TFDA’s Strategies in Enhancing Drug Quality

1. TFDA’s Strategies in Enhancing Drug Quality Meir-Chyun Tzou, Ph.D. Director, Division of Drugs and New Biotechnology Products, Taiwan Food and Drug Administration, Department of Health, Taiwan, R.O.C. 2011.04.29 The Orange Book, Generic Drugs and Bioequivalence

2. Outline • Organization and Responsibility • Management of Drug Quality-product Life Cycle Management • Pre-Marketing Approval • Post-Marketing Management • Regulation strategies in Enhancing Drug Quality

3. Taiwan FDA (TFDA) was inaugurated on Jan. 1, 2010 TFDA supersedes the following 4 bureaus of Department of Health Bureau of Food Safety Bureau of Pharmaceutical Affairs Bureau of Food and Drug Analysis Bureau of Controlled Drugs Establishment of Taiwan FDA 3 3 3

4. TFDA Organization Chart 4 4 4

5. Drug Medical Devices/cosmetics Food Risk Management And Quality Assurance TFDA Center for Regional Administration Controlled Drug Research & Analysis Establish Taiwan Food and Drug Safety Management System 5 5 5

6. Statistics on Pharmaceutical Licenses(2010) Generic drug New drug API 23201 84.13% Biologics Orphan Drugs

7. Statistics on Pharmaceutical Licenses (2010) 7 7

8. Statistics on drug registration and post-approval changes (Jan~Dec.2010) category cases NDA ANDA

9. Management of Drug Quality-product Life Cycle Management

10. Quality Quality The suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity. -ICH Q6A ,ICH Q8 Quality objective The holder of a manufacturing authorization must manufacture medicinal products so as to ensure their products： 1.Fit for their intended use, comply with the requirements of the marketing authorization 2. Do not place patients at risk due to inadequate safety, quality or efficacy -PIC/S GMP Guide 2007 10

11. Management of Drug Quality-product Life Cycle Management Basic research Pre- clinical Clinical Trials Product Launch Production Marketing & Sales Review CTD：Safety、Efficacy 、Quality (審查) Inspection GLP、GCP GPvP GMP/GTP (稽查) Analysis Testing / Trial/Analysis (檢驗) 11

12. 1998 CDE 2001 TDRF 2010 TFDA 1983 PV/PMS 1998 ADR 2008 GPvP Milestones on Drug Regulation 1980 2000 2010 1990 1982 GMP 1987 BA/BE 1999 cGMP 2009 DMF 2010 PIC/S GMP 1993 Local clinical trial 1996 GCP 1998 GLP 2000 BS * Evaluation /ICH E5 2001 Pivotal trial/ early phase trial *Bridging Study Evaluation in accordance with ICH E5 12

13. Pre-Marketing Approval

14. Pre-marketing review

15. BE studies

16. Bioequivalence IND/NDAs Establish links between (1) Early and late clinical trial formulations (2) Formulations used in clinical trial and stability studies, if different (3) Clinical trial formulations and to-be-marketed drug product; and (4) Other comparisons, as appropriate. ANDAs BE is a primary element in the determination of therapeutic equivalence BE, together with the determination of PE allows a regulatory conclusion of therapeutic equivalence

17. Therapeutic Equivalence Pharmaceutical equivalence (PE) Bioequivalence (BE) Proper labeling CMC/cGMP/GLP/GCP FDA deemed two products therapeutic equivalence-PE+BE+ proper labeling +CMC/cGMP /GLP-GCP

18. BE Requirement Product Quality and in vivo Performance BE study is required once therapeutic outcome demonstrated BE is required whenever changes are significant enough so that they lead to questions of product quality/performance or therapeutic outcome Pre-approval Pilot formulation vs pivotal clinical formulation Pivotal clinical formulation vs final market formulation Generic product vs RLD Significant post-approval changes BE requirement should be applied to both the brand name and the generic products

19. Regulatory requirement on BE studies Regulations Guideline of Bioavailability and Bioequivalence studies (1987) Regulations of BA/BE Studies (2009) Drug Application New drugs Generic drugs Since 1983 Retrospectively request BE studies for drugs approved before 1983 with BE concern e.g., Diltiazem 、Glyburide、Furosemide、Isosorbide dinitrate、Atenolol、Nifedipine、Rifampin、Digoxin、Carbamazepine

20. Licenses of BE products in Taiwan * Products approved before 1983

21. Post-marketing Management

22. Regulation on post approval changes • Types of Post-approval Changes • Scale of manufacturing, Manufacturing process, equipment, site, manufacturer, etc. • Particle size, crystalline form, polymorphs, in-process, controls, product release specification, etc. • Synthetic procedures, source of API and excipients, supplier, etc. • Regulation Requirement Scale-Up and Post Approval Changes (SUPAC) （2001 public Announcement ） • For products that have passed the BE testing and registered for marketing, any changes, depending on the level and extent of change are required to submit Bioequivalence testing report or Dissolution Rate Profile to assure and verify its quality.

23. Post-approval commitment • Surveillance on Safety and Efficacy • Post-marketing Surveillance, Phase-IV trial • ADR/quality defect reporting and investigation • REMS/RMP • Maintenance for Drug Quality-Life Cycle Management • Well controlled process and quality system • batch to batch release • On-going stability protocol • Post-approval changes, annual report • Inspection

24. The role of Government and Industry in ensuring Drug quality * It is majorly the responsibility of industry to ensure product quality throughout product life cycle

25. Post-marketing Management System Post-marketing Management system Post-approval changes Safety Pharmacovigilance Quality surveillance GMP Post-approval commitment ADR reporting system Product quality defect reporting system Compliance Review Review Review/ Testing Inspection 25 25 25

26. Post-marketing Safety and Quality Surveillance-Risk Management Drug Product quality defect reporting system Passive Quality surveillance Therapeutic Inequivalence Reporting System Surveillance Post-marketing product quality and safety surveillance National Quality surveillance Program Active Passive National ADR reporting system Safety surveillance Manufacturer：Drug safety report on a regular basis(PSUR) Active • Reassessment / Inspection • Labeling change • Withdrawal/Recall Government：ADR active Monitoring Network 26

27. National Drug Quality surveillance and Testing Survey on Marketed Drug Product Quality(1989-2009)

28. Therapeutic Inequivalence Reporting in Taiwan • Establishing" Drug Therapeutic Inequivalence Reporting System in Taiwan“ since 2009 • Establishing committee for identification and evaluation of reports • Summarizing 70 reports from 2009 to 2010 • One brand name drug (thyroxin)： • Formulation and manufacturing site changed • Following a switch, unexpected AE (allergy) occurred in patients • TFDA investigation and ongoing review • One injectable drug（iron sucrose complex） • AE (allergy) occurred in patients • Suspect difference in structure and particle size • Others: poor data (ex insufficient information, lack of lab data) or single case

29. Therapeutic Inequivalence Reporting in US FDA • Therapeutic Inequivalence Action Coordinating Committee (TIACC) in CDER to evaluate these reports • For example: Bupropion（Antidepressant） Brand name drug (Wellbutrin XL 300 mg) vs.generic drug (Budeprion XL 300 mg) • In 2007, FDA received 85 AE reports following a switch • US FDA's evaluation and conclusion • The generic form of bupropion bioequivalent and • therapeutically equivalent to the brand name drug • The number of AE reports following a switch • were fewer than the drug and placebo groups in • clinical trials • Natural history of disease：The AE may occur • throughout the course of the therapy, even patients • on a stable dose of medicine or receiving placebo.

30. Regulation Strategies in Enhancing Drug Quality

31. Strategies on BE approaches Strategies for API and Generic Drug Regulation Strategies in Enhancing Drug Quality Strategies for Post-Approval Changes Strategies for GMP regulation

32. Strategies on BE approaches • Initiatives on BE studies • BE issues for certain drug products • Alternative approaches for in vivo performance evaluation • Drugs with special dosage forms

33. Initiatives on BE studies • Retrospectively request BE studies for drugs approved before 1983 • Products with special concern on therapeutic equivalence • BE Study Inspections • Primarily Domestic Inspection, Foreign Inspections in plans

34. Initiatives on BE studies • Therapeutic Inequivalence Action Coordinating Committee (TIACC) • Establishment on April, 2009 • Provide a systematic evaluation of therapeutic failure and toxicity • Strengthen CRO management • Guidance for organizations performing bioequivalence studies (Announced on April 18, 2011)

35. BE issues for certain drug products Alternative approaches for in vivo performance evaluation • Nasal aerosols or Nasal sprays Metered-dose inhalers or metered dose spray • In vitro studies • PK/PD/clinical study • Oral drugs rarely absorbed by GI tract • e.g., Sevelamer (phosphate binder ) • In vitro studies • Topical and vaginal antifungals • In vitro studies (Franz cell system) • Potential in vivo performance evaluation methods is still developing

36. BE issues for certain drug products Drugs with special dosage forms • Transdermal patches Single or Multiple doses • Liposome products • Bioanalytical Methods Encapsulated and uncapsulated

37. Strategies for API and Generic Drug • Establishing the review strategies for DMF of API and CTD of Generic Drugs • Time-line and action plans to implement API’s DMF and CTD for Generic Drug • Communication with the industry association • Training /Education

38. Implement API’s DMF for Generic Drug Implementation status of API’s DMF Area Management model

39. EU FDA MHLW New chemical entities included included included New biologic included included* included New indication included included included New dosage forms included included included New route of administration included included included Generics included included not included OTC included included not included * with the exception of blood and blood components Implement Common Technical Document for generic drug Common Technical Document (CTD)Implementation Coordination Group organized by: Implementation Coordination Group Members plus members in CTD-Q, CTD-S, CTD-E & eCTD presented in June 13 `02 General Information on the CTD

40. Strategies for Post-Approval Changes • Regulation strategies for post-approval changes • Establish DMF database of API • Monitor and inspect API changes • Revise guideline for Scale-Up and Post Approval Changes (SUPAC) • Strengthen regulation on Post-Approval Changes-Product Quality Review • Regulation Strategy for management of product license 40

41. Revise Post-Approval Change Guideline, based on SUPAC (USA), BACPAC (USA) and variation regulation (EMA) Strengthen post-approval changes regulation system, based on EMA’s regulation-Annual Product Quality Review(PIC/S GMP) Industry’s duty: be responsible for drug product quality, and make commitment to the drug quality assurance. Major change: submit data for pre-approval All quality related changes: annual product quality review Strategies for Post-Approval Changes

42. Product Quality Review (PIC/S GMP)

43. Strategies for GMP regulation Quality Assurance for Drug Manufacturing • Good Manufactory Practice (GMP) • Documentations, SOP, QC, QA • Current GMP (cGMP) • Validations- analytical method, process, data treatment • PIC/S GMP by 2014 43 43 43

44. Milestones of Pharmaceutical GMP Development in Taiwan GMP cGMP PIC/S GMP number of domestic pharmaceutical manufacturer 21 pharmaceutical manufacturers are in compliance with PIC/S GMP ◆ ◆ ◆ ◆ ◆ 1982 1988 1999 2005 2010.11 Overseas Inspection since 2002

45. Evolution of Quality concept Quality Systems Quality by Design Quality by Manufacturing process- Quality Assurance Quality by Testing- Quality Control 1980s 1990s 2000s 1970s

46. Internationalize quality guidelines Implementation status of ICH quality Guidelines in Taiwan

47. New Quality Initiative How to do What to do Fixed controls state Dynamic controls state Product -1970s Process 1980s~1990s Systems 21st Century Quality Control Quality Assurance Quality Systems

48. Goal The three-way win Consumer Ensure Drug quality, safety& efficacy International harmonization on drug management Increase international competitiveness Industry Government