HEAVY METAL IN THE USP

About 4300 monographs in USP/NF

1331 for drug substances
619 have a limit on Heavy Metals (<231>)
374 for excipients (NF monographs)
203 have a limit on Heavy Metals
2452 for drug products
97 have a limit on Heavy Metals
Heavy Metal Limits
in USP/NF Monographs
Lead Limits
in USP/NF Monographs
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)
Background

Heavy Metals Chapter <231> has been

problematic for many years
Difficulties 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>
Comparisons Between Instrumental Methods and <231> (Lewen, N. et al J. Pharm. &
Biomed. Anal. 35 (2004) 739-752)

120
100
A v erag e % R eco v eries

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
What Metals to MonitorConsiderations

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
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
Proposed Limits Initial Discussions

Element Draft USP Oral Limit, ug/day

Aluminum 5000
Antimony 2
Arsenic 1.5
Beryllium 10
Boron 1000
Cadmium 2.5
Chromium 15
Cobalt 100
Copper 50
Indium 10
Iridium 1300
Proposed Limits Initial Discussions

Element Draft USP Oral Limit, ug/day

Iron 1500
Lead 1
Lithium 60
Manganese 700
Mercury 1.5
Molybdenum 25
Nickel 100
Osmium 10
Palladium 10
Platinum 10
Rhodium 10
Proposed Limits Initial Discussions

Element Draft USP Oral Limit, ug/day

Selenium 25
Strontium 3000
Thallium 0.4
Tin 3000
Tungsten 37.5
Zinc 1500
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.
EU Approach

Europe, the Middle East and Africa (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)
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
Potential Detection Techniques

Atomic absorption (flame, graphite furnace,

cold vapor)
ICP-OES
ICP-MS
XRF
LIBS
Ion Chromatography
Flame Emission Spectroscopy
Draft Sample Preparation Flow Chart
Isthecompound Isthecompoundsoluble PerformClosedVessel
solubleinaqueous inother(including MicrowaveDigestion
solutions? organic)solvent?
No
No
Yes

Preparesample,monitorsolutionandUSPreferencesolutionaccordingtosampleprep.
procedure

PerformanalysisviaICPOESorICPMS

Yes
DidthemonitorandUSP Performanalysisusingelement
referencesolutionrecover specificmethod
towithin20%?

No

Yes

ReportResult
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.