadership
evaluated the implementation of QBR
recommended steps to improve the quality of submissions andmove the generic industry and OGD toward QbD
QbD example for generics Developed by OGD working group
Industry working group will provide comments
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OGD & QbD -Modified Release (MR) Products
Industry/OGD workshop in J une 2009 goal to move toward a common understanding of QbD for generics
Agreement on that there are challenges with both productdesign and manufacturing process of the MR dosage forms
QbD for modified release products can mitigate some of the observed concerns about modified releaseproducts
will lead to more efficient approvals of generic products that will meetboth the quality and consumer expectations
OGD and industry have formed parallel MR working groups toimplement
ANDA submission requirements for MR products maychange in the future
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Remaining Challenges and Gaps PQS and GMP Implementation Gaps Harmonized implementation, training, technical issues
Ongoing ICH IWG Activities Better understanding of the linkage between quality,
safety and efficacy
DIA Meeting, J une 23, 2009 New manufacturing approaches
Continuous manufacturing initiative
FDA CPAC collaborative research Utilization of modeling in pharmaceutical developmentand manufacturing AAPS Modeling Workshop, April 27, 2009
QbD and analytical development and testing HPLC Conference, Dresden, Germany, J uly 1, 2009
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PQS and GMP Implementation Gaps Emphasis on change control management with
understanding of the effects on product qualitye.g. movement within the design space
Use of CAPA as an effective system for
continual improvement Using process performance monitoringinformation to monitor the critical quality
attributes throughout the entire batch (not asmall sample)
Maintenance of mathematical models used in
design space under the quality system
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PQS and GMP Implementation Gaps Adaptation of the control strategy through tech
transfer and to be reflective of current productand process understanding
Quality System GMP aspects of real time
release testing including appropriate samplesize and regional requirements for the qualifiedperson (QP) role in other regions
Illustrative uses of knowledge managementthroughout the product lifecycle
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Concluding CommentsThe new quality paradigm (Q 8, 9& 10) is
moving into the implementation phaseo New ICH and FDA guidelines are in place to
facilitateo Internal staffing and systems being placed to
support science and risk-based quality review
and inspectiono Specific implementation programs (ONDQA
Pilot, OBP Pilot, OGD QBR) have providedopportunities for implementing QbD
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Acknowledgments
Helen Winkle OPSJ oe Famulare - OC
Gary Buhler and Lawrence Yu OGD
Steve Kozlowski OBP
Christine Moore - ONDQA