Transcript Heavy Metals - Background

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January 17, 2013
Elemental Impurities: Recent Changes
<231> Heavy Metals - Background
 Introduced
in USP VIII (1905)
 Consists of three procedures, all involving
– Sulfide precipitation of metals
– Visual comparison to lead standards
 Methods in the EP and JP are similar to the USP
methods
<231> Heavy Metals - Issues
 Difficulties
in reproducibility
– Monitor solutions/standards change with time, recovery issues
 Difficulties
with reagents – safety issues
– All procedures generate H2S (USP via thioacetamide reaction
with base). H2S more toxic than cyanide
– Thioacetamide not allowed in California and several European
countries (EP uses Na2S)
 Nondiscriminatory
screening test
– Not element specific
– Sensitivity varies by element
– Only a few elements respond at required sensitivities
 Visual
comparison test
– Limits based on visual acuity, not toxicology
Heavy Metals Background
Average % Recoveries
120
100
80
USP Results
60
ICP-MS Results
40
20
0
Pb As Se Sn Sb Cd Pd Pt Ag Bi Mo Ru
In
Hg
Elements
Comparisons Between Instrumental Methods and <231>
(Lewen, N. et al J. Pharm. & Biomed. Anal. 35 (2004) 739-752)
Toxicology
 USP
is proposing an approach to elemental impurity
control that is both health based and risk based
 Control
metals that are toxic
 At
limits that are toxicologically relevant
 At
all times during a drug product’s shelf life
 With
a risk-based approach as to what and when to test
<232>: Elements
in the environment – critical contaminant are Lead,
Arsenic, Mercury and Cadmium (the “Big Four”)
 Elements
 EMEA Guideline
on the Specification Limits for Residues of
Metal Catalysts (CPMP/SWP/4446/00) lists 14 catalysts used
in pharmaceutical synthesis
– Exclude zinc and iron, which are not toxic at levels relevant in
pharmaceuticals
 Need
to control in drug products if presence is possible
– Deliberately added (catalyst)
– Possible supply-chain contaminant or adulterant
– Process issue (equipment)
<232> : Basics
 Applies
to:
– Drug products, but levels in excipients and API’s must be known
and reported
– Veterinary products, levels must be adjusted based on species,
dosage, and toxicology
 Does
not apply to dietary supplements
 Speciation
is not addressed in this Chapter
 Procedures
<233>
are specified in Elemental Impurities – Procedures
Elemental Impurities <232>
Element
Oral Daily
Dose PDE
(µg/day)
Parenteral
Inhalational Daily
Dose PDE (µg/day)
LVP Component
Limit (µg/g)
Daily Dose
PDE (µg/day)
Inorganic
Arsenic
1.5
1.5
1.5
0.15
Cadmium
25
2.5
1.5
0.25
Lead
5
5
5
0.5
Inorganic
15
1.5
1.5
0.15
Mercury
9
Elemental Impurities <232>
Element
Oral Daily
Dose PDE
(µg/day)
Parenteral
Inhalational Daily
Dose PDE (µg/day)
LVP Component
Limit (µg/g)
Daily Dose
PDE (µg/day)
Chromium
*
*
25
*
Copper
1000
100
70
25
Molybdenum
100
10
10
1.0
Nickel
500
50
1.5
5.0
Palladium
100
10
1.5
1.0
Platinum
100
10
1.5
1.0
Vanadium
100
10
30
1.0
Osmium
100
10
1.5
1.0
Rhodium
100
10
1.5
1.0
Ruthenium
100
10
1.5
1.0
Iridium
100
10
1.5
1.0
10
Options to Determine Content
 Drug Product Analysis Option
– Sample and measure dosage form
– Scale results to daily dose
 Summation Option
– Sample and measure all components
– Validate process will add no additional impurities
– Sum each metal and scale to daily dose
 Individual
Component Approach for LVP
<2232> : Basics
 Applies
to Dietary Supplements
–Dietary Ingredients
–Excipients
 Does not apply to drug products
 Procedures in Elemental Impurities – Procedures <233>
are specified
 Speciation
is critical for Dietary Supplements
–Arsenic and Mercury procedures addressed in this
Chapter
 Only “the big four” Elemental Impurities considered
Elemental Impurities - Procedures <233>
 Elemental Impurities - Procedures <233>
 Definitions
 Compendial Procedures
• Procedure 1: ICP-OES
• Procedure 2: ICP-MS
 Validation
• Limit Procedures
• Quantitative Procedures
 Calculations and Reporting
 Comment on Method Verification per <1226>
Key Issues Page on www.usp.org
Implementation and Postponement
• Chapters <232> and <233> appear in Second
Supplement to USP35 (official Dec 1, 2012), but…
– The official dates of these chapters have been postponed via
Revision Bulletin
• The postponement will allow the Executive Committee
of the Council of Experts adequate time to rule on three
appeals related to the chapters.
• A planned General Notices proposal will appear in PF
39(1) in January 2013, which if approved, will make the
two chapters applicable to all monographed articles as
of May 1, 2014.
• All references to USP general chapter Heavy Metals
<231> will be removed from the monographs in USP37,
but requirements still apply via General Notices.
Errata from October 1, 2012 for <232>
• Limits in Table 1 (Elemental Impurities for Drug
Products) for Molybdenum: Inhalation Daily Dose = 10
µg/day (not 250)
• Limits in Table 2 (Default Concentration Limits for Drug
Substances and Excipients):
– Ruthenium and Vanadium limits for oral, parenteral and
inhalational products were incorrectly increased by factor of 10
– Molybdenum inhalation limit incorrectly increased by a factor of
25
• Last line under Analytical Testing: “when testing is
done…minimally include As, Cd, Pb (not Pd) and Hg in
the Target Element evaluation.”
– Same errata for <233> in the Target Elements Definition
Contact Information
General Chapters <231>, <232> and <233>
Kahkashan Zaidi, Ph.D., Senior Scientist [email protected]