1. USP Monographs Roger L. Williams, M.D. CEO/Chair, Council of Experts 6 th Annual Science and Standards Symposium January 16, 2013 Istanbul

2.  The Basics  Management  The Future—Science  The Future—Putting It Together Topics

3. Assignments

4. Documentary Standards-setting Process

5. Expert Committee Participation by Compendium Expert Committee Participation Public Review and Comment Forum Frequency and Terminology Compendium Publication USP−NF  Involves the majority of the Expert Committees  Pharmacopeial Forum (PF)  90 days  Free, Web access only to start in January 2011  Includes new and revised standards  6 times per year (Jan, Mar, May, July, Sep, and Nov)  In Process Revision (IPR)  Official, legally enforceable text  Book and 2 Supplements published annually Food Chemicals Codex (FCC)  Food Ingredients  Nomenclature, Safety and Labeling  FCC Forum (FF)  90 days  Free, Web access only  Includes new and revised standards  2 times per year (June and Dec)  Proposed Changes and Additions (PCA)  Effective text  Published every 2 years with three intervening Supplements

6. Expert Committee Participation by Monograph Initiative Expert Committee Participation Scope Public Review and Comment Terminology Pending Monographs  Primarily Small Molecules  Possibly Excipient Monographs  Nomenclature, Safety and Labeling  Monographs based on generic applications awaiting FDA approval  Not legally enforceable  Pending can become official USP−NF monograph via Revision Bulletin (separate EC approval needed)  90 days  Web only  Content updated monthly  Proposals are “Draft”  EC-approved content is “Authorized” Non-US Monographs  Small Molecules Expert Committees, possibly others  Articles approved outside the U.S.  Voluntary public standard  Remains on Web site--not intended to become official USP−NF monograph  90 days  Web only  Content updated monthly  Proposals are “Draft”  EC-approved content is “Authorized”

7. Accelerated Revisions by Compendium Accelerated Revision Type USP–NFRevision Bulletin Revision Interim Announcement Errata FCC Immediate Standard Expedited StandardErrata EC ApprovalRequired Not required Notice and Comment None60 days (will be 90 days as of Jan 2011) None UsesCompliance, urgent safety issues, correction of substantive broad-impact errors Non-urgent safety issue, non-working procedures Correction of minor, low-impact errors and errors that do not reflect intended requirement as approved by the EC decision PublicationMonthly on Web site 6 times per year on Web site Official or Effective Date As of the date indicated in the posting As of the date indicatedImmediate

8.  The Basics  Management  The Future—Science  The Future—Putting It Together Topics

9. Key Elements of Science & Standards Division: Organization Flow

10. Drivers for Change  Increase/improve interface between different parts of USP  Increase efficiency on work flow within SSD –External to USP –Internal within USP  Expert Committees were recently restructured to manage monographs and reference standards  To make project ownership for each product clear (single point of accountability in the context of the team)  Maximize capacity of our work load (identify constraints and provide solutions)

11.  Products (monographs, reference materials) to our customers are synchronized and reference standards are available as early as possible  There is a portfolio owner for each segment of the portfolio for Small Molecules, Biologics, Excipients, Dietary Supplements, Food Ingredients, General Chapters/Pharmacists’ Pharmacopeia, Healthcare Quality Standards  A uniform criteria for priority setting. Drivers For Change: Outcomes

12. Current Status for US Compendia CompendiumExpert Committee Missing from Compendia (Estimate) Total Monograph Universe (Estimate) Small Molecules15135042 Biologics297415 Pharmacy 105 204 19375661 34% Excipients163563 29% Dietary Supplements10911500 73% Food Ingredients25353675 69% Total572611399 New Monographs CompendiumExpert CommitteeNeeded Work in ProcessWork in Process Small Molecules2600419214 Biologics44061 Pharmacy00 46 2644419324 70%11%17% Excipients966236 24%16%22% Dietary Supplements1002483 24%6%8% Food Ingredients2503454 22%3%2% Total3090539608 USP Total NF DS FCC 5695 Modernization USP DS 409 27% FCC 1140 31% USP Total 3746 66% NF 400 71% In Compendia USP 3529 118 99

13. Current Status: OTC Modernization (Focus for FY’13) SubstancesDosage FormsTotal Official in USP-NF240500740 Modernization Required141325466 % of OTC Monographs59%65%63%

14. 41 28% 2 1% 6 4% 32 21% 10 7% 48 32% 10 7% New Monograph Breakdown (As of April 30, 2012) Small Molecules (USP) Biologics (USP) Pharmacy (USP) Excipients (NF) Foods (FCC) Dietary Supplements (DSC) Medicines Compendium Pending Monographs Received by Portfolio Category

15. Reference Standards: Pipeline vs. Process

16. Reference Standard Lot Releases Note: This information is updated from what appeared in briefing materials.

17.  The Basics  Management  The Future—Science  The Future—Putting It Together Topics

18. Drug Product Monographs and General Chapters

19.  A PBM can include: –Specified tests Identification, Assay, others –Specific acceptance criteria 97%-103%, NMT 0.1%, others –Criteria-based procedures with: Procedure Performance Measures (Precision, accuracy, others) Procedure Performance Acceptance Criteria (% RSD, Bias, R 2, others) Performance Based Monograph

20. Glutathione Example: Assay

21.  USP General Chapter Validation of Compendial Procedures defines the critical validation parameters necessary to validate a procedure.  Pre-set criteria assure that an acceptable procedure will reliably assess whether an article meets acceptance criteria of its Tests.  USP now terms these criteria as Procedure Performance Measures (PPM) and the Procedure Performance Acceptance Criteria (PPAC).  PPM and PPAC may be used to determine suitability of multiple acceptable procedures. PPMs and PPACs

22.  Small Molecules Collaborative Group, Williams RL, Abernethy DR, Koch WF, Hauck WW, Cecil TL. Performance-based monographs. Pharm Forum. 2009;35(3):765-771.  Hauck WW, DeStefano AJ, Cecil TL, Abernethy DR, Koch WF, Williams RL. Acceptable, equivalent, or better: approaches for alternatives to official compendial procedures. Pharm Forum. 2009;35(3):772-778.  Koch WF, Hauck WW, de Mars SS, Williams RL. Measurement science for food and drug monographs: toward a global system. Pharm Res. 2010;27:1203-1207.  Williams RL, de Mars S, Koch WF, Hauck WW, Cecil TL. USP responses to comments on Stimuli article: performance-based monographs. Pharm Forum. 2010;36(4):1074-1079. References

23. USP Medicines Compendium: www.usp-mc.org

24. Key Points About the Medicines Compendium  MC is applicable to medicines legally marketed outside of the US; USP-NF covers articles legally marketed in the US  Science based  Authoritative, not official; the approval by the Council of Experts makes it authoritative  Supplements donor model  Helps modernize USP-NF  Experimental, unique, and innovative

25. USP Medicines Compendium Process

26.  The Basics  Management  The Future—Science  The Future—Putting It Together Topics

27. Compendial Globalization (Merck)

28. Pioneers and Harmonization