Status and Implementation of ICH Q8, Q9, and Q10 Quality Guidelines

Topic Introduction and FDA Perspective

Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting August 5, 2009 Rockville, MD

Moheb M. Nasr, Ph.D. Office of New Drug Quality Assessment OPS/CDER/FDA

Outline
Session Introduction Recent quality guidances and ICH activities Quality by Design (QbD) OPS infrastructure improvements FDA CMC review office activities and initiatives Remaining challenges and gaps Concluding comments
2

Status and Implementation of ICH Q8, Q9, and Q10 Quality Guidelines - Session Introduction
FDA Perspective Industry Perspective ICH Q IWG QbD Aspects ICH Q IWG PQS Aspects Moheb M. Nasr, Ph.D. Robert Baum, Ph.D. Jean M. Wyvratt, Ph.D. Swroop Sahota, Ph.D.

Recent Quality Guidance and Initiatives

rt o ep am r R l g INITIATIVES ro na i ed P e F c v t i un ilo ive iat t o t P i a C nn In iti M n A h I t ry bR AC Pa u l t Q Q ca st Cen i ND t GD i O r O C 21
t i lo P P OB gram Pro

2004

2005

2006

2007

2008

2009

e nc ed a z i d s l i r) a u m e d d n e ap Fi alize ed st alize TG z P y d i 8 A l t e S Q Fin P p in y na liz e t i H F i a c l F 9 C I ua ance Q on 1) on Fin f t) Q C a R H 0 ( r ( 8 id ti IC (D Q1 11 a Q d n Gu Q i H H l o IC IC s Va visi ICH es e Re GUIDANCE c 4 o Pr idanc Gu

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
5

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)
6

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 oversight

o Streamline post approval manufacturing changes and regulatory processes

Cost saving and efficiency for industry

o o o o Increase efficiency of manufacturing process Minimize/eliminate potential compliance actions Provide opportunities for continual improvement Facilitate innovation

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
8

Example QbD Approach - Q8(R1)

Product profile

Quality Target product profile (QTPP) Determine critical quality attributes (CQAs) Link raw material attributes and process parameters to CQAs and perform risk assessment Develop a design space Design and implement a control strategy Manage product lifecycle, including continual improvement
9

CQAs

Risk assessment

Design space Control strategy

Continual Improvement

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 and distribution Includes principles and examples of tools for quality risk management

ICH Q10 Pharmaceutical Quality Systems

Describes systems that facilitate establishment and maintainence of a state of control for process performance and product quality Facilitates continual improvement Applies to drug substance and drug product throughout product lifecycle

10

Quality Risk Management Process - Q9

Process Development

Control Strategy Development

Continual 11 Improvement

Pharmaceutical Quality System

(PQS) ICH Q10
Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation

Investigational products

GMP
Management Responsibilities Process Performance & Product Quality Monitoring System Corrective Action / Preventive Action (CA/PA) System PQS Change Management System elements Management Review Knowledge Management Quality Risk Management

Enablers

Why Focus on Quality Systems? - Q10

The regulatory flexibility provided with a design space approach requires effective change management at the manufacturing site
o Track and trend product quality o Respond to process trends before they become problems o Maintain and update models as needed o Internally verify that process changes are 13 successful

ICH Where do we go from here?

ICH Q11 Drug Substance
Proposed harmonized guidance for development and manufacture 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
14

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 available tools

Expected outcomes
Aid in implementation of QbD Provide more consistent approaches within and between review 15 offices

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

16

Implementation of QbD Across OPS 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)
17

ONDQAs Pharmaceutical Assessment System

Introduced in 2004 as part of FDA Quality initiatives Objectives
Facilitate product innovation and continuous improvement Provide regulatory flexibility for specification setting and postapproval changes Streamline the submission and review processes

Key Elements
More relevant information on critical quality attributes and how they 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

18

ONDQAs CMC Pilot Program

Objectives
o To provide participating firms an opportunity to submit CMC information demonstrating QbD o To enable FDA to implement new QbD concepts

Status
o 9 original and 2(3) supplemental NDAs accepted o All submitted to date: 10 approved, 2 under review (as of July 2009)

Common factors
o Submission of design space o Use of risk assessment o Proposals of regulatory flexibility under firms quality system
19

Findings from CMC Pilot Program

Provided valuable experience for industry and FDA in implementing QbD
o 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
20

Recent QbD ExperiencesOutside the CMC Pilot

Number of QbD meetings and applications have been increasing Applications containing QbD elements, outside of pilot (as of May 2009):
12 NDAs 18 INDs 3 supplemental NDAs

New proposals have contained challenging regulatory approaches Additional experience is helping to coalesce review approaches

21

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 July 2009

Development of platform approaches

monoclonal antibodies
22

OBP Pilot Program

FR Notice July 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, 2 Supplements)
more under consideration
23

OGD & QbD Generic Drug Quality Assessment

OGD has developed a question-based review (QBR) for quality 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 and move the generic industry and OGD toward QbD

QbD example for generics

Developed by OGD working group Industry working group will provide comments
24

OGD & QbD Modified Release (MR) Products

Industry/OGD workshop in June 2009
goal to move toward a common understanding of QbD for generics

Agreement on that there are challenges with both product design and manufacturing process of the MR dosage forms QbD for modified release products
can mitigate some of the observed concerns about modified release products will lead to more efficient approvals of generic products that will meet both the quality and consumer expectations OGD and industry have formed parallel MR working groups to implement

ANDA submission requirements for MR products may change in the future

25

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, June 23, 2009 New manufacturing approaches Continuous manufacturing initiative FDA CPAC collaborative research Utilization of modeling in pharmaceutical development and manufacturing
AAPS Modeling Workshop, April 27, 2009

QbD and analytical development and testing

HPLC Conference, Dresden, Germany, July 1, 2009
26

PQS and GMP Implementation Gaps

Emphasis on change control management with understanding of the effects on product quality e.g. movement within the design space Use of CAPA as an effective system for continual improvement Using process performance monitoring information to monitor the critical quality attributes throughout the entire batch (not a small sample) Maintenance of mathematical models used in design space under the quality system
27

PQS and GMP Implementation Gaps

Adaptation of the control strategy through tech transfer and to be reflective of current product and process understanding Quality System GMP aspects of real time release testing including appropriate sample size and regional requirements for the qualified person (QP) role in other regions Illustrative uses of knowledge management throughout the product lifecycle
28

Concluding Comments
The new quality paradigm (Q 8, 9& 10) is moving into the implementation phase
o New ICH and FDA guidelines are in place to facilitate o Internal staffing and systems being placed to support science and risk-based quality review and inspection o Specific implementation programs (ONDQA Pilot, OBP Pilot, OGD QBR) have provided opportunities for implementing QbD 29

Acknowledgments
Helen Winkle OPS Joe Famulare - OC Gary Buhler and Lawrence Yu OGD Steve Kozlowski OBP Christine Moore - ONDQA

30