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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