FDA Update on Implementation of Quality by Design (QbD)

Richard (Rik) Lostritto, Ph.D.Director, DPAMSOffice of New Drug Quality AssessmentCDER/FDA

The New Jersey Pharmaceutical AssociationFor Science and Technology

September 17, 2009

Outline

• FDA quality initiatives background

• QbD guidances

• QbD activities and initiatives

• Remaining challenges and gaps

• Concluding comments

• 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

FDA Initiatives: “Pharmaceutical Quality for the 21st Century”

The Desired State

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

Janet Woodcock, M.D.Pharmaceutical Quality Assessment WorkshopOctober 5, 2005

Characteristics of Desired State

Janet Woodcock, M.D.Deputy Commissioner/Chief Medical Officer, FDAPharmaceutical Quality Initiatives WorkshopMarch 2, 2007

• 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)

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?

Define desired product

performance upfront;

identify product CQAs

Design formulation and process to meet

product CQAs

Understand impact of material

attributes and process parameters

on product CQAs

Identify and control sources of

variability in material and

process

Continually monitor and

update process to assure consistent

quality Risk assessment and risk control

Product & process design and development

Qualityby

Design

Why QbD?• Higher level of assurance of product quality for patient

o Improved product and process design and understandingo Quality risk management in manufacturing

o Monitoring, tracking and trending of product and processo Continual improvement

• Cost saving and efficiency for industryo Increase efficiency of manufacturing processo Minimize/eliminate potential compliance actionso Provide opportunities for continual improvemento Facilitate innovation

• More efficient regulatory oversighto 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

21st Century Initiative Final R

eport

Critical Path Initia

tive

ONDQA CMC Pilot Program

OGD QbR Announced

OBP Pilot

Program

INITIATIVES

2004 2005 2006 2007 2008 2009

ICH Q8 Finalized

ICH Q9 FinalizedPAT Guidance

Quality Systems

Guidance Finalized

ICH Q10 Finalized

ICH Q8(R1) Finalized

ICH Q11 (Concept Paper)

Process Validation

Guidance Revision (Draft)

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

• 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

Product profile

CQAs

Risk assessment

Design space

Control strategy

ContinualImprovement

Example QbD Approach (Q8R1)

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

40

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on

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0.2

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eter 2

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Surface Plot Contour Plot

Design Space(non-linear)

Design Space(linear ranges)

• 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 Example

Design Space and Quality Control Strategy

Process (or Process Step)

Design Space

Monitoring ofParameters

or Attributes

Process Controls/PAT

InputProcess

Parameters

Input Materials

Product (or Intermediate)

ProductVariability

ReducedProductVariability

ProcessVariability

ProcessDevelopment

Control StrategyDevelopment

Continual Improvement

Quality Risk Management Process (Q9)

Example of Risk Assessment Toolsin 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 inDevelopment & Manufacturing

Manufacturing

Process Scale-up & Tech Transfer

Quality Risk Management

Process Development

Product Development

Product qualitycontrol strategy

RiskControl

RiskAssessment

Process design space

ProcessUnderstanding

Excipient & drug substance design space

Product/prior Knowledge

RiskAssessment

Continualimprovement

ProcessHistory

RiskReview

• The regulatory flexibility provided with a design space approach requires effective change management at the manufacturing siteo Track and trend product qualityo Respond to process trends before they become

problemso Maintain and update models as neededo Internally verify that process changes are successful

Why Focus on Quality Systems? (Q10)

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

purposeso 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)

ONDQA’s 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 post-

approval 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

ONDQA’s 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 acceptedo All submitted to date: 11 approved, 1 under review

(as of August 2009)• Common factors

o Submission of design spaceo Use of risk assessmento Proposals of regulatory flexibility under firm’s 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,

includingo On-line analyzerso In-process testing in lieu of end-product testso Real time release using PAT

Example Control Strategy forReal Time Release Testing

Tablet Compression

Pan CoatingSifting

Roller compaction

Blending

Raw materials & API dispensing• Specifications based on product

NIR MonitoringBlend Uniformity

Laser DiffractionParticle Size

Dispensing

NIR Spectroscopy(At-Line) • Identity• Assay • API to Excipient ratio

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 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 programo 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

• ONDQA encourages and accepts applications using QbD approaches

Come in, we’re

OPEN

Acknowledgements

• Christine Moore

• Moheb Nasr

Thank you!Questions, comments, concerns:

NewDrugCMC@fda.hhs.gov