the standard of quality tm usp controls on lead in pharmaceuticals heavy metals – usp perspective...
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The Standard of QualityTM
USP Controls on Lead in Pharmaceuticals
Heavy Metals – USP Perspective
Darrell R. Abernethy, MD, Ph.D.
Chief Science Officer
The Standard of QualityTM
Controls on Lead: USP/NF (1)
• Two key tests– USP <231> 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 <251> 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
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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 <231> 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?
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Controls on Lead: USP/NF (3)
• About 4300 monographs in USP/NF– 1331 for drug substances
• 619 have a limit on Heavy Metals (<231>)• 22 have a limit for Pb (<251>)
– 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
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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
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Heavy Metal Limitsin USP/NF Monographs
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Lead Limitsin USP/NF Monographs
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Limit on Lead <251> (ppm)
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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
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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)
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Background
Heavy Metals Chapter <231> has been problematic for many yearsDifficulties in achieving anticipated results
(monitor solutions, standards, etc.)Difficulties with reagents (moved from use
of H2S to other sulfide sources) With the increased use of instrumental
techniques for metals analysis, some investigators began to compare instrumental methods vs. <231>
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Comparisons Between Instrumental Methods and <231>
“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).
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Comparisons Between Instrumental Methods and <231>
“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)
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Comparisons Between Instrumental Methods and <231>
“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)
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Comparisons Between Instrumental Methods and <231> (Lewen, N. et al J. Pharm. &
Biomed. Anal. 35 (2004) 739-752)
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Pb As Se Sn Sb Cd Pd Pt Ag Bi Mo Ru In Hg
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USP Results
ICP-MS Results
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USP Began to Look More Closely at <231>
Expert Committee on General Chapters appointed a Heavy Metals subcommittee
Subcommittee disbanded and Advisory Panel Initiated
Project Team Initiated
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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 <231>?
How does dosage form impact monitoring? How does daily dosage impact monitoring?
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What Metals to Monitor—Considerations
Toxicity of potential target metalsToxicity of individual metalsToxicity of combined groups of metals
Potential target organsWhat if individual metals are not terribly
toxic, but more than one has an impact on the same target organ?
Cultural/political concernsHg, Pd
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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
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Background
The current chapter <231> 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
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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.
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Current Status
USP has commissioned an Advisory Panel of toxicologists to consider appropriate levels.
The initial values are shown on the next few slides.
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Proposed Limits – Initial Discussions
Element Draft USP Oral Limit, ug/day
Aluminum 5000Antimony 2Arsenic 1.5Beryllium 10Boron 1000Cadmium 2.5Chromium 15Cobalt 100Copper 50Indium 10Iridium 1300
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Proposed Limits – Initial Discussions
Element Draft USP Oral Limit, ug/day
Iron 1500Lead 1Lithium 60Manganese 700Mercury 1.5Molybdenum 25Nickel 100Osmium 10Palladium 10Platinum 10Rhodium 10
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Proposed Limits – Initial Discussions
Element Draft USP Oral Limit, ug/day
Selenium 25Strontium 3000Thallium 0.4Tin 3000Tungsten 37.5Zinc 1500
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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.
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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)
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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”
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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.
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Advisory Panel Discussed Potential Detection Techniques
Atomic absorption (flame, graphite furnace, cold vapor)
ICP-OES ICP-MS XRF LIBS Ion Chromatography Flame Emission Spectroscopy
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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
NoNo
Yes
Report Result
No
Yes
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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.
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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.
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Proposed Next Steps
The Heavy Metals Chapter <231> 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 <231> 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.
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