Implementation of Quality-by-Design: OGD Initiatives

1. Implementationof Quality-by-Design:OGD Initiatives Lawrence Yu, PhD Director for Science Office of Generic Drugs Food and Drug Administration Advisory Committee for Pharmaceutical Science October 5, 2006

2. What is Quality by Design? • Pharmaceutical Quality by Design (QbD) • QbD means designing and developing formulations and manufacturing processes to ensure predefined product quality • Understanding and controlling formulation and manufacturing process variables affecting the quality of a drug product

3. Question-based Review • Question-based Review (QbR) is a general framework for a science and risk-based assessment of product quality • QbR contains the important scientific and regulatory review questions to • Comprehensively assess critical formulation and manufacturing process variables • Set regulatory specifications relevant to quality • Determine the level of risk associated with the manufacture and design of the product

4. Questions Come FirstSay What You Do and Do What You Say • Questions guide reviewers • Prepare a consistent and comprehensive evaluation of the ANDA • Assess critical formulation & manufacturing variables • Questions guide industry • Recognize issues OGD generally considers critical • Direct industry toward QbD • Questions inform readers of the review • How QbD was used in the ANDA • Provide the basis for a risk assessment

5. FDA’s Pharmaceutical cGMP for the 21st Century QbD Initiative Generic Sponsor: Implementing QbD in development and manufacturing FDA OGD: Developed a Question- based Review System that assesses sponsor’s QbD ANDAs

6. Process Understanding Continuous Improvement Product Knowledge Product Quality Attributes Process Controls Process Parameters Product Specifications Product Design Unit operations, control strategy, etc. Process Design Desired Product Performance Dosage form, stability, formulation, etc. Process Performance Cpk, robustness, etc. Quality by Design QbR Questions Embodies QbD What attributes should the drug product possess?

7. Process Understanding Continuous Improvement Product Knowledge Product Quality Attributes Process Controls Process Parameters Product Specifications Product Design Unit operations, control strategy, etc. Process Design Desired Product Performance Dosage form, stability, formulation, etc. Process Performance Cpk, robustness, etc. Quality by Design QbR Questions Embodies QbD How was the product designed to have these attributes? Were alternative formulations or mechanisms investigated? How were the excipients selected? How was the final formulation optimized?

8. Process Understanding Continuous Improvement Product Knowledge Product Quality Attributes Process Controls Process Parameters Product Specifications Product Design Process Design Desired Product Performance Dosage form, stability, formulation, etc. Process Performance Cpk, robustness, etc. QbR Questions Embodies QbD Unit operations, control strategy, etc. Quality by Design What are the unit operations in the drug product manufacturing process? Why was the manufacturing process selected? How are the unit operations related to the drug product quality?

9. Process Understanding Continuous Improvement Product Knowledge Product Quality Attributes Process Controls Process Parameters Product Specifications Product Design Unit operations, control strategy, etc. Process Design Desired Product Performance Dosage form, stability, formulation, etc. Process Performance Cpk, robustness, etc. Quality by Design QbR Questions Embodies QbD How were the critical process parameters identified, monitored, and controlled? In the proposed scale up plan what operating parameters will be adjusted to ensure the product meets all in-process and final product specifications? What evidence supports the plan to scale up the process to commercial scale?

10. Why is QbD for Generic Drugs Unique? Biopharmaceutical properties of drugs already known such as polymorphism, absorption, and pharmacokinetics information Target product quality profile well defined such as dissolution, purity, uniformity, and stability Extensive formulation and manufacturing experience for many generic manufacturers

11. 10/30 out of 10,000,000 Assay Uniformity Impurity Metal Res Solvents Moisture Diss Drug Substance Meet Spec? Unit Operations Mixing Compression Coating… Yes No Excipients CFR 314.70 Change Guidance Quality by End Product Testing ?

12. Quality by Design Clinical Relevance Drug Substance Unit Operations Mixing Compression Coating… PAT “Always” Meet Spec Assay Uniformity Purity Diss Excipients

13. QbD More Information to Review Quality By Testing Quality by Design

14. Quality Assessment under Old CMC Review? • Reviewers prepare a summary of the application • Write deficiency letters in response to missing information or insufficient specifications • No pharmaceutical development information in ANDAs

15. Quality Assessment under QbR • The QbR quality review includes • Comprehensively evaluate sponsor’s Quality by Design • Set regulatory specifications relevant to quality • Determine the level of risk associated with the manufacture and design of the product • Explain the reason for each deficiency

16. No PD Inf Assess QbD No PD Info Reviewer Assessment Assess spec Assess spec performance Reviewer Summary Summary QbD Summary Sponsor Body of Data Body of Data Body of Data QbD Sponsor Old CMC Review to QbR Assessment Old QbR

17. Diagram of the ICH Common Technical Document QOS Summary of Critical CMC Elements Body of Data CMC Submission Package

18. OGD Model QOS • Model QOS for ER Product (1/2006) • http: //www.fda.gov/cder/ogd/ OGD_Model_Quality_Overall_Summary.pdf • Model QOS for IR Product (3/2006) • http: //www.fda.gov/cder/ogd/ OGD_Model_QOS_IR_Product.pdf

19. QbR: Where Are We Today? • Generic Drug Industry On Board • GPhA Technical Committee QbR WG • Over 35 QbR ANDAs • Over 20 Generic Companies • First QbR Approval • CMC Review Time = 4 months, 1 cycle • Total Review Time = 8 months

20. Experience with Assessment of QbR ANDAs: Technical Advantages • “Enhanced product and review assessment • Critical formulation and manufacturing process variables identified and controlled in QbR-QOS • Insight into sponsor’s development plans • Product & Process Design, and Development • Directly address the OGD’s questions • Better understanding of sponsors' rationale for decisions and therefore, less misunderstandings”

21. Experience with Assessment of QbR ANDAs: Documentation Advantages • “Primary reviewer saves time (~20%) • Summary of application • Facts finding • Tables & charts • Chemical structures • Specifications etc • No transcriptional errors”

22. Question-based Review: Progress/Communication 2004 1/2005 2/2005 6/2005 6/2005 8/2005 10/2005 10/2005 1/2006 1/2006 2/2006 5/2006 7/2006 9/2006 9/2006 1/2007 FDA’s cGMP Initiative and Initiation of QbR QbR Questions drafted GPhA Technical Advisory Committee Meeting OGD GPhA Technical Advisory Committee Joint Meeting GPhA Technical Advisory Committee Meeting OGD QbR White Paper OGD GPhA Technical Advisory Committee Joint Meeting GPhA Fall Technical Workshop ANDA Submission Checklist Example Quality Overall Summary GPhA Technical Advisory Committee Meeting GPhA QbR Webcast GPhA Teleconference on Quality of QOS OGD QbR Retreat First QbR ANDA Approval Full implementation of QbR

23. Challenges • Quality of QOS prepared by sponsors • Too long • Non-critical data; Multiple tables: same data • Analytical Validation: USP methods • Leaving out questions • Inconsistencies between QOS and body of data • OGD’s Actions • Communication • Training; first October 20, 2006

24. Challenges • Knowledge of formulation and manufacturing science • Chemists • OGD’s Actions • Recruiting • Formulation scientists and process engineers • Internal training • QbR seminars and workshops • Review papers or commentary • External training • Purdue NIPTE; 12 review chemists attended Purdue NIPTE liquid and solid dosage form training

25. Next Step • Risk Assessment and Supplement Reduction • Two opportunities for supplement reduction • For QbR ANDAs: at the time of approval • For all ANDAs: after sufficient product commercial manufacturing history

26. Conclusions • OGD is implementing a new pharmaceutical quality assessment system that • Enhances quality of generic drugs • Improves review quality and consistency • Reduces review time • Reduces supplements

27. OGD QbR Initiative Andre Raw Robert Lionberger Radhika Rajagopalan Lai Ming Lee Frank Holcombe Rashmikant Patel Florence Fang Vilayat Sayeed Paul Schwartz Richard Adams Lawrence Yu (Chair) , Brenda Arnwine, Gururaj Bykadi, James Fan, Scott Furness, Dave Gill, Hossein Khorshidi, Shing Hou Liu, Albert Mueller, Susan Rosencrance, Michael Smela, Glen Smith, Ubrani Venkataram, Naiqi Ya, Susan Zuk Karen Bernard, Christina Bina, Barbara Davit, Tom Hinchliffe, Robert Iser, Andrew Langowski, Koung Lee, MaryJane Mathews, Yanping Pan, Susan Pittinger, Roslyn Powers, Ramnarayan Randad, Shanaz Read, Dominick Roselle, Xiumei Ruan, Barbara Scott, Mouna Selvam, Aloka Srinivasan, Guoping Sun, Neeru Takiar, Ruth Warzala, Quan Zhang, Susan Zuk Gary Buehler, Robert West, Rita Hassall, Helen Winkle, Keith Webber, Mansoor Khan, Joseph Famulare, Nicholas Buhay, Albinus D Sa, Rick Friedman, Brian Hasselbalch