Global Harmonization—Challenges and Opportunities

1. Global Harmonization—Challenges and Opportunities Angela G. Long, M.S. Senior Vice President, Global Alliances and Organizational Affairs Executive Secretariat, Council of Experts

2. Topics • About USP • Pharmacopoeias Overview • Current Harmonization Efforts and Challenges • Opportunities

4. USP is a Global Organization

5. Greetings from Ron Piervincenzi, USP CEO • Tenure started February 1, 2014 • Formerly with Biogen Idec and a partner in McKinsey & Company's Global Pharmaceutical and Medical Products Practice • Earned his M.S. and Ph.D. from Duke University in Biomedical Engineering with research focused on protein engineering • Also Executive Vice President, USP Convention; Ex-officio member of the Board; Chair, Council of Experts

6. USP – An Overview • Since 1820, not-for-profit, private, independent, and self-funded • Headquartered in Rockville, Maryland; over 800 employees worldwide • Facilities in India, China, Brazil, Switzerland, Ghana, and Ethiopia (and soon Indonesia and Nigeria) • Over 1,000 expert volunteers; the Council of Experts and its Expert Committees are USP’s scientific decision-makers • Internationally recognized and globally focused

7. USP Governing and Advisory Bodies Council of the Convention Convention Membership Councilof Experts & Expert Committees Expert Panels Board of Trustees & Board Committees USP Staff Stakeholder Forums & ProjectTeams Advisory Bodies

8. USP Convention Membership • Up to 600 Organizations Representing Six Categories • Academic Institutions and Associations • Health Practitioner Professional and Scientific Associations • Manufacturer, Trade, and Affiliated Associations • Governmental Bodies, Divisions and Associations • Consumer and Other Organizations Representing the Public Interest • Non-governmental Standards-setting and Conformity Assessment Bodies • Meets Every Five Years (next meeting: April 2015): • Elect Officers and Trustees • Elect the Council of Experts (Expert Committee Chairs) • Adopt resolutions • Adopt changes to Bylaws

9. USP Board of Trustees 2010–2015 PresidentTimothy R. Franson, B.S. Pharm., M.D. Treasurer John E. Courtney, Ph.D. Past President René H. Bravo, M.D., F.A.A.P. Public TrusteeCarolyn H. Asbury, Ph.D., Sc.M.P.H. At-Large Trustee Robert L. Buchanan, Ph.D. At-Large Trustee Thomas E. Menighan, B.S., Pharm., M.B.A, Sc.D., F.A.Ph.A At-Large Trustee Kiran Mazumdar Shaw Medical Sciences Trustee Robert M. Russell, M.D. Pharmaceutical Sciences Trustee Duane M. Kirking, Pharm.D., Ph.D. Medical Sciences TrusteeStephen P. Spielberg, M.D., Ph.D. Pharmaceutical Sciences Trustee Marilyn K. Speedie, Ph.D. At-Large Trustee Jeffrey L. Sturchio, Ph.D. At-Large Trustee Thomas R. Temple, R.Ph., M.S. At-Large Trustee Gail Wilensky, Ph.D. Ronald T. Piervincenzi, Ph. D

10. Elements of the Board’s Strategic Plan

12. 2010-2015 Council of Experts - Demographics • 1010 experts serving on 26 Expert Committees, 72 Expert Panels and 1 Advisory Group • 412 Expert Committee members • 440 Expert Panel members* • 28 Advisory Group members* • 130 Government Liaisons • 116 FDA Liaisons • CDER: 75 – ORA: 4 • CFSAN: 15 – OC/ONDQA: 2 • CBER: 10 – CDRH: 2 • CVM: 8 • 3 Brazil (ANVISA, Brazilian Pharmacopoeia, INCQS) • 1 CCAYAC/COFEPRIS (Mexico) • 2 Centers for Disease Control and Prevention • 1 Centers for Medicare and Medicaid Services • 2 Chinese Pharmacopoeial Commission Representatives • 2 Health Canada Representatives • 1 NIST Representative • 1 Saudi Food and Drug Authority • 1 U.S. Public Health Service * Does not include Expert Committee members also serving on Expert Panels or Advisory Groups

13. 2010–2015 Council of Experts - Demographics • 880 Expert Committee, Expert Panel and Advisory Group members • 272 (31%) international experts from 48 countries: • Argentina 4 • Australia 4 • Austria 2 • Azerbaijan 1 • Bangladesh 2 • Belgium 6 • Brazil 10 • Canada 33 • Chile 2 • China 37 • Colombia 2 • Costa Rica 1 • Denmark 6 • England 1 • France 10 • Georgia 1 • Germany 21 • India 42 • Ireland 2 • Israel 2 • Italy 4 • Japan 1 • Jordan 2 • Korea 4 Mexico 3 Netherlands 5 New Zealand 1 Pakistan 2 Peru 2 Portugal 1 Republic of Armenia 1 Republic of Belarus 2 Republic of Kazakhstan 1 Russia 7 Saudi Arabia 2 Scotland 1 Singapore 1 South Africa 1 Spain 2 Sweden 2 Switzerland 9 Taiwan 1 Ukraine 4 United Kingdom 20 Uruguay 1 Uzbekistan 1 Venezuela 1 West Malaysia 1

14. 2015–2020 Council of Experts Recruiting www.usp.org

15. USP Compendia • The United States Pharmacopeia • National Formulary (USP–NF) • Food Chemicals Codex (FCC) • USP Dietary Supplements Compendium (DSC) • USP Medicines Compendium (MC) • USP on Compounding • Herbal Medicines Compendium (HMC) • Other Resources • Pharmacopeial Forum (PF) • FCC Forum (FCCF) • USP Dictionary • Chromatographic Columns

16. Translations Spanish Translation Russian Translation Chinese Translation Also…Chinese Translation of the FCC

17. USP Reference Standards • Trusted for pharmaceutical quality control worldwide • Over 3,200 Reference Standards now available • Support FDA-enforceable standards and tests in the USP–NF • Highly pure, with purity values provided for quantitative standards • Available through USP’s iStorehttp://store.usp.org

18. USP Works Globally—Sites EXEC293G_2013-07

19. USP Works Globally—Worldwide Regions

20. USP Brazil Facility

21. FDA-USP Interactions • FDA enforces USP standards, under the 1938 Federal Food, Drug, and Cosmetic Act • FDA reviews proposed standards in Pharmacopeial Forum and provides comments • Convention Participation:Delegates, Resolutions, Council of the Convention, Convention Committees • Provides FDA Liaisons to USP’s Expert Committees • Participates in workshops and stakeholder forums • Cooperative Research and Development Agreements • Office of the Commissioner: Substance Registry System • ORA: Collaborative Testing, Monograph Modernization, Rapid Screening Methods • Informal Collaborations: Quarterly Meeting; Pharmacopoeial Discussion Group; OTC Monograph Modernization; Compounding • Detail of Senior staff member

23. Topics • About USP • Pharmacopoeias Overview • Current Harmonization Efforts and Challenges • Opportunities

24. Pharmacopoeias in the World (According to WHO/2012)29 of the 49 are part of the European Pharmacopoeia

25. Global Market of Medicines • RxNorm: 11,000 approved drug products and their ingredients in the US??

26. Pharmacopoeial Monographs * Drug substance monographs only ** 2014 Edition

27. Topics • About USP • Pharmacopoeias Overview • Current Harmonization Efforts and Challenges • Opportunities

28. USP Convention Resolution 5 • USP resolves to strengthen and expand its efforts to work with pharmacopeias, industry, academia, regulators, international organizations and other stakeholders around the world to develop harmonized global standards.

29. Current Harmonization Efforts • Pharmacopoeial Discussion Group • Prospective Harmonization • Informal Harmonization (e.g., Bilateral Agreements, MOUs, etc.) • Regional Harmonization Efforts

30. Global Harmonization Challenges • A global industry wants harmonized standards • Regulators need standards • Pharmacopoeias are downstream from regulatory authorities • National pharmacopoeias reflect their markets • Other approaches are emerging, e.g., “convergence” • Harmonization is hard, especially retrospective

31. Pharmacopoeial Discussion Group (PDG) • Founded in 1989 • Includes the European Pharmacopoeia, Japanese Pharmacopoeia, United States Pharmacopeia, and WHO (an observer since 2001) • PDG delinked from ICH in 2011 when Q6A chapters harmonization accomplished • PDG activities have focused on harmonizing certain general chapters and excipient monographs • Steady but limited progress • Currently assessing its processes

32. PDG Definition of Harmonization • Harmonized: A pharmacopeial general chapter or other pharmacopeial document is harmonized when a pharmaceutical substance or product tested by the document’s harmonized procedure as published in European Pharmacopoeia, Japanese Pharmacopoeia and USP-NF yields the same results, and the same accept/reject decision is reached. • Text does NOT have to be identical. • Each Pharmacopeia can adapt the text to local style, and take into consideration local reference standards and reagents.

33. PDG: Challenges • General Chapters: 29 of 36 Harmonized • Excipients: 46 of 62 Harmonized • Three pharmacopoeias + WHO’s International Pharmacopoeia • Experts meet separately • Retrospective harmonization is hard

34. PDG Challenges, continued • Time required to bring harmonized monographs and general chapters to public is very long and process is burdensome. • Pharmacopeias operate on different publishing schedules. • Comments are often received too late in the PDG process. • Differences in legal and/or regulatory requirements in the different regions can be barriers to harmonization. • PDG uses “harmonization by attribute” to be able to move forward items within a monograph or general chapter that are not in dispute

35. Prospective Harmonization • Initiated in July 2008 in response to proposals from manufacturers • Initial Pilot study between the European Pharmacopoeia and USP to develop early harmonized monographs and reference standards for four drug substances • Monographs • Celecoxib • Montelukast Sodium • Rizatriptan Benzoate • Sildenafil Citrate • Reference Standards • Eleven materials to support the four monographs • See Stimuli articles in PF 36(6)

36. Prospective Harmonization • All four monographs now official in both Ph Eur and USP • All eleven reference materials available for use • Some corresponding drug product monographs are being developed by the British Pharmacopoeia (BP)/USP • Additional projects are underway with one company; one additional pharmacopoeia may participate • Pilot phase extended to assess revision process to maintain harmonized status

37. Prospective Harmonization: Challenges • Two manufacturers then one • Three pharmacopoeias but others interested • Difficult to bring together pharmacopeial processes • Coordination is resource-demanding • Timing of publication in different pharmacopoeias • Revisions and maintaining harmonized texts • Reference Standards logistics • Terminology of “Harmonization” can be limiting

38. Informal/Bilateral Harmonization

39. Harmonization through Bilateral Agreements • Adopt/Adapt Agreements • Translations • Visiting Scientist Program/International Training Program • Science and Standards Symposia • Study Tours • Education Programs • Capacity Building Support (e.g., Technical Assistance) • USP Standards-setting Activities • Chemical Medicines • Biological Medicines • Excipients • Herbal Medicines/Dietary Supplements

40. Informal/Bilateral Harmonization—Challenges • Limited resources—USP • Limited resources—other pharmacopoeias

41. Regional Pharmacopoeias • European Pharmacopoeia • 36 Member States • 29 pharmacopoeias harmonized (drug substance monographs and general chapters) • Mercosur Pharmacopoeia • Activities beginning • ASEAN Pharmacopoeia • Discussions beginning

42. Regional Pharmacopoeias—Challenges • European model is good but it has a long history (50 years) and governance structure • Compromise is key • Sovereignty is important to national pharmacopoeias • It’s difficult to start a new pharmacopoeia

43. Topics • About USP • Pharmacopoeias Overview • Current Harmonization Efforts and Challenges • Opportunities

44. Pharmacopoeial Meetings • ICDRA • Singapore 2002 , Madrid 2004, October 2012 • WHO International Meeting of World Pharmacopoeias • Geneva February-March 2012 (#1), • India April 2013 (#2) • London April 2014 (#3) • Chinese Pharmacopoeia and USP (Global Summit of the Pharmacopoeias) • Beijing November 2011 (#1) • Xi’an September 2012 (#2) • Baltimore September 2013 (#3)

45. WHO Good Pharmacopoeial Practices • Introduction • Purpose and Scope of Good Pharmacopoeial Practices • Monograph Development • General Considerations • Technical Guidance • Monographs for starting materials, including active pharmaceutical ingredients and excipients • Monographs for finished pharmaceutical products • Monographs for compounded pharmaceutical preparations • Monographs for biologicals • Monographs for herbals • Monographs for other products • Reference Substances • Analytical Test Procedures and Methodologies • Principles of Collaboration and Exchanges Among Pharmacopoeias • Collaboration with Stakeholders

46. Global Summit of the Pharmacopoeias • Sponsored by the Chinese Pharmacopoeia and USP and includes all pharmacopoeias • Pharmacopoeias signed a statement that… “envisions a day when all medicines moving in national and international commerce will have optimal public standards….working in a science-based, transparent and collaborative way, seeking input from all interested parties.” • Three meetings; the first two in China, the third in Baltimore • Focus areas: • Optimal Drug Substance and Product Monographs • Global Pharmacopoeial Database/Index (ChP) • Spectral Libraries (USP)

47. WHO and GSP Meetings Combined April 2014

48. Opportunities • PDG: June 2014 Press Release: • “PDG members agreed on concrete actions to improve its working procedures and improve transparency to stakeholders.” • “In light of the anticipated sign-off of the ICH Q3D guideline for elemental impurities, PDG members agreed to harmonize their general chapters on methods related to elemental impurities, with USP serving as the coordinating pharmacopoeia.” • In addition to excipients, globally harmonize drug substance and drug product monographs by evolving Prospective Harmonization to include collaboration with other pharmacopoeias and other companies

49. Opportunities • “Formalize” Informal Harmonization (Adopt/Adapt) • Utilize WHO’s Good Pharmacopoeial Practices as a common framework for standards development • Continue to bring global pharmacopoeias together with a goal to harmonize priority drug substances and products: Europe October 2014; US April 2015; China Fall 2015 • Leverage other resources—work collaboratively with regulatory authorities/universities/industry on standards development • Future new approaches?

50. Muito Obrigado!