1. 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. 2 Outline FDA Presentations Topic Introduction - Moheb Nasr, Ph.D. FDA Perspective ONDQA InitiativesChi-Wan Chen, Ph.D. OGD InitiativesLawrence Yu, Ph.D. OBP InitiativesSteven Kozlowski, M.D. GPHA PerspectivesGordon Johnston PhRMA PerspectivesRobert Baum, Ph.D. Summary and Next StepsHelen Winkle Discussions and Recommendations

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

4. 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. Quality by Design

6. Approaches to Pharmaceutical Development AspectsCurrentQbD Pharmaceutical Development Empirical, Random, Focus on optimization Systematic, Multivariate experiments, Focus on control strategy and robustness Manufacturing Process FixedAdjustable within design space, managed by company’s quality systems Process Control Some in-process testingPAT 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 inspectionRisk-based control strategy, real-time release possible

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

8. 8 Terminology Quality Attributes 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. 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. 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. 11 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 Dosage Form and Manufacturing Process Development

12. 12 Dosage Form and Manufacturing Process Development 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. 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. 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. 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. 16 Implementation Challenges Different strategies/approaches to accommodate d iversity 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. 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. 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. 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. 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?