1. Implementation of Quality by Design (QbD): Status, Challenges and Next Steps
Moheb M. Nasr, Ph.D.
Office of New Drug Quality Assessment (ONDQA), OPS, CDER
Advisory Committee for Pharmaceutical Science (ACPS)
October 5, 2006

2. Outline FDA Presentations Topic Introduction - Moheb Nasr, Ph.D.
FDA Perspective
ONDQA Initiatives Chi-Wan Chen, Ph.D.
OGD Initiatives Lawrence Yu, Ph.D.
OBP Initiatives Steven Kozlowski, M.D.
GPHA Perspectives Gordon Johnston
PhRMA Perspectives Robert Baum, Ph.D.
Summary and Next Steps Helen Winkle
Discussions and Recommendations

3. The Desired State: A Mutual Goal of Industry, Society, and the Regulators
A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight.
Janet Woodcock, M.D.
October 5, 2005

4. What is Quality by Design (QbD)?
In a Quality by Design system:
The product is designed to meet patient needs and performance requirements
The process is designed to consistently meet product critical quality attributes
The impact of starting raw materials and process parameters on product quality is understood
The process is evaluated and updated to allow for consistent quality over time
Critical sources of process variability are identified and controlled
Appropriate control strategies are developed

5. Product Knowledge Continuous Improvement Quality by Design
Process Understanding
Product Knowledge
Product Specifications
Product Quality Attributes
Process Controls
Process Parameters
Desired Product
Performance
Process Design
Unit operations, control
strategy, etc.
Product Design
Dosage form, stability,
formulation, etc.
Cpk, robustness, etc.
Process Performance
Quality by
Design

6. Approaches to Pharmaceutical Development
Aspects
Current
QbD
Pharmaceutical Development
Empirical, Random, Focus on optimization
Systematic, Multivariate experiments, Focus on control strategy and robustness
Manufacturing Process
Fixed
Adjustable within design space, managed by company’s quality systems
Process Control
Some in-process testing
PAT utilized, Process operations tracked and trended
Product Specification
Primary means of quality control, based on batch data
Part of the overall quality control strategy, based on desired product performance
Control Strategy
By testing and inspection
Risk-based control strategy , real-time release possible

7. Why QbD? Current System Desired State Submission (Lack of PD
Traditional CMC Review
Development
(Empirical)
& MS)
Desired State
Submission (Knowledge Rich in PD
Development
(QbD)
PQAS
& MS)

8. Terminology Quality Attributes Critical Quality Attributes (CQAs)
A physical, chemical, or microbiological property or characteristic of a material that directly or indirectly impacts quality
Critical Quality Attributes (CQAs)
A quality attribute that must be controlled within predefined limits to ensure that the product meets its intended safety, efficacy, stability and performance
Critical Process Parameters (CPPs)
A process parameter that must be controlled within predefined limits to ensure the product meets its pre-defined quality attributes

9. Dosage Form and Manufacturing Process Development
Start product design in early phases of development
This may be an iterative/continuous process
Base critical quality attributes on desired/targeted product performance requirements
QbD is full understanding of product and process and implementation of that understanding
QbD is more than traditional process and formulation optimization
QbD is more than justification of CQAs and CPPs

10. Dosage Form and Manufacturing Process Development
Product design
Evaluate early phase data - determination of optimum dose, route of administration, therapeutic index, PK profile, site of absorption, chemical stability, etc.
Identify and justify desired quality attributes
Prior knowledge can also be used to justify selection of certain quality attributes

11. Dosage Form and Manufacturing Process Development
Formulation development
Materials
Chemical and physical properties affect CQA e.g., moisture and particle size distribution, which may influence downstream process parameters and product performance
Need to understand variability in order to adjust process and/or set appropriate controls
Selection of formulation components based on compatibility and performance requirements

12. Dosage Form and Manufacturing Process Development
For each unit operation
Understand how process parameters affect CQA
Conduct risk analysis/assessment to:
Identify significant process parameters and raw materials attributes
Develop risk mitigation strategies
Establish appropriate control strategy to minimize effects of variability on CQAs

13. Dosage Form and Manufacturing Process Development – Design Space
ICH Q8 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
Design space is proposed by the applicant and is subject to regulatory assessment and approval
Design space concept is applicable to new and legacy drug products
Manufacturing experience and product knowledge

14. Designing/Setting Specifications in the Future
Relate specifications to critical quality attributes
Provide scientific rationale to justify proposed acceptance criteria
In a QbD system, certain traditional end product release testing may prove to be unnecessary

15. Real Time Release (RTR)
Ability to evaluate and ensure acceptable quality of in-process and/or final product based on process data, including valid combination of:
Assessment of material attributes by direct and/or indirect process measurements,
Assessment of critical process parameters and their effect on in-process material attributes
Process controls

16. Implementation Challenges
Different strategies/approaches to accommodate diversity of drug products:
Small chemicals vs. large Biologicals
Oral solids vs. complex/novel dosage forms
Drug vs. Combination Products
Expectations for a QbD - based submissions while addressing traditional requirements
Providing regulatory flexibility while assuring product quality

17. Implementation Challenges
Industry continuous apprehension in sharing information with FDA
Different regulatory processes (BLA, NDA, ANDA, follow-on, etc.) and associated regulatory practices and cultures
Integration of review and inspection
Workload
FDA Resources
Cultural changes needed in industry and FDA

18. FDA’s Expectations
The current system is adequate for regulatory submission
Quality is assured by testing and inspection
Considerable regulatory oversight
Substantial efforts and considerable waste
However, QbD is the desired approach
QbD principles should result in a higher level of assurance of product quality
Additional product and process understanding could lead to regulatory flexibility
Implementation of QbD by industry could enhance manufacturing efficiency
Focus remains on availability of safe, effective and high quality pharmaceuticals

19. Questions
Do you agree that application of QbD principles should result in (1) a higher level of assurance in product quality, (2) more flexibility for the applicant to make continuous improvement; and (3) less need for FDA regulatory oversight on post-approval changes?
Should FDA develop a new guidance on QbD to facilitate its implementation or rely only on ICH guidelines?
What are the relevant scientific areas of disagreement among the stakeholders that the FDA should seek to establish consensus through additional efforts?

20. Questions
Are there additional mechanisms for educating reviewers and industry on changes being made?
Are the ONDQA plans and efforts adequate to implement QbD?
OGD Question-based Review initiative is currently limited to generic drug product. Should it be expanded to include drug substance?
Should FDA develop a pilot program to explore specific QbD issues that are important for biotechnology products?