Global Harmonization—Challenges and OpportunitiesAngela G. Long, M.S.Senior Vice President, Global Alliances and Organizational AffairsExecutive Secretariat, Council of Experts

About USP

Pharmacopoeias Overview

Current Harmonization Efforts and Challenges

Opportunities

Topics

USP is a Global Organization

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

Greetings from Ron Piervincenzi, USP CEO

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Headquartered in Rockville, Maryland; over 800 employees worldwide

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Over 1,000 expert volunteers; the Council of Experts and its Expert Committees are USP’s scientific decision-makers

Internationally recognized and globally focused

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President

Timothy R. Franson,

B.S. Pharm., M.D.

Treasurer

John E. Courtney, Ph.D.

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René H. Bravo, M.D.,

F.A.A.P.

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Carolyn H. Asbury,

Ph.D., Sc.M.P.H.

At-Large Trustee

Robert L. Buchanan, Ph.D.

Pharmaceutical

Sciences Trustee

Duane M. Kirking, Pharm.D.,

Ph.D.

Medical Sciences Trustee

Stephen P. Spielberg,

M.D., Ph.D.

At-Large Trustee

Thomas E. Menighan,

B.S., Pharm., M.B.A,

Sc.D., F.A.Ph.A

Medical Sciences Trustee

Robert M. Russell, M.D.

Pharmaceutical

Sciences Trustee

Marilyn K. Speedie, Ph.D.

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R.Ph., M.S.

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Gail Wilensky, Ph.D.

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At-Large Trustee

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– 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

2010-2015 Council of Experts - Demographics

* Does not include Expert Committee members also serving on Expert Panels or Advisory Groups

2010–2015 Council of Experts - Demographics

• 880 Expert Committee, Expert Panel and Advisory Group members– 272 (31%) international experts from 48 countries:

1. Argentina 4

2. Australia 4

3. Austria 2

4. Azerbaijan 1

5. Bangladesh 2

6. Belgium 6

7. Brazil 10

8. Canada 33

9. Chile 2

10. China 37

11. Colombia 2

12. Costa Rica 1

13. Denmark 6

14. England 1

15. France 10

16. Georgia 1

17. Germany 21

18. India 42

19. Ireland 2

20. Israel 2

21. Italy 4

22. Japan 1

23. Jordan 2

24. Korea 4

25. Mexico 3

26. Netherlands 5

27. New Zealand 1

28. Pakistan 2

29. Peru 2

30. Portugal 1

31. Republic of Armenia 1

32. Republic of Belarus 2

33. Republic of Kazakhstan 1

34. Russia 7

35. Saudi Arabia 2

36. Scotland 1

37. Singapore 1

38. South Africa 1

39. Spain 2

40. Sweden 2

41. Switzerland 9

42. Taiwan 1

43. Ukraine 4

44. United Kingdom 20

45. Uruguay 1

46. Uzbekistan 1

47. Venezuela 1

48. West Malaysia 1

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

1. The United States Pharmacopeia

2. National Formulary (USP–NF)

3. Food Chemicals Codex (FCC)

4. USP Dietary Supplements Compendium (DSC)

5. USP Medicines Compendium (MC)

6. USP on Compounding

7. Herbal Medicines Compendium (HMC)

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Spanish Translation Russian Translation Chinese Translation

Also…Chinese Translation of the FCC

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EXEC293G_2013-07

USP Works Globally—Worldwide Regions

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FDA reviews proposed standards in Pharmacopeial Forum and provides comments

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Provides FDA Liaisons to USP’s Expert CommitteesParticipates in workshops and stakeholder forumsCooperative Research and Development Agreements

Office of the Commissioner: Substance Registry SystemORA: Collaborative Testing, Monograph Modernization, Rapid

Screening Methods Informal Collaborations: Quarterly Meeting; Pharmacopoeial

Discussion Group; OTC Monograph Modernization; Compounding

Detail of Senior staff member

FDA-USP Interactions

22

About USP

Pharmacopoeias Overview

Current Harmonization Efforts and Challenges

Opportunities

Topics

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

24

ArgentinaCzech

RepublicHungary Japan Pakistan Slovakia Ukraine

Austria Denmark Iceland Kazakhstan Philippines SloveniaUnited

Kingdom

Belarus Egypt India Korea Poland SpainUnited States

Belgium Finland Indonesia Lithuania Portugal Sweden Viet Nam

Brazil France Iran Mexico Romania Switzerland Chile

China Germany Ireland MontenegroRussian

FederationThailand Europe

Croatia Greece Italy Norway Serbia Turkey WHO

RxNorm: 11,000 approved drug products and their ingredients in the US??

Global Market of Medicines

Pharmacopoeia Total

Argentina Pharmacopoeia ~800

Brazilian Pharmacopoeia ~600

British Pharmacopoeia ~3,300

Chinese Pharmacopoeia 4,569

European Pharmacopoeia 2,224*

Indian Pharmacopoeia ~2,500

Japanese Pharmacopoeia 1,764

Mexican Pharmacopoeia ~1,300

United States Pharmacopeia 4,700

Pharmacopoeial Monographs

* Drug substance monographs only** 2014 Edition

About USP

Pharmacopoeias Overview

Current Harmonization Efforts and Challenges

Opportunities

Topics

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.

USP Convention Resolution 5

Pharmacopoeial Discussion Group Prospective Harmonization Informal Harmonization (e.g., Bilateral Agreements,

MOUs, etc.) Regional Harmonization Efforts

Current Harmonization Efforts

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

Global Harmonization Challenges

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

Pharmacopoeial Discussion Group (PDG)

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.

General Chapters: 29 of 36 Harmonized

Excipients: 46 of 62 Harmonized

Three pharmacopoeias + WHO’s International Pharmacopoeia

Experts meet separately

Retrospective harmonization is hard

PDG: Challenges

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

• 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)

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

Prospective Harmonization

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

Prospective Harmonization: Challenges

Informal/Bilateral Harmonization

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

Harmonization through Bilateral Agreements

Limited resources—USP

Limited resources—other pharmacopoeias

Informal/Bilateral Harmonization—Challenges

European Pharmacopoeia 36 Member States 29 pharmacopoeias harmonized (drug substance monographs and

general chapters)

Mercosur Pharmacopoeia Activities beginning

ASEAN Pharmacopoeia Discussions beginning

Regional Pharmacopoeias

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

Regional Pharmacopoeias—Challenges

About USP

Pharmacopoeias Overview

Current Harmonization Efforts and Challenges

Opportunities

Topics

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)

Pharmacopoeial Meetings

– 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

WHO Good Pharmacopoeial Practices

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)

Global Summit of the Pharmacopoeias

WHO and GSP Meetings Combined April 2014

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

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?

Muito Obrigado!