FDA Update on Implementation of Quality by Design (QbD)

The New Jersey Pharmaceutical Association For Science and Technology

September 17, 2009

Richard (Rik) Lostritto, Ph.D. Director, DPAMS Office of New Drug Quality Assessment CDER/FDA

Outline
FDA quality initiatives background QbD guidances QbD activities and initiatives Remaining challenges and gaps Concluding comments

FDA Initiatives: Pharmaceutical Quality for the 21st Century

In 2002, FDA assessed the ongoing problems and issues in pharmaceutical manufacturing The final report issued in 2004, recommended:
Outreach and collaboration with industry Encourage risk-based pharmaceutical quality management systems for industry Implement quality management systems within FDA Introduce new manufacturing science into regulatory paradigm
Science and risk based approaches Change the CMC review process

Harmonize concepts internationally

The Desired State

A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces highquality drug products without extensive regulatory oversight.

Janet Woodcock, M.D. Pharmaceutical Quality Assessment Workshop October 5, 2005

Characteristics of Desired State

Manufacturers have extensive knowledge about critical product and process parameters and quality attributes Manufacturers control process through quality systems over life cycle and strive for continuous improvement FDA Role: Initial verification, subsequent audit No manufacturing supplements (may be needed for formulation change)
Janet Woodcock, M.D.
Deputy Commissioner/Chief Medical Officer, FDA

Pharmaceutical Quality Initiatives Workshop March 2, 2007

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(R1)

What are the elements of QbD?

Product & process design and development
Quality by Design

Define desired product performance upfront; identify product CQAs

Design formulation and process to meet product CQAs

Continually monitor and update process to assure consistent quality

Identify and control sources of variability in material and process

Understand impact of material attributes and process parameters on product CQAs

Risk assessment and risk control

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

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

More efficient regulatory oversight

o Streamline post approval manufacturing changes and regulatory processes

What are some barriers to QbD?

Culture challenges
Move from prescriptive approach More sharing of scientific and risk information

Business Challenges
Business justification Management Support Budgeting silos across business units

Implementation Challenges
Collaboration between functions Experience with new concepts Workload and resource limitations

International harmonization

How can we break down barriers?

New guidances on quality
International participation

New review processes

Greater information sharing in application Enhanced communication between regulator and applicant Enhanced interactions between review and field investigator

Gain experience through working together

Regulatory sponsored pilot programs Industry consortium, mock submission documents, etc.

Sharing information and experience

Regulators sharing with industry through meetings and conferences Sharing amongst industry through publications and presentations

Recent Quality Guidance and Initiatives

INITIATIVES

2004

2005

2006

2007

2008

2009

GUIDANCE

Recent ICH Quality Guidance

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

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

Example QbD Approach (Q8R1)

Product profile

Target the product profile 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

CQAs

Risk assessment

Design space Control strategy

Continual Improvement

Design Space
Definition
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality

Regulatory flexibility
Working within the design space is not considered a change

Important to note
Design space is proposed by the applicant and is subject to regulatory assessment and approval

Design Space Determination

First-principles approach
combination of experimental data and mechanistic knowledge of chemistry, physics, and engineering to model and predict performance

Non-mechanistic/empirical approach
statistically designed experiments (DOEs) linear and multiple-linear regression

Scale-up correlations
translate operating conditions between different scales or pieces of equipment

Risk Analysis
determine significance of effects

Any combination of the above

Design Space Example

Surface Plot
100.0 95.0 90.0 85.0 80.0 75.0 70.0 65.0 60.0 55.0 50.0 40 2 50 ram ete r1

Contour Plot
2 1.8 1.6 1.4 Dissolution (%) 90.0-95.0 85.0-90.0 80.0-85.0 75.0-80.0 70.0-75.0 0.6 0.4 0.2 40 42 44 46 48 50 52 54 56 58 0 60 65.0-70.0 60.0-65.0

Dissolution (%)

Parameter 2

1.2 1 0.8

Design Space
(linear Designranges) Space

Pa

60 0

er et am ar

(non-linear)

Parameter 1

Design space proposed by the applicant Design space can be described as a mathematical function or simple parameter range Operation within design space will result in a product meeting the defined quality attributes

Design Space and Quality Control Strategy

Design Space
Input Materials
(or Process Step) Reduced Product Variability

Process

Product (or Intermediate)

Process Variability

Input Process Parameters

Monitoring of Parameters or Attributes

Process Controls/PAT

Quality Risk Management Process (Q9)

Process Development

Control Strategy Development

Continual Improvement

Example of Risk Assessment Tools in Product & Process Development

Tools for parameter screening
Examples: Ishikawa diagrams, What-if analysis, HAZOP analysis

Tools for risk ranking

Examples: FMEA/FMECA, Pareto analysis, Relative ranking

Experimental tools for process understanding

Examples: Statistically designed experiments (DOE), mechanistic models

Role of Quality Risk Management in Development & Manufacturing

Product Development Process Development Process Scale-up & Tech Transfer

Manufacturing

Product/prior Knowledge

Process Understanding

Process History

Risk Assessment
Excipient & drug substance design space

Risk Assessment
Process design space

Risk Control
Product quality control strategy

Risk Review
Continual improvement

Quality Risk Management

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 successful

ICH Where do we go from here?

ICH Q11 Drug Substance
o Proposed harmonized guidance for development and manufacture of drug substance o Guidance to includes both small molecule and biotechnology products

ICH Implementation Work Group (IWG)

o Provide clarity and resolve ambiguity regarding ICH quality topic (e.g., terminology, documentation) o Provide examples for implementation for training purposes o Evaluate progress of implementation

FDA Review Office 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)

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

ONDQA Restructuring
ONDQA was restructured in 2005, coincident with move to White Oak campus
Consolidation of CMC reviewers into single location Separation of post-marketing review activities Shift from small review teams to larger, integrated review Branches Introduction of CMC project managers Introduction of Pharmaceutical Assessment Leads (PALs)

Proposed ONDQA Realignment in 2009

Better alignment of CMC review functions Should be imperceptible to applicants

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: 11 approved, 1 under review (as of August 2009)

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

CMC Pilot Observations

Wide variety of design spaces proposed:
o Most included drug product, some included drug substance o Most included process parameters, some included formulation components o Developed using varied experimental techniques & mathematical models o Several utilized risk assessment in development

Wide variety of control strategies utilized, including

o On-line analyzers o In-process testing in lieu of end-product tests o Real time release using PAT

Example Control Strategy for Real Time Release Testing

NIR Monitoring Blend Uniformity Raw materials & API dispensing Specifications based on product Laser Diffraction Particle Size NIR Spectroscopy (At-Line) Identity Assay API to Excipient ratio

Dispensing Blending

Sifting

Roller compaction

Tablet Compression

Pan Coating

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 Q8(R1) Refinement of concepts still ongoing
o QbD applications within and outside of pilot program

Recent QbD Experiences

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 concepts for regulatory flexibility Additional experience is helping to coalesce review approaches

Considerations for QbD Applications

End of Phase II is usually a good time to start discussions about QbD approaches Discuss how design space was developed Present a clear and comprehensive quality control strategy (including design space, in-process controls, specifications) Ensure quality system are capable to handle demands of QbD, PAT, and/or RTRT Continually monitor product and process to ensure quality

ONDQA Where do we go from here?

ONDQA is accepting QbD applications outside of pilot program
o Early communication encouraged

Continued work with ICH and international community Internal and external training Further refinement of QbD approaches for legacy products and for changes post-launch

Concluding Comments
Quality by Design has moved into the implementation phase
ONDQA is putting the staffing and systems in place to support implementation of QbD New guidelines are in place or are being developed to help facilitate implementation Recent NDAs (both within and outside of the CMC pilot program) have provided opportunities for implementing QbD
Come in, were

OPEN

ONDQA encourages and accepts applications using QbD approaches

Acknowledgements
Christine Moore Moheb Nasr

Thank you!
Questions, comments, concerns: NewDrugCMC@fda.hhs.gov