1. USP: Water for Pharmaceutical Purposes NCSLI – Metrological Traceability in Pure Water Testing August 22, 2011 Antonio Hernandez-Cardoso Senior Scientific Liaison AHP@usp.org

2. U.S. Pharmacopeia – An Overview  Mission: To improve the health of people around the world through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods.  What we do: Set public quality standards that define the authenticity, identity, purity or impurity of food, drugs and dietary supplements, thus helping to ensure product integrity and the safety of consumers and brands.  How we do it: Since 1820, nonprofit, private, independent, and self-funded Headquartered in Rockville, MD; 600+ employees; facilities in India, China, Switzerland, Brazil Expert volunteers are scientific decision-makers

3. USP Sites

4. Why Is a Public Standard Important?  USP provides quality standards, test methods and reference standards for the drug products as well as food ingredients and dietary supplements that are in commerce to: Assess the quality Provide specifications that new manufacturers can target Monitor for counterfeit and substandard products Ensure a consistent approach to quality for innovator and generic/mainstream products Enabling the monitoring the quality of imported products

5. Core Compendial Programs  The United States Pharmacopeia and the National Formulary (USP–NF)  Food Chemicals Codex  USP Dietary Supplements Compendium  Reference Standards  Standards for quality criteria (authenticity, identity, purity), test methods for their verification and reference materials from one source.

6. Government Other Pharmacopoeias Industry Expert Committees Scientific Staff Liaisons Revision of standards - A Collaborative Process

8. USP’s Recognition in Federal Legislation 1848 Drug Import Act: USP legislatively mandated 1906 Federal Pure Food & Drugs Act: USP standards recognized 1938 Federal Food, Drug, and Cosmetic Act (FD&C Act): USP standards recognized as FDA-enforceable Definition of a drug Adulteration Misbranding Drug product name 1994 Dietary Supplement Health & Education Act: A dietary supplement represented as conforming to USP–NF specifications shall be deemed misbranded if it fails to do so. 2003 Medicare Prescription Drug, Improvement, and Modernization Act: USP will create Model Guidelines – a list of categories and classes that prescription drug plans may use as they design their formularies

9. How USP and FDA Work Together  FDA staff communicate regularly with USP as “USP Expert Committee FDA Liaisons” and through the FDA Office of Compendial Operations  FDA staff review and comment on USP–NF and FCC proposals  FDA staff members participate in USP meetings and workshops— including internationally  USP works with multiple FDA Centers, e.g., Center for Drug Evaluation and Research, Center for Food Science and Nutrition Research, Center for Veterinary Medicine, and others  FDA and USP leadership have worked on increasing and improving communications across all areas of FDA

10. Pharmaceutical Water Monographs  Water for Injection (WFI)  Purified Water  Sterile WFI  Sterile Purified Water  Sterile Water for Inhalation  Sterile Water for Irrigation  Bacteriostatic WFI  Water for Hemodialysis  Pure Steam

11. Water Types in Pharmacopoeia Water TypeUSP 34EP 6.3JP XV 1Water for Injection (bulk) +++ 2Water for Injection/sterilized (containers) +++ 3Highly Purified Water (bulk) + 4Purified Water (bulk) +++ 5Purified Water (containers) ++ 6Sterile Purified Water (bulk) + 7Sterile Purified Water (containers) + 8Bacteriostatic Water for Injection (containers) + 9Sterile Water for Inhalation (containers) + 10Sterile Water for Irrigation (containers) + 11Water for Hemodialysis (bulk + containers) ++ 12Water (tap, well) + 13Pure Steam +

12. Key Pharmaceutical Water Chapters   643  Total Organic Carbon (TOC)   645  Water Conductivity   71  Sterility   85  Bacterial Endotoxins Tests (BET)   1230  Water for Hemodialysis Applications   1231  Water for Pharmaceutical Purposes Specific to Water

13. Characteristics of Impurities in Water

14. Purified Water – Microbiology

15. History of Water Monographs/Chapters  1989 – PhRMA stakeholders advocate for improved water quality testing – not improved water  1991 – PhRMA/WQC proposes Conductivity and TOC to replace most existing chemistry tests for BULK Purified Water and WFI  1991-1995 - PhRMA/WQC evaluates TOC and conductivity instrumentation and methods for BULK waters  Conductivity challenges  TOC challenges

16. Evolution of  645  Water Conductivity  WQC develops method and limit based on criteria from chemistry tests  WQC reviews conductivity measurement systems  Lab samples do not correlate to in-line samples  Disable temperature compensation  Generate temperature-based limits  Create pH dependent limits for air-sat’d samples  The conductivity limit is 1.3  S/cm  What about at other temperatures - is Cl - still the ion that generates the lowest conductivity?

17. Evolution of  645  Water Conductivity  WQC re-publishes modified method  Stage 1 test proposed to have a temperature- dependent conductivity limit  Stage 3 test includes ions resulting from innocuous CO 2  Stage 2 limit is 2.1  S/cm

18. Evolution of  645  Water Conductivity

20. Evolution of  643  Total Organic Carbon  Laboratory and on-line TOC instrumentation evaluated  Determine implementation plans  500 ppb limit determined  Determine instrumentation acceptance criteria  Sucrose and p-benzoquinone selected

21. Evolution of USP water monographs/chapters  1996-1998 USP 23 Supplement 5, May 1996 USP 23 Supplement 8, November 1998  1998-2000 USP eliminates pH test for PW and WFI EP changes tests for Purified Water and WFI Deletes most chemistry tests Requires conductivity test Requires TOC for WFI

22.  2001-2002 EP defines Highly Purified Water. 2002 – USP, EP, and JP agree to begin harmonization of some aspects of Pharmaceutical Waters  2002-2004 Jan 2002 – EP publishes proposal to revise conductivity limits for PW and WFI 2004 - EP changes Conductivity limits effective July 1, 2004 2004 - Approve Water for Hemodialysis Evolution of USP water monographs/chapters

23.  2005-2007 Pure Steam monograph official in 2005 Continued support for JP and ChP harmonization JP implements conductivity and TOC tests similar to  645  and  643 , retains chemical tests Harmonization of Sterile WFI in process USP - Chemistry tests for several sterile waters replaced with conductivity test  2008-2011 2008 - Packaged water loophole removed 2009 -  645  Water Conductivity and  643  Total Organic Carbon get first significant revisions in over 10 years TOC testing adopted for several Sterile waters Evolution of USP water monographs/chapters