1. The Standard of Quality TM USP Controls on Lead in Pharmaceuticals Heavy Metals – USP Perspective Darrell R. Abernethy, MD, Ph.D. Chief Science Officer

2. The Standard of Quality TM Controls on Lead: USP/NF (1) Two key tests –USP Heavy Metals detects metals colored by sulfide ion (Pb, Hg, Bi, As, Sb, Sn, Cd, Ag, Cu, Mo) thioacetamide test solution color of sample compared to standard –USP Lead depends on extraction of Pb from aqueous phase into organic phase by dithizone (diphenylthio- carbazone; PhN=N(CS)NHNHPh) color produced by sample compared to standard

3. The Standard of Quality TM Controls on Lead: USP/NF (2) Main USP/NF controls are colorimetric –Aren’t there more accurate or more specific tests for Pb? FDA and Albemarle both used more modern procedures to obtain their data (ICP-OES or -MS) Other alternatives exist USP has published a Stimuli Article considering replacing the methodology in with instrument-based technology such as AA or ICP Firms can use alternative analytical methods provided appropriate acceptance criteria are met –Is there a need for another test?

4. The Standard of Quality TM Controls on Lead: USP/NF (3) About 4300 monographs in USP/NF –1331 for drug substances 619 have a limit on Heavy Metals ( ) 22 have a limit for Pb ( ) –374 for excipients (NF monographs) 203 have a limit on Heavy Metals 60 have a limit for Pb –2452 for drug products 97 have a limit on Heavy Metals 8 has a limit for Pb

5. The Standard of Quality TM Controls on Lead: USP/NF (4) Limits on heavy metals or lead exist predominantly for the components of drug products, not the drug products themselves –47% of drug substances, 54% of excipients, and 4% of drug products have a limit on heavy metals –Only 2% of drug substances and 16% of excipients have a limit on lead –Some have limits on heavy metals AND lead

6. The Standard of Quality TM Heavy Metal Limits in USP/NF Monographs

7. The Standard of Quality TM Lead Limits in USP/NF Monographs

8. The Standard of Quality TM IOM Meeting on Metal Impurities  Currently in development, scheduled for August 26-28, 2008  Independent advisory group named by IOM  Nominees from USA, nominees from Europe via EP have been solicited  Advisory group has planned meeting  1.5 day meeting, 12 presentations  Link known clinical toxicology with acceptable analytical methodology

9. The Standard of Quality TM Introduction  Heavy metals have been monitored in APIs for many years.  Some are toxic  Some are not toxic but reflect quality issues  Sources  Deliberately added (e.g., catalysts)  Carried through the process (e.g., starting materials)  From the process (e.g., leaching from pipes and other equipment)

10. The Standard of Quality TM Background  Heavy Metals Chapter has been problematic for many years  Difficulties in achieving anticipated results (monitor solutions, standards, etc.)  Difficulties with reagents (moved from use of H 2 S to other sulfide sources)  With the increased use of instrumental techniques for metals analysis, some investigators began to compare instrumental methods vs.

11. The Standard of Quality TM Comparisons Between Instrumental Methods and “It was concluded from this experiment that approximately 50% of the metals may be lost during the ash process.... Note that mercury, which is one of the more toxic heavy metals, was not recovered from either set of samples.... Because of the loss of metals during ignition, the validity of test results obtained with the current USP, JP and EP general test procedures is questionable.” (“Stimuli to the Revision Process,” Pharmacopeial Forum, Vol. 21, No. 6, 1995, Katherine Blake).

12. The Standard of Quality TM Comparisons Between Instrumental Methods and “Although still widely accepted and used in the pharmaceutical industry, these methods based on the intensity of the color of sulfide precipitation are non-specific, insensitive, time-consuming, labor intensive, and more often than hoped, yield low recoveries or no recoveries at all.” (Wang, T. et al, J. Pharm. & Biomed. Anal., Vol. 23 (2000) 867-890)

13. The Standard of Quality TM Comparisons Between Instrumental Methods and “A survey method that permits simultaneous qualitative to quantitative (depending on the elements and the concentration levels) detection of up to 69 elements (including all those of pharmaceutical interest) in less than 15 min would be viewed by some as a giant leap compared with the antiquated USP and EP methods. The use of such a method, which employs a very sophisticated and expensive instrument, as an alternative to a seemingly economical wet chemical test that has been in use for decades would be viewed by others as technological overkill. We take a less extreme view, and believe that since the technology is here, and present in the laboratory to address, often very challenging analytical problems, its application to more mundane uses is simply good resource management. We have found that the extensive use of ICP-MS for this metal survey analysis does not degrade its capability for even more challenging tasks.” (Wang, T. et al, J. Pharm. & Biomed. Anal., Vol. 23 (2000) 867-890)

14. The Standard of Quality TM Comparisons Between Instrumental Methods and (Lewen, N. et al J. Pharm. & Biomed. Anal. 35 (2004) 739-752)

15. The Standard of Quality TM USP Began to Look More Closely at  Expert Committee on General Chapters appointed a Heavy Metals subcommittee  Subcommittee disbanded and Advisory Panel Initiated  Project Team Initiated

16. The Standard of Quality TM Topics Being Addressed by Advisory Panel  Do we want to eliminate “heavy metals” as a test and adopt an “inorganic impurities” method, instead?  What metals do we need to monitor?  What concentration limits do we need to meet?  Do we need a wet-bench approach?  Can we use an instrumental approach?  Do we provide results for individual elements?  How do we reconcile results from any new procedure with results obtained previously using ?  How does dosage form impact monitoring?  How does daily dosage impact monitoring?

17. The Standard of Quality TM What Metals to Monitor—Considerations  Toxicity of potential target metals  Toxicity of individual metals  Toxicity of combined groups of metals  Potential target organs  What if individual metals are not terribly toxic, but more than one has an impact on the same target organ?  Cultural/political concerns  Hg, Pd

18. The Standard of Quality TM What Concentration Limits are Required?  Depends on patient population  Depends on daily dosage  Depends on type of dosage form  Depends on whether it’s for an acute or a chronic condition  Depends on metal

19. The Standard of Quality TM Background  The current chapter relies on tests which are limited in the metals detected.  The test limit reflects all metals detected and is not toxicologically based.  The tests can be  Unreliable  Difficult to perform correctly  Difficult to perform safely

20. The Standard of Quality TM Proposed Way Forward  EMEA draft guidance - specific to residues of metal catalysts  USP is proposing a broader-reaching chapter on inorganic impurities that reflects  Modern instrumentation (e.g., inductively- coupled plasma or atomic absorption spectroscopy)  Realistic toxicological limits for individual metals  The requirement to control the levels of metals in foods and dietary supplements.

21. The Standard of Quality TM Current Status  USP has commissioned an Advisory Panel of toxicologists to consider appropriate levels.  The initial values are shown on the next few slides.

22. The Standard of Quality TM Proposed Limits – Initial Discussions ElementDraft USP Oral Limit, ug/day Aluminum5000 Antimony2 Arsenic1.5 Beryllium10 Boron1000 Cadmium2.5 Chromium15 Cobalt100 Copper50 Indium10 Iridium1300

23. The Standard of Quality TM Proposed Limits – Initial Discussions ElementDraft USP Oral Limit, ug/day Iron1500 Lead1 Lithium60 Manganese700 Mercury1.5 Molybdenum25 Nickel100 Osmium10 Palladium10 Platinum10 Rhodium10

24. The Standard of Quality TM Proposed Limits – Initial Discussions ElementDraft USP Oral Limit, ug/day Selenium25 Strontium3000 Thallium0.4 Tin3000 Tungsten37.5 Zinc1500

25. The Standard of Quality TM Comments on Limits  Limits are still tentative and under active discussion.  Oral PDE for Dosage Forms are 10X higher.  USP Parenteral Limits are proposed 10X lower.  PDE limit for lead from FDA bottled water limit of 5 ug/L assuming 2L/day.

26. The Standard of Quality TM EU Approach  EMEA classifies impurities by risk level  Class 1 Metals – Significant safety concern (e.g., Pt, Pd)  Class 2 Metals – Metals with low safety concern (e.g., Cu, Mn)  Class 3 Metals – Metals with minimal safety concern (e.g., Fe, Zn)

27. The Standard of Quality TM EMEA Approach – Other Issues to Consider  Route of Administration  Oral  Parenteral  Inhalation  Duration of exposure  Age at Exposure  Genotoxicity or Carcinogenicity Potential  Extrapolation of Toxicological Data “Safety Factor”

28. The Standard of Quality TM Conclusions on Levels  A General Chapter can only provide levels based on the best available toxicology data and a set of use instructions.  Risk can be dependent on dose form, route of administration, age, gender, and length of exposure.  Covering the range from Active Pharmaceutical Ingredients to foods and dietary supplements will necessitate including many elements in the chapter.

29. The Standard of Quality TM Advisory Panel Discussed Potential Detection Techniques  Atomic absorption (flame, graphite furnace, cold vapor)  ICP-OES  ICP-MS  XRF  LIBS  Ion Chromatography  Flame Emission Spectroscopy

30. The Standard of Quality TM Draft Sample Preparation Flow Chart Is the compound soluble in aqueous solutions? Is the compound soluble in other (including organic) solvent? Perform Closed-Vessel Microwave Digestion Prepare sample, monitor solution and USP reference solution according to sample prep. procedure Perform analysis via ICP-OES or ICP-MS Did the monitor and USP reference solution recover to within  20%? Perform analysis using element- specific method Yes No Yes Report Result No Yes

31. The Standard of Quality TM Methodology  Methodology will depend on the number of elements that need to be monitored on a routine basis, and the levels to be measured.  For the routine monitoring of a few specific elements in an API made without catalysts, atomic absorption may be acceptable.  For most elements, it is anticipated that ICP- OES will be the method of choice.  For some, particularly in difficult matrices and very low levels, ICP-MS may be necessary.

32. The Standard of Quality TM Proposed Next Steps  Stimuli article prepared by advisory panel.  Conference in June/July to gain consensus on  Levels  Sample preparation techniques  Measuring tools  Work with other pharmacopeias in an effort to reach consensus on levels and scope of chapter.  Begin formal chapter revision process.

33. The Standard of Quality TM Proposed Next Steps  The Heavy Metals Chapter impact approximately 1000 monographs.  USP realizes that eliminating or replacing the test for existing compounds and compounds late in development is unrealistic.  It is believed that many manufacturers are already testing beyond the use of and going forward the introduction of new methodology will not be overly burdensome.  USP will work closely with its stakeholders to determine the best way forward from both a scientific and timing perspective.

34. The Standard of Quality TM