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emen a mpur es n p a e
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Topics
Background
Elemental Impurities- USP Approach
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Elemental Impurities in Dietary Supplements
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Heavy Metals - Background
Introduced in USP VIII (1905)
,
Sulfide precipitation of metals
Methods in the EP and JP are similar to the USP
methodsProcedure suffers from lack of selectivity &
sensitivity
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Topics
Background
Elemental Impurities- Limits Update
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Activities---and
Stimuli Article published in PF 34(5) [September-October ]
2008
Res onses to the multi le comments ublished as stimuli article
in
PF 36(1) January-February 2010 Stimuli article with rationale
for the proposed limits published in PF
36 1 Januar - Februar 2010
Draft revisons published for public comment in PF 36(1),
[January-
February] 2010 < >
Methodology chapter
Dietary Supplement chapter
Revisions in PF 37(3)[May-June 2011]
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Topics
Background
Elemental Impurities- USP Approach
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Elemental Impurities in Dietary Supplements
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Elemental Impurities- USP Approach
USP approach to elemental impurity control is both
Control metals that are toxic
At limits that are toxicologically relevant
At all times during a drug products shelf life
With a risk-based approach as to what and when to test
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Elemental Impurities- Definition
nv ronmenta contam nants
Catalysts
Naturally occurring
Added intentionall
Introduced inadvertently
Through interactions with processing equipment
Through non-GMP routes
A risk-based control strategy may assure compliance.
However, compliance with the limits is required for alldrug
products at all times.
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Elemental Impurities- Limits
Applies to drug products
Dru substances
ExcipientsDoes not apply to dietary supplements
Does not apply to Veterinary products
Speciation not addressed in this chapter roce ures spec e n
genera c apter ementa
Impurities Procedures
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Elemental Impurities Limits
anuary- e ruary
Revised draft addressing comments received
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Approved by the General Chapters EC for adoption in
USP35 Su lement 2
Available on the USP website.
http://www.usp.org/usp-nf/hot-topics/elemental-impurities
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Elemental Impurities-Limits
Element
OralDaily
Dose
PDEa
(g/day)
Parenteral
Daily Dose
PDE (g/day)
Inhalational
Daily Dose
PDE (g/day)
LVP
Component
Limit
(g/g)
Cadmium 25 2.5 1.5 0.25
Lead 5 5 5 0.5
Inorganicarsenicb 1.5 1.5 1.5 0.15
Inorganic
ercury 15 1.5 1.5 0.15
Iridium 100 10 1.5 1.0
Osmium 100 10 1.5 1.0
Palladium 100 10 1.5 1.0
a num 100 10 1.5 1.0
Rhodium 100 10 1.5 1.0
Ruthenium 100 10 1.5 1.0
Chromium * * 25 *
1.0
Nickel 500 50 1.5 5.0
Vanadium 100 10 30 1.0
Copper 1000 100 70 25
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.b See Speciation section.* not a safety concern
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Options to Determine Content
Drug Product Analysis Option
amp e an measure osage orm
Scale results to daily dose
Sample and measure all components
Sum each metal and scale to dail dose
Individual Component Approach for Large Volume
Parenterals (LVP)
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Elemental Impurities Procedures
New chapter which focuses on only the procedures
anuary- e ruary
Revised draft addressing comments received
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Approved by the General Chapters EC for adoption in
USP35 Su lement 2
Available on the USP website.
http://www.usp.org/usp-nf/hot-topics/elemental-impurities
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Elemental Impurities - Procedures
Elemental Impurities - Procedures
e n ons
Compendial Procedures
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Procedure 2: ICP-MS
Validation Limit Procedures
Quantitative Procedures
Comment on Method Verification per
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Procedure Validation Requirements
Defines a procedure acceptance criteria
Validation criteria for alternative procedures
Verification criteria for compendial procedures are
identical
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Implementation
Chapters and will appear in SecondSupplement to USP35 (official
Dec 1, 2012).
Will be implemented through General Notices with ae aye mp emen
a on a e o ay ,
will be removed from the monographs in USP37.
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Elemental Contaminants in Dietary Supplements
Published first in PF 36(1) [Jan.Feb. 2010]
Published again with changes in PF38(3) May-Jun 2012
,
http://www.usp.org/usp-nf/notices/general-chapter-elemental-contaminants-
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Elemental Contaminants in Dietary Supplements
Applies to Dietary Supplements
Dietary Ingredients
xc p en s
Does not apply to drug products
Procedures in Elemental Im urities Procedures are
specified
Speciation is critical for Dietary Supplements
chapter
Only the big four Elemental Impurities considered
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Elemental Contaminants in Dietary Supplements
Element
PDEa
/da
Arsenic (inorganic)c 15
Cadmium 5
Lead 10
Mercury (total) 15
(as Hg)
a Permitted Daily Exposure (PDE) is derived from the Provisional
Tolerable Weekly Intake
(PTWI) that is recommended by the Food and Agriculture
Organization of the United
Nations
and World Health Organization (FAO/WHO) by subtracting the daily
exposure (g/day) to
each
elemental contaminant from air, food, and drinking water. A body
weight of 50 kg and a
safety
factor are used to calculate the PDE.
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Contact Information
emen a mpur es m s < >
Elemental Impurities Procedures
. .
http://www.usp.org/usp-nf/hot-topics/elemental-impurities
Elemental Contaminants in Dietary Supplements
Dr. Chris Okunji [email protected]
http://www.usp.org/usp-nf/notices/general-chapter-elemental-contaminants-dietary-supplements
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