lead control in products - bp specs
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The Standard of QualityTM
USP Controls on Lead inPharmaceuticals
Heavy MetalsUSP Perspective
Darrell R. Abernethy, MD, Ph.D.
Chief Science Officer
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The Standard of QualityTM
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 phaseinto 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 Arent 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) Otheralternatives exist
USP has published a Stimuli Article consideringreplacing 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 needfor another test?
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The Standard of QualityTM
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
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The Standard of QualityTM
Controls on Lead: USP/NF (4)
Limits on heavy metals or lead existpredominantly 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
0
50
100
150
200
250
300
350
0.2 0.3 1 2 5 10 13 15 20 25 30 40 50 60 83 100
Limit on Heavy Metals (ppm)
Number
ofUSP/NFMono
graphswith
SpecificLimit
Drug Substance
Drug Product
Excipient
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Lead Limitsin USP/NF Monographs
0
5
10
15
20
25
2 3 5 10 15 20 25 30 40 50
Limit on Lead (ppm)
NumberofUSP/NFMonog
raphswith
SpecificLimit
Drug Substance
Excipient
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IOM Meeting on Metal Impurities
Currently in development, scheduled forAugust 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 withacceptable analytical methodology
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The Standard of QualityTM
Introduction
Heavy metals have been monitored in APIsfor 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 pipesand other equipment)
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Background
Heavy Metals Chapter has beenproblematic for many years
Difficulties in achieving anticipated results(monitor solutions, standards, etc.)
Difficulties with reagents (moved fromuse of H2S to other sulfide sources)
With the increased use of instrumentaltechniques for metals analysis, someinvestigators began to compare instrumental
methods vs.
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Comparisons Between Instrumental Methods and
It was concluded from this experiment thatapproximately 50% of the metals may belost during the ash process. . . . Notethat mercury, which is one of the moretoxic heavy metals, was not recovered
from either set of samples.. . . Because of the loss of metals duringignition, the validity of test resultsobtained with the current USP, JP and EPgeneral 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
Although still widely accepted and used in thepharmaceutical industry, these methodsbased on the intensity of the color of sulfideprecipitation are non-specific, insensitive,
time-consuming, labor intensive, and moreoften than hoped, yield low recoveries or norecoveries at all.
(Wang, T. et al, J. Pharm. & Biomed. Anal., Vol. 23 (2000) 867-890)
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Comparisons Between Instrumental Methods and
A survey method that permits simultaneous
qualitative to quantitative (depending on the elementsand the concentration levels) detection of up to 69elements (including all those of pharmaceutical interest)in less than 15 min would be viewed by some as a giantleap compared with the antiquated USP and EP methods.The use of such a method, which employs a verysophisticated and expensive instrument, as analternative to a seemingly economical wet chemical testthat has been in use for decades would be viewed byothers as technological overkill.
We take a less extreme view, and believe that sincethe technology is here, and present in the laboratory toaddress, often very challenging analytical problems, its
application to more mundane uses is simply goodresource management. We have found that theextensive use of ICP-MS for this metal survey analysisdoes not degrade its capability for even morechallenging tasks.
(Wang, T. et al, J. Pharm. & Biomed. Anal., Vol. 23 (2000) 867-890)
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Comparisons Between Instrumental Methods and (Lewen, N. et al J. Pharm. &
Biomed. Anal. 35 (2004) 739-752)
0
20
40
6080
100
120
Pb As Se Sn Sb Cd Pd Pt Ag Bi Mo Ru In Hg
Elements
Average%Reco
veries
USP Results
ICP-MS Results
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The Standard of QualityTM
USP Began to Look More Closely at
Expert Committee on General Chaptersappointed a Heavy Metals subcommittee
Subcommittee disbanded and Advisory PanelInitiated
Project Team Initiated
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Topics Being Addressed by Advisory Panel
Do we want to eliminate heavy metals as atest and adopt an inorganic impuritiesmethod, 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 previouslyusing ?
How does dosage form impact monitoring?
How does daily dosage impact monitoring?
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What Metals to MonitorConsiderations
Toxicity of potential target metalsToxicity of individual metals
Toxicity of combined groups of metals
Potential target organs
What if individual metals are not terriblytoxic, but more than one has an impacton the same target organ?
Cultural/political concerns
Hg, 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 its for an acute or achronic condition
Depends on metal
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Background
The current chapter relies on testswhich 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 residuesof metal catalysts
USP is proposing a broader-reaching chapter
on inorganic impurities that reflectsModern instrumentation (e.g., inductively-
coupled plasma or atomic absorptionspectroscopy)
Realistic toxicological limits for individualmetals
The requirement to control the levels ofmetals in foods and dietary supplements.
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Current Status
USP has commissioned an Advisory Panel oftoxicologists 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/dayAluminum 5000
Antimony 2
Arsenic 1.5
Beryllium 10Boron 1000
Cadmium 2.5
Chromium 15
Cobalt 100
Copper 50
Indium 10
Iridium 1300
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Proposed Limits Initial Discussions
Element Draft USP Oral Limit, ug/dayIron 1500
Lead 1
Lithium 60
Manganese 700Mercury 1.5
Molybdenum 25
Nickel 100
Osmium 10
Palladium 10
Platinum 10
Rhodium 10
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Proposed Limits Initial Discussions
Element Draft USP Oral Limit, ug/daySelenium 25
Strontium 3000
Thallium 0.4
Tin 3000
Tungsten 37.5
Zinc 1500
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Comments on Limits
Limits are still tentative and under activediscussion.
Oral PDE for Dosage Forms are 10X higher.
USP Parenteral Limits are proposed 10Xlower.
PDE limit for lead from FDA bottled waterlimit 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 SafetyFactor
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Conclusions on Levels
A General Chapter can only provide levelsbased on the best available toxicology dataand a set of use instructions.
Risk can be dependent on dose form, route
of administration, age, gender, and length ofexposure.
Covering the range from ActivePharmaceutical Ingredients to foods and
dietary supplements will necessitateincluding 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 aqueoussolutions?
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
No
Yes
Report Result
NoYes
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The Standard of QualityTM
Methodology
Methodology will depend on the number ofelements that need to be monitored on aroutine basis, and the levels to bemeasured.
For the routine monitoring of a few specificelements 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 benecessary.
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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 toreach consensus on levels and scope ofchapter.
Begin formal chapter revision process.
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Proposed Next Steps
The Heavy Metals Chapter impactapproximately 1000 monographs.
USP realizes that eliminating or replacing thetest 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 ascientific and timing perspective.
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