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USP 41 Chemical Tests / 233 6151

Table 3. Permitted Concentrations of Elemental Impurities for Individual Component Option

Parenteral Inhalation
Oral Concentration Concentration Concentration
Element Class (g/g) (g/g) (g/g)
Cadmium 1 0.5 0.2 0.2
Lead 1 0.5 0.5 0.5
Arsenic 1 1.5 1.5 0.2
Mercury 1 3 0.3 0.1
Cobalt 2A 5 0.5 0.3
Vanadium 2A 10 1 0.1
Nickel 2A 20 2 0.5
Thallium 2B 0.8 0.8 0.8
Gold 2B 10 10 0.1
Palladium 2B 10 1 0.1
Iridium 2B 10 1 0.1
Osmium 2B 10 1 0.1
Rhodium 2B 10 1 0.1
Ruthenium 2B 10 1 0.1
Selenium 2B 15 8 13
Silver 2B 15 1 0.7
Platinum 2B 10 1 0.1
Lithium 3 55 25 2.5
Antimony 3 120 9 2
Barium 3 140 70 30
Molybdenum 3 300 150 1
Copper 3 300 30 3
Tin 3 600 60 6
Chromium 3 1100 110 0.3

ANALYTICAL TESTING

If, by process monitoring and supply-chain control, manufacturers can demonstrate compliance, then further testing may
not be needed. When testing is done to demonstrate compliance, proceed as directed in Elemental Impurities—Procedures
233.

233 ELEMENTAL IMPURITIES—PROCEDURES

INTRODUCTION

General Chapters
This chapter describes two analytical procedures (Procedures 1 and 2) for the evaluation of the levels of the elemental impuri-
ties. The chapter also describes criteria for acceptable alternative procedures. By means of validation studies, analysts wil l
confirm that the analytical procedures described herein are suitable for use on specified material.

Change to read:

Use of Alternative Procedures

The chapter also describes criteria for acceptable alternative procedures. Alternative procedures that meet the validation re -
quirements herein may be used in accordance with General Notices, 6.30 Alternative and Harmonized Methods and Proce-
dures. (CN 1-May-2018) Information on the Requirements for Alternate Procedure Validation is provided later in this chapter.
Speciation
The determination of the oxidation state, organic complex, or combination is termed speciation. Analytical procedures for spe-
ciation are not included in this chapter, but examples may be found elsewhere in USP–NF and in the literature.
PROCEDURES
• COMPENDIAL PROCEDURES 1 AND 2
System standardization and suitability evaluation using applicable reference materials should be performed on the day of
analysis.

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Procedure and detection technique: Procedure 1 can be used for elemental impurities generally amenable to detection by
inductively coupled plasma–atomic (optical) emission spectroscopy (ICP–AES or ICP–OES). Procedure 2 can be used for ele-
mental impurities generally amenable to detection by ICP–MS. Before initial use, the analyst should verify that the proce-
dure is appropriate for the instrument and sample used (procedural verification) by meeting the alternative procedure vali -
dation requirements below.
Sample preparation: Forms of sample preparation include Neat, Direct aqueous solution, Direct organic solution, and Indi-
rect solution. The selection of the appropriate sample preparation depends on the material under test and is the responsibil -
ity of the analyst. When a sample preparation is not indicated in the monograph, an analyst may use any of the f ollowing
appropriately validated preparation procedures. In cases where spiking of a material under test is necessary to provide an
acceptable signal intensity, the blank should be spiked with the same Target elements, and where possible, using the same
spiking solution. Standard solutions may contain multiple Target elements. [NOTE—All liquid samples should be weighed.]
Neat: Used for liquids or alternative procedures that allow the examination of unsolvated samples.
Direct aqueous solution: Used when the sample is soluble in an aqueous solvent.
Direct organic solution: Used where the sample is soluble in an organic solvent.
Indirect solution: Used when a material is not directly soluble in aqueous or organic solvents. Total metal extraction is
the preferred sample preparation approach to obtain an Indirect solution. Digest the sample using the Closed vessel diges-
tion procedure provided below or one similar to it. The sample preparation scheme should yield sufficient sample to allow
quantification of each element at the limit specified in the corresponding monograph or chapter.
Closed vessel digestion: This sample preparation procedure is designed for samples that must be digested in a Concen-
trated acid using a closed vessel digestion apparatus. Closed vessel digestion minimizes the loss of volatile impurities. The
choice of a Concentrated acid depends on the sample matrix. The use of any of the Concentrated acids may be appropri-
ate, but each introduces inherent safety risks. Therefore, appropriate safety precautions should be used at all times.
[NOTE—Weights and volumes provided may be adjusted to meet the requirements of the digestion apparatus used.]
An example procedure that has been shown to have broad applicability is the following. Dehydrate and predigest 0.5 g of
primary sample in 5 mL of freshly prepared Concentrated acid. Allow to sit loosely covered for 30 min in a fume hood.
Add an additional 10 mL of Concentrated acid, and digest, using a closed vessel technique, until digestion or extraction is
complete. Repeat, if necessary, by adding an additional 5 mL of Concentrated acid. [NOTE—Where closed vessel digestion
is necessary, follow the manufacturer’s recommended procedures to ensure safe use.]
Alternatively, leachate extraction may be appropriate with justification following scientifically validated metal disposition
studies, which may include animal studies, speciation, or other means of studying disposition of the specific metal in the
drug product.
Reagents: All reagents used for the preparation of sample and standard solutions should be free of elemental impurities,
in accordance with Plasma Spectrochemistry 730.
• PROCEDURE 1: ICP–OES
Standardization solution 1: 1.5J of the Target element(s) in a Matched matrix
Standardization solution 2: 0.5J of the Target element(s) in a Matched matrix
Sample stock solution: Proceed as directed in Sample preparation above. Allow the sample to cool, if necessary. For mer-
cury determination, add an appropriate stabilizer.
Sample solution: Dilute the Sample stock solution with an appropriate solvent to obtain a final concentration of the Target
elements at NMT 1.5J.
Blank: Matched matrix
Elemental spectrometric system
(See Plasma Spectrochemistry 730.)
General Chapters

Mode: ICP
Detector: Optical detection system
Rinse: Diluent used
Standardization: Standardization solution 1, Standardization solution 2, and Blank
System suitability
Sample: Standardization solution 1
Suitability requirements
Drift: Compare results obtained from Standardization solution 1 before and after the analysis of the Sample solution.
Suitability criteria: NMT 20% for each Target element. [NOTE—If samples are high in mineral content, rinse system
well before introducing the Sample in order to minimize carryover.]
Analysis: Analyze according to the manufacturer's suggestions for program and wavelength. Calculate and report results
on the basis of the original sample size. [NOTE—Appropriate measures must be taken to correct for matrix-induced inter-
ferences (e.g., wavelength overlaps).]
• PROCEDURE 2: ICP–MS
Standardization solution 1: 1.5J of the Target element(s) in a Matched matrix
Standardization solution 2: 0.5J of the Target element(s) in a Matched matrix
Sample stock solution: Proceed as directed for Sample preparation above. Allow the sample to cool, if necessary. For
mercury determination, add an appropriate stabilizer.

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USP 41 Chemical Tests / 233 6153

Sample solution: Dilute the Sample stock solution with an appropriate solvent to obtain a final concentration of the Target
elements at NMT 1.5J.
Blank: Matched matrix
Elemental spectrometric system
(See Plasma Spectrochemistry 730.)
Mode: ICP. [NOTE—An instrument with a cooled spray chamber is recommended. (A collision cell or reaction cell may
also be beneficial.)]
Detector: Mass spectrometer
Rinse: Diluent used
Standardization: Standardization solution 1, Standardization solution 2, and Blank
System suitability
Sample: Standardization solution 1
Suitability requirements
Drift: Compare results obtained from Standardization solution 1 before and after the analysis of the Sample solution.
Suitability criteria: Drift NMT 20% for each Target element. [NOTE—If samples are high in mineral content, rinse sys-
tem well before introducing the Sample in order to minimize carryover.]
Analysis: Analyze according to the manufacturer's suggestions for program and m/z. Calculate and report results based
on the original sample size. [N OTE—Appropriate measures must be taken to correct for matrix-induced interferences (e.g.,
argon chloride interference with arsenic determinations).]

Change to read:

REQUIREMENTS FOR ALTERNATE PROCEDURE VALIDATION

If the specified compendial procedures do not meet the needs of a specific application, an alternative procedure may be devel -
oped (see General Notices, 6.30 Alternative and Harmonized Methods and Procedures). (CN 1-May-2018) Alternative procedures
must be validated and shown to be acceptable, in accordance with the validation requirements for alternative procedures as
described below. The level of validation necessary to ensure that an alternative procedure is acceptable depends on whether
a limit test or a quantitative determination is specified in the monograph. The requirements for the validation of an elemen -
tal impurities procedure for each type of determination are described below. Any alternative procedure that has been valida-
ted and meets the acceptance criteria that follow is considered to be suitable for use.
LIMIT PROCEDURES
The following section defines the validation parameters for the acceptability of alternative limit procedures. Meeting these re-
quirements must be demonstrated experimentally using an appropriate system suitability procedure and reference material.
The suitability of the method must be determined by conducting studies with the material or mixture under test supplemen -
ted with known concentrations of each Target element of interest at the appropriate acceptance limit concentration. The ma-
terial or mixture under test must be spiked before any sample preparation steps are performed.
• DETECTABILITY
Standard solution: A preparation of reference materials for the Target element(s) at the Target concentration
Spiked sample solution 1: Prepare a solution of sample under test, spiked with appropriate reference materials for the
Target elements at the Target concentration, solubilized or digested as described in Sample preparation.
Spiked sample solution 2: Prepare a solution of the sample under test, spiked with appropriate reference materials at
80% of the Target concentration for the Target elements, solubilized or digested as described in Sample preparation.
Unspiked sample solution: A sample of material under test, solubilized or digested in the same manner as the Sample
solutions

General Chapters
Acceptance criteria
Non-instrumental procedures: Spiked sample solution 1 provides a signal or intensity equivalent to or greater than that
of the Standard solution. Spiked sample solution 2 must provide a signal or intensity less than that of Spiked sample solu-
tion 1. [NOTE—The signal from each Spiked sample solution is NLT the Unspiked sample solution determination.]
Instrumental procedures: The average value of the three replicate measurements of Spiked sample solution 1 is within
±15% of the average value obtained for the replicate measurements of the Standard solution. The average value of the
replicate measurements of Spiked sample solution 2 must provide a signal intensity or value less than that of the Standard
solution. [NOTE—Correct the values obtained for each of the spiked solutions using the Unspiked sample solution.]
• PRECISION FOR INSTRUMENTAL METHODS (REPEATABILITY)
[NOTE—Non-instrumental precision is demonstrated by meeting the Detectability requirement above.]
Sample solutions: Six independent samples of the material under test, spiked with appropriate reference materials for
the Target elements at the Target concentration
Acceptance criteria
Relative standard deviation: NMT 20% for each Target element

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• SPECIFICITY
The procedure must be able to unequivocally assess (see Validation of Compendial Procedures 1225) each Target element in
the presence of components that may be expected to be present, including other Target elements, and matrix compo-
nents.
QUANTITATIVE PROCEDURES
The following section defines the validation parameters for the acceptability of alterna tive quantitative procedures. Meeting
these requirements must be demonstrated experimentally, using an appropriate system suitability procedure and reference
materials. Meeting these requirements demonstrates that the procedure is equivalent to the compend ial procedure for the
purpose of quantifying the Target elements.
• ACCURACY
Standard solutions: Prepare solutions containing the Target elements at concentrations ranging from 50% to 150% of J,
using appropriate reference materials.
Test samples: Prepare samples of the material under test spiked with appropriate reference materials before any sample
preparation steps (digestion or solubilization) at concentrations ranging from 50% to 150% of J for each Target element.
Acceptance criteria
Spike recovery: 70%–150% for the mean of three replicate preparations at each concentration
• PRECISION
Repeatability
Test samples: Six independent samples of material under test (taken from the same lot) spiked with appropriate refer -
ence materials for the Target element(s) at the indicated level
Acceptance criteria
Relative standard deviation: NMT 20% (N = 6) for each Target element
Intermediate precision (ruggedness)
Perform the Repeatability analysis again either on a different day, with a different instrumentation, with a different analyst,
or a combination thereof. Combine the results of this analysis with the Repeatability analysis so the total number of anal-
yses is 12.
Acceptance criteria
Relative standard deviation: NMT 25% (N = 12) for each Target element
• SPECIFICITY
The procedure must be able to unequivocally assess (see 1225) each Target element in the presence of components that
may be expected to be present, including other Target elements, and matrix components.
• LIMIT OF QUANTITATION, RANGE, AND LINEARITY
Demonstrated by meeting the Accuracy requirement.

GLOSSARY
Concentrated acid: Concentrated ultra-pure nitric, sulfuric, hydrochloric, or hydrofluoric acids or Aqua regia
Aqua regia: Aqua regia is a mixture of concentrated hydrochloric and nitric acids, typically at ratios of 3:1 or 4:1, respective-
ly.
Matched matrix: Solutions having the same solvent composition as the Sample solution. In the case of an aqueous solution,
Matched matrix would indicate that the same acids, acid concentrations, and mercury stabilizer are used in both prepara -
tions.
Target elements: Elements with the potential of being present in the material under test. Include arsenic (As), cadmium
(Cd), lead (Pb), and mercury (Hg) in the target element evaluation when testing is done to demonstrate compliance. Target
General Chapters

elements should also include any elements that may be added through material processing or storage.
Target limit or Target concentration: The acceptance value for the elemental impurity being evaluated. Exceeding the Tar-
get limit indicates that a material under test exceeds the acceptable value. The determination of compliance is addressed in
other chapters. [NOTE—When applying this chapter to Elemental Impurities—Limits 232 and Elemental Contaminants in Diet-
ary Supplements 2232, Target limits can be approximated by dividing the Daily Dose PDEs by the maximum daily dose for
the Drug Product Analysis Option in 232 or the Daily Serving PDE divided by the maximum daily serving size in 2232.]
J: The concentration (w/w) of the element(s) of interest at the Target limit, appropriately diluted to the working range of the
instrument. For example, if the target elements are lead and arsenic for an analysis of an oral solid drug product with a daily
dose of 10 g/day using inductively coupled plasma–mass spectrometry (ICP–MS), the target limit for these elements would
be 0.5 g/g and 1.5 g/g (see Table 2 in 232). However, in this case, the linear dynamic range of the ICP–MS is known to
extend from 0.01 ng/mL to 0.1 g/mL for these elements. Therefore, a dilution factor of at least 1:100 is required to ensure
that the analysis occurs in the linear dynamic range of the instrument. J would thus equal 5 ng and 15 ng/mL for lead and
arsenic, respectively, when the dilution factor is added.

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USP 41 Chemical Tests / 251 6155

Appropriate reference materials: Where Appropriate reference materials are specified in the chapter, certified reference ma-
terials (CRM) from a national metrology institute (NMI), or reference materials that are traceable to the CRM of an NMI
should be used. An example of an NMI in the United States is the National Institute of Standards and Technology.

241 IRON

This limit test is provided to demonstrate that the content of iron, in either the ferric or the ferrous form, does not excee d
the limit for iron specified in the individual monograph. The determination is made by concomitant visual comparison with a
control prepared from a standard iron solution.

SPECIAL REAGENTS
Standard Iron Solution

Dissolve 863.4 mg of ferric ammonium sulfate [FeNH 4(SO4)2 · 12H2O] in water, add 10 mL of 2 N sulfuric acid, and dilute
with water to 100.0 mL. Pipet 10 mL of this solution into a 1000-mL volumetric flask, add 10 mL of 2 N sulfuric acid, dilute
with water to volume, and mix. This solution contains the equivalent of 0.01 mg (10 g) of iron per mL.

Ammonium Thiocyanate Solution

Dissolve 30 g of ammonium thiocyanate in water to make 100 mL.

STANDARD PREPARATION

Into a 50-mL color-comparison tube pipet 1 mL of Standard Iron Solution (10 g of Fe), dilute with water to 45 mL, add 2
mL of hydrochloric acid, and mix.

TEST PREPARATION

Into a 50-mL color comparison tube place the solution prepared for the test as directed in the individual monograph and if
necessary dilute with water to 45 mL; or, dissolve in water, and dilute with water to 45 mL the quantity, in g, of the substa nce
to be tested, as calculated by the formula:
1.0/(1000L)
in which L is the Iron limit in percentage. Add 2 mL of hydrochloric acid, and mix.

PROCEDURE

To each of the tubes containing the Standard Preparation and the Test Preparation add 50 mg of ammonium peroxydisulfate

General Chapters
crystals and 3 mL of Ammonium Thiocyanate Solution, and mix: the color of the solution from the Test Preparation is not darker
than that of the solution from the Standard Preparation.

251 LEAD

The imposition of stringent limits on the amounts of lead that may be present in pharmaceutical products has resulted in the
use of two methods, of which the one set forth in this chapter depends upon extraction of lead by solutions of dithizone.
Select all reagents for this test to have as low a content of lead as practicable, and store all reagent solutions in containers of
borosilicate glass. Thoroughly rinse all glassware with warm dilute nitric acid (1 in 2), followed by water.

SPECIAL REAGENTS
Ammonia-cyanide solution: Dissolve 2 g of potassium cyanide in 15 mL of ammonium hydroxide, and dilute with water to
100 mL.

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