Question-Based Review: An Enhanced Pharmaceutical Quality Assessment System

1. Question-Based Review: An Enhanced Pharmaceutical Quality Assessment System Lawrence X. Yu, Ph. D. Director for Science Office of Generic Drugs Food and Drug Administration GPhA Fall Technical Conference, October 25, 2005

2. Acknowledgement • Andre Raw Robert Lionberger • Radhika Rajagopalan Lai Ming Lee • Frank Holcombe Rashmikant Patel • Florence Fang Vilayat Sayeed • Paul Schwartz Richard Adams • Lawrence Yu (Chair) Gary Buehler, Robert West, Rita Hassall, Brenda Arnwine, Gururaj Bykadi, James Fan, Scott Furness, Dave Gill, Shing Hou Liu, Albert Mueller, Susan Rosencrance, Michael Smela, Glen Smith, Ubrani Venkataram 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, Barbara Scott, Mouna Selvam, Aloka Srinivasan, Guoping Sun, Neeru Takiar, Ruth Warzala, Quan Zhang, Susan Zuk Janet Woodcock, Steven Galson, Helen Winkle, Ajaz Hussain, Keith Webber

3. Question-based Review: Timetable • 1/2005 – 2/2005: Question-based Review Drafted • 3/2005 – 4/2005: Division Directors Discussion • 5/2005 – 6/2005: Team Leaders Discussion • 7/2005 – 8/2005: Reviewers Discussion • 9/2005 – 1/2006: Model Pharmaceutical Development Report and Quality Overall Summary • 2/2005 – 12/2005: Discussions with Stakeholders and Upper Management • 1/2005 – 12/2006: Gradual Implementation • 1/2007: Full Implementation

4. Receipts of ANDAs

5. Receipts of Supplements

6. How to Respond? • Need to allocate review resources • How? According to risk! • cGMPs for the 21st Century Initiative • “Regulatory policies and procedures are tailored to recognize the level of scientific knowledge…” • “Risk based regulatory scrutiny is associated with the level of scientific understanding...”

7. Current Review Process • Does not adjust review to the level of scientific understanding • All products (simple and complex) use the same approach • All products are subject to the same post-approval supplements

8. What is Question-based Review? • Question-based Review is a general framework for a science and risk-based assessment of product quality • Question-based Review contains the important scientific and regulatory review questions to • Comprehensively assess critical manufacturing processes • Determine the level of risk associated with the manufacture and design of the product

9. QbR Principles • Quality built in by design, development, and manufacture and confirmed by testing • Risk-based approach to maximize economy of time, effort, and resources • Preserve the best practices of current review system and organization • Best available science and wide consultation to ensure high quality questions

10. CMC Review Under QbR • Questions guide reviewers to provide a high quality and comprehensive evaluation of the application • Some CMC deficiencies under the current system are related to reviewer chemists’ education and experience • Allow reviewers to derive bioequivalence inferences • Pharmaceutical development/quality by design information and prior knowledge

11. CMC Review Under QbR (Continued) • The risk and science-based regulatory assessment • Level of assessment is associated with complexity of drug products • Post-approval change supplements are related to scientific understanding

12. ANDAs Under QbR • Common Technical Document Format • Quality Overall Summary that will • address the reviewers’ questions and guide reviewers through the application • eliminate unnecessary fact finding of information such as composition, specification, and manufacturing process, etc.

13. ANDAs Under QbR (Continued) • Product Development Report that will explain • how drug substance and formulation variables affect the performance of the drug product • how the sponsor identifies the critical manufacturing steps, determines operating parameters, selects in-process tests to control the process, and scales up the manufacturing process

14. ANDAs Under QbR (Continued) • The 1999 Guidance for Industry “Organization of an ANDA” • Does not include Quality by Design principles • Does not provide for a QoS • Is no longer current for the OGD Question-based Review

15. ANDAs Under QbR (Continued) • Future Generic Applications • We strongly recommend that generic sponsors submit generic applications based on the format of ICH CTD, preferably, electronically • Module 1: Administrative Information • Module 2: Quality Overall Summary and Clinical Summary • Module 3: Quality • Pharmaceutical Development; Quality by Design • Module 4: Nonclinical • Module 5: Clinical (Bioequivalence)

16. Benefits • Quality by design and performance-based based specifications assure product quality • Risk assessment facilitates continuous improvement and reduces CMC supplements • Standardized review enhances the quality of CMC evaluation • QbR-based QoS assists CMC review and reduces review time

17. Reviewer Education • Regulatory Science Training Series • Past training workshops • Polymorphism, Controlled Release, Injectable Drug Products, Aerosols and Sprays, Impurities, Excipients, and Manufacturing • Future training workshops • Preformulation, Biopharmaceutics, Dissolution • Process Identification, Simulation, Monitoring, and Control

18. Communication with Stakeholders • February 24, 2005: GPhA Technical Committee meeting • June 8, 2005: GPhA Technical Steering Committee meeting • June 29, 2005: GPhA Technical Meeting • October 5, 2005: AAPS Workshop • October 21, 2005: GPhA QbR WG Meeting • October 25, 2005: OGD QbR Report

19. Expectations • Office of Generic Drugs • Ask the right questions and produce a consistent, science and risk-based comprehensive CMC review • Industry • Accelerated approval of applications • Reduced supplements • Public • Availability of low cost and high quality generic products

20. OGD QbR Presentations • Question-Based Review: An Enhanced Pharmaceutical Quality Assessment System Lawrence Yu • Question-Based Review: Pharmaceutical Development Report/Quality by Design Robert Lionberger • Question-Based Review: Quality Overall Summary Andre Raw • Question-Based Review: Impact on CMC Post-Approval Changes Radhika Rajagopalan • Question & Answer Session Lawrence Yu and OGD Question-Based Review Committee

21. OGD QBR (Draft)The question based review (QBR) serves as a general framework for the CMC assessment of ANDAs that focuses on critical pharmaceutical attributes of product quality. With justification, deviations or alternate approaches to this framework can be utilize, as necessary, to ensure the adequacy of the assessment of product qualityFor ease of discussion, a simple dosage form is defined as a solution or an immediate release (IR) solid oral dosage form.

22. QBR: Drug Substance • Description and Characterization • What are the nomenclature, molecular structure, molecular formula, and molecular weight? • What are the pKa, aqueous solubility (as function of pH), partition coefficient, polymorphism, hygroscopicity, and melting points? • Control of Drug Substance • Appearance and Identification • Are the specifications for appearance and identification appropriate? • Assay • Is the proposed drug substance assay limit acceptable? • Is the analytical method validated and stability-indicating? • Impurities and Residual Solvents • Are all the possible impurities accounted for? • What is the justification for the impurity acceptance limits? • Are the analytical methods validated and suitable for their intended function? • Additional Specifications • Based on the review of the drug product and manufacturing process are specification(s) required on particle size, solid state form, moisture content, or other properties of the drug substance and why? • For each additional specification: What is the justification for the acceptance limit? Is it suitable for its intended function?

23. QBR: Drug Product • Description and Composition • What are the components and composition of the final product? What is the function of each excipient? • Do any excipients exceed IIG limits in the context of maximum daily dose and route of administration? • If product is an NTI drug or a non-simple dosage form • Are there significant differences between this formulation and the RLD that present potential concerns with respect to product performance? • Control of Excipients • What are the specifications for the inactive ingredients and are they appropriate per their intended function? Simple Dosage Form: Either a solution or an IR solid oral dosage form

24. QBR: Drug Product (Continued) • Manufacture • For all products • Does the batch formula accurately reflect the drug product composition? If not, what are the differences and the justifications (e.g. potency adjustment, overage, excess coating solution, etc.)? • If product is not a solution • What are the key unit operations in the drug product manufacturing process? • Are in-process tests identified by the sponsor appropriate? • What is the difference in size between commercial scale and biobatch and do they use the same unit operations? • If product is an NTI drug or a non-simple dosage form • What are the critical steps in the manufacturing process? • What are the in-process tests/controls that ensure each critical step is successful? • In the proposed scale up process what operating conditions will be adjusted to ensure the product meets all in-process and final product specifications? • Why do you believe the sponsor has demonstrated a reasonable plan to scale up the process?

25. QBR: Drug Product (Continued) • Control of Drug Product • Identity • Is the specification for the identity of the drug product appropriate? • Assay and Uniformity • Are the proposed drug assay limits acceptable? • Is the assay method validated and stability-indicating? • How is the content uniformity evaluated? Is it acceptable? • Impurities/Degradation Products • Are the degradation products and their origins adequately described? • What is the justification for the acceptance limits on degradation products? • Are the analytical methods validated and suitable for their intended function? • Dissolution • What are the dissolution methods and acceptance criteria and how were they selected? • What is the significant role of dissolution testing for this product? • Additional Specifications • Are there additional specifications that are required to ensure the product will perform as labeled and why? • For each additional specification: What is the justification for the acceptance limit? Are the analytical methods validated and suitable for their intended function?

26. QBR: Drug Product (Continued) • Reference Standard • Are there a qualification report and COA provided for the reference standard or is this material purchased from an appropriate source? • Container/Closure System • Has the container/closure system been used in a previously approved product or otherwise qualified for this dosage form? • What specific container/closure attributes are necessary to ensure product performance? • Drug Product Stability • Data • What stability data has been submitted? Has the sponsor provided stability data for the drug product packaged in the proposed container/closure? • Acceptance limits • Are all attributes that could change over time evaluated in the stability tests? • What are the acceptable limits on these attributes? • Shelf-life recommendation • What is the justification of shelf life? • Is the post-approval stability protocol acceptable?

27. QBR: Product Development Report for Complex Dosage Forms and NTI Drugs • Drug Substance • Which properties or physical chemical characteristics of the drug substance affect drug product performance? • Excipients • Is there any evidence of incompatibility between the excipients and drug substance? • Formulation • What is the formulation intended to do? • What mechanism does it use to accomplish this? • Were any other formulation alternatives investigated and how did these perform? • Were any formulation optimization or sensitivity studies carried out for variations in composition around the final formulation? Were these studies sufficient to establish a design space for formulation composition? • Is the formulation design consistent with the dosage form classification in the label? • Drug Product • What are the critical quality attributes that ensure the product will perform as labeled?

28. QBR: Process Development Report • Process Description • Why was this manufacturing process selected for this drug product? • Were alternative unit operations investigated by process development studies? • Critical Steps and Scale Up • How were the critical steps in the process identified? • What are the critical process parameters for each critical step and how were they identified, monitored and/or controlled? • Were process development studies that varied starting materials or operating parameters conducted? Were these studies sufficient to establish a design space for process? • In process tests • Why is each in process test required? • How were the acceptance limits chosen? • Why were the in-process tests identified as critical to product quality? • What scale-up experience does the sponsor have with the unit operations in this process?

29. QBR: Risk Summary • NTI drug • Classified as a non-NTI drug, risk score = + 0 • Classified as an NTI drug, risk score = +1 • Dosage Form • Simple Dosage Form, risk score = + 0 • Other Dosage Forms and NTI drugs, risk score = + 1 • Development Report • If the sponsor submits a development report that addresses the FDA’s questions: Risk score = + 0 • Solution and IR Products: Product Development Report • Other Dosage Forms: Product and Process Development Reports • Insufficient or missing development report, risk score = + 1 • If the application is of high overall quality • Less than or equal to 2 cycles, risk score = + 0. • Greater than 2 cycles, risk score = + 1

30. QBR: Risk-Based Conclusion • Should the application be approved? • What post-approval waivers/commitments are appropriate for this product? • If the total risk score is less than or equal to 1 • CBE0 and CBE30 changes may be in annual reports • Many PAS to CBE 30 • If the total risk score is greater than 1 • All supplements should be submitted as usual