1. 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 FDA’s ACPS Meeting October 2005

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