Ajaz S. Hussain, Ph.D. Deputy Director, OPS/CDER/FDA

1. FDA’s ACPS Meeting October 2005 Achieving and Demonstrating “Quality-by-Design” with Respect to Drug Release/dissolution Performance for Conventional or Immediate Release Solid Oral Dosage Forms Ajaz S. Hussain, Ph.D. Deputy Director, OPS/CDER/FDA

2. Topic Introduction • At the May 2005 meeting of the ACPS we proposed that significant opportunities exist to further improve the effectiveness and efficiency of dissolution rate control and related regulatory decisions: • FDA’s PAT & CGMP Initiatives; the shared vision (“desired state”) • ICH Q8 Guideline and PAT Guidance • PQAS [ONDQA, QbR in OGD,…] • FDA proposed tactical plan

3. Topic Introduction • At the May 2005 meeting we extended invitations to all stakeholders to consider our proposed tactical plan as a first step and to comment and/or develop their proposals. • Today, USP, GPhA, and PhRMA will present their perspectives/proposals • A report on dissolution test variability from two academicians (included in the background packet) • FDA presentations

4. QbD Guiding Principles? • The term “quality-by-design” has been the foundation of the current regulatory system; yet there is a lack of common understanding or uncertainty of what this means • High degree of variability on how different companies approach quality-by-design • QbD approach to drug release specification can serve to illustrate the fundamental guiding principles

5. QbD Guiding Principles: Drug Release Rate • Rate of drug release from solid oral dosage forms is a critical quality attribute • A desired release characteristic (in vivo, target value and acceptable variability) should be designed to meet the performance objectives (intended use) of a proposed product in the intended patient population - Design specification

6. QbD Guiding Principles: Drug Release Rate • Ideally, design specifications should be proposed and established early in drug development such that the pivotal clinical trial product produced is in conformance. • For conventional dosage forms, certain design specifications, or certain aspects of specifications, are generally based on prior knowledge. • Bioequivalence goal post (90% CI T/R in 80 -125% range); IR dosage forms: Q-15%, extended release dosage forms: Q ± 10%

7. QbD Guiding Principles: Drug Release Rate • Design specification decisions should be guided by information obtained from pre-clinical and pre-formulation drug characterization • Design specifications then guide the development of a proposed product, its manufacturing process, and the quality assurance strategy • Structured product and process development should identify a set of variables and their ranges that can reliably deliver the desired design specification (Design space)

8. QbD Guiding Principles: Drug Release Rate • Clinical evaluation during various phases of drug development provides both quantitative (e.g., pharmacokinetics/pharmacodynamics analysis) and qualitative (e.g., clinical observations) opportunities to verify that selected design specifications were achieved and are optimal for the intended use. • These opportunities should be leveraged as early as feasible to maximize the likelihood that a product design can be used in pivotal clinical trials and can be considered to have achieved quality-by-design (e.g., design specification and control strategy).

9. QbD Guiding Principles: Drug Release Rate • When regulatory evaluation of the clinical safety and efficacy reaches a conclusion to approve a new drug application: • clinical trial product design specifications should become regulatory specifications, and • a regulatory risk-based control strategy is established to ensure that production lots will consistently deliver a set of regulatory- design specifications

10. QbD Guiding Principles: Drug Release Rate • The inherent variability (“common cause”) in a clinical trial product design is qualified through • the structured product and process development information that demonstrates that critical variables relevant to a product and process design were identified and adequately controlled (i.e., all significant “special cause” variability), and • acceptable performance of the product clinical trials

11. QbD Guiding Principles: Drug Release Rate • It is recognized that during drug development, a limited number of batches are generally manufactured and the scale of manufacture may be smaller compared to the “to-be-marketed” batches • In a QbD paradigm, limited manufacturing experience should not impact on design specifications, but it can be related to the establishment of “alert” and “action” process and product control limits by a sponsor

12. QbD Guiding Principles: Drug Release Rate • Following scale-up and/or technology transfer (R&D to Industrial Operations) the “action” and “alert” limits may need to be modified to ensure that a process remains in a desired state of control • These decisions should be based on sound scientific basis and the principles of statistical process control • Managed under a company’s quality system and subject to CGMP regulatory inspections

13. QbD Guiding Principles: Drug Release Rate • Product and process control strategy should be designed to facilitate continuous quality verification (as opposed to discrete “3 batch – process validation”) and continuous improvement (e.g., improving efficiency, reducing variability,…) • Regulatory - design specifications should be articulated in terms of “continuous variables” • as opposed to discrete counts (e.g., no unit is outside..) • Understanding the sources of variability and measuring and controlling critical material attributes (raw and in-process materials) as a means for process control • Minimize the need for using process “time” and machine settings as the primary means for process control • Incorporating engineering control approaches • as opposed to primary reliance on end-product testing after a batch has been manufactured

14. QbD Guiding Principles: Drug Release Rate • Dissolution testing is a tool for: • Product development & optimization • Quality control • Product characterization and comparison for decisions of waiver of in vivo bio studies • Establishing performance tests in compendial monographs • A clear distinction of the purpose for which this tool is to be used is necessary • E.g., a part of the quality control strategy vs. waiver of in vivo bio studies

15. Pre-Clinical Studies Pre-Formulation Studies QbD of Clinical Trial Product “Design Specifications & Control Strategy” Prior Knowledge (Manufacturing Science) Clinical Studies Acceptable Safety & Efficacy Demonstrated in Clinical Trials Regulatory Specifications and Control Strategy Post-Approval AERS & Risk Mgmt Risk Based CGMP Inspections & Continuous Improvement Summary: QbD Flow Diagram