Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World

Food and Drug Administration Public Meeting May 1, 2009

Economically Motivated Adulteration Academic/Government Panel

Roger L. Williams, M.D.

Chief Executive Officer Chair, Council of Experts [email protected]

Topics

• USP Convention • USP in Law • USP and Heparin • Issues and Summary

USP Governing and Advisory Bodies

Board of Trustees & Board Committees Council of the Convention Convention Membership USP Staff Council of Experts & Expert Committees Advisory Panels Advisory Bodies Stakeholder Forums & Project Teams

USP Global Laboratory Sites

China Rockville, Maryland Brazil India

USP 32 –NF 27

 Time-tested, international resource. USP standards are used in more than 130 countries  More than 4,200 monographs  Official authority —FDA-enforceable for drugs manufactured in, exported to, or marketed in the U.S.

 Continuously updated —published annually in a main edition and two

Supplements

 Available in English (print, online, CD) and Spanish (print)

USP’s Legal Recognition (FD&C Act)

•

SEC. 201.

For the purposes of this chapter – (g)(1) The term ''drug'' means articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them – (j) The term ''official compendium'' means the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, official National Formulary, or any supplement to any of them.

USP

’

s Legal Recognition: FD&C Act Section 501(b) Adulteration

• A drug or device shall be deemed to be adulterated if it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in such compendium.

• Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium…

USP’s public standards can help assure the quality and safety of all drugs sold in U.S. market

2005-2010 USP Council of Experts

Food Ingredients Expert Committee

Blood and Blood Products Expert Committee and Advisory Panel

•

Expert Committee Chair:

Jean Huxsoll, Ph.D.

Members:

– Timothy Hayes, Ph.D.

– Christopher Bryant, Ph.D.

– Pamela Clark, M.D., J.D.

– Elaine Gray, Ph.D.

– Patrick McKee, M.D.

– Michael Passwater, BS – John Sokolowski, MS •

Advisory Panel Chairs:

Wesley Workman, Ph.D & Kristian Johansen, Ph.D.

Members:

– Edward Chess, Ph.D.

– Neil Desai, Ph.D.

– Gyöngyi Gratzl, Ph.D.

– Elaine Gray, Ph.D.

– Hester Hasper-van Heusden, Ph.D.

– Craig Jackson, Ph.D.

– Robert Linhardt, Ph.D

– Barbara Mulloy, Ph.D.

– Zachary Shriver, Ph.D.

– Christian Viskov, Ph.D.

FDA liaison:

Ali Al-Hakim, Ph.D.

Changes to USP Heparin Sodium Monograph

Procedure Stage 1 Revisions Stage 2 Revisions

Identification Potency Organic Impurities 1 H NMR CE No revision No revision -Expanded 1 H NMR procedure -Replaced CE method with anion-exchange HPLC procedure -Added ratio of anti-factor Xa activity to anti-factor IIa potency -Replaced sheep plasma clotting assay with chromogenic anti-factor IIa assay -Added limit of total galactosamine in total hexosamine (a measure of dermatan sulfate and other galactosamines) -Revised protein impurities -Added nucleotidic impurities -Added residual solvents Absence of OSCS New USP Reference Standards See Identification -USP Heparin Sodium Identification RS -USP Heparin Sodium System Suitability RS -References Identification tests A and B -USP Oversulfated Chondroitin Sulfate RS -USP Dermatan Sulfate RS -USP Galactosamine Hydrochloride RS -USP Glucosamine Hydrochloride RS

Prior Efforts to Revise

• WHO – 1998 working group develops chromogenic anti-factor IIa potency test • 2004 Stimuli article in

Pharmacopeial Forum

(

PF)

30(5) on the qualification of chromogenic test – proposes replacement of sheep plasma assay • 2006 Advisory Panel is formed • 2007 revision proposal in PF 33(2) to replace the sheep plasma clotting potency test with chromogenic anti-factor IIa potency test

Comparison of Monograph Requirements

Monograph Requirement Identification Assay Old USP Old EP New USP

•

Flame test for sodium

•

Sheep plasma clotting

•

Optical rotation

•

Zone electrophoresis

•

Residue on ignition

•

Sheep plasma clotting

•

Sheep plasma clotting

• •

Proton NMR Anion Exchange Chromatography

•

Anti-Factor Xa to anti-Factor IIa Ratio

•

Flame test for sodium

•

Chromogenic anti Factor IIa

Issues and Summary

• Current USP View: An up to date public monograph in USP with careful attention to GMPs, including careful in-process testing, could have prevented access to commercially contaminated heparin drug substances in the US market • Many other USP monographs are either missing or out of date • The FDA-USP partnership created in law more than 100 years ago needs to be strengthened – No mechanism for ensuring that USP receives information it needs to create and update monographs • This will need involvement from all stakeholders

Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World

Thank you