You are on page 1of 20

Procedures for the Evaluation

of the Levels of Elemental


Impurities
Marticio | Mas | Ocampo
Ph Ch 137 PHB
● Analytical procedures for the evaluation of the levels of elemental impurities

● Criteria for acceptable alternative procedures

○ Validation requirements

○ System standardization and suitability evaluation

● Requirement for elemental impurity test

○ General Notices and Requirements

○ Monograph

● Verification studies
Definition of Terms
● Aqua regia

● Matched Matrix

● Target Elements

● Target Limit or Target Concentration

● J

● Appropriate Reference Materials


Methodology
a. Sample Preparation
b. Procedure 1 and 2 Comparison
c. Procedure Overview
a. Sample Preparation
Purpose: Recovery of Inorganic Compounds

Selection of Appropriate Sample Preparation Depends on:


(1) material under test
(2) responsibility of the analyst

If spiking is needed to provide acceptable intensity, blank should have:


(1) spiked with same Target Elements
(2) using same spiking solution
Types of Sample Preparation
(1) Neat: unsolvated samples

(2) Direct Aqueous Solution: soluble in aqueous solvent

(3) Direct Organic Solution: soluble in organic solvent

(4) Indirect Solution: materials not directly soluble in aqueous/organic solvent


*use Closed Vessel Digestion

(5) Closed Vessel Digestion: samples should be digested in Concentrated Acid in


Closed Vessel Apparatus

Concentrated Acid choice: dependent on sample matrix


Closed Vessel Digestion Apparatus

0.5 g sample

Dehydrate and predigest.

Concentrated Acid

Sit loosely covered in fumehood


(30 mins)

+ additional acid Figure 1. Closed vessel digestion apparatus


Comparison between ICP -AES vs. ICP-MS
Parameters ICP- AES ICP-MS
Inductively coupled atomic emission
Name spectrometry
Inductively coupled mass spectrometry

measurement of excited atoms and ions


Basis of
at the wavelength characteristics for the Atom’s mass thru mass spectrometry
measurement specific elements being measured

Detection Limit Parts per billion (ppb) Parts per trillion (ppt)

-samples with high total dissolved solids (TDS) or


suspended solids and is, therefore, more robust
for analyzing ground water, wastewater, soil, and
-samples with low regulatory limits
solid waste.
Sample -requires sample dilution
-if a sample contains analytes of great difference in concentration
-contaminants for environmental safety
assessment and elements with a higher
regulatory limit

Instrument/Detector ICP with Optical Detection System ICP ( with cooled spray chamber) and Mass Spectrometer
(1) ICP-AES

(2) ICP-MS
Procedure Overview
Sample stock solution: Allow the sample to cool, if necessary. For mercury 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 2J.
Blank: Matched Matrix
Rinse for instrument: 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
solutions.
Suitability criteria: NMT 20% for each Target Element.
Analysis: Analyze according to the manufacturer's suggestions for program and wavelength. Calculate and
report results on the basis of the original sample size.
Alternative Procedure Validation
- Used if a specified compendial procedure does not meet the needs of a
specific application

- Must be validated and must be acceptable and therefore equivalent to the


compendial procedures for the purposes of the test

- The level of validation necessary to ensure that an alternative procedure is


acceptable depends on whether a limit test or a quantitative determination is
necessary.

- Any alternative procedure that has been validated and meets the acceptance
criteria that follow is considered to be equivalent to the compendial
procedures for the purposes of this test.
Limit Procedures
a. Detectability

b. Precision for Instrumental Methods (Repeatability)

c. Specificity
Detectability
Parameters Spiked Sample Solution 1 Spiked Sample Solution 2
Standard A preparation of reference materials for the Target Element(s) at the Target Concentrations

Preparation Prepare a solution of sample under test,


Prepare a solution of the sample under test,
(Unspiked sample solution: A spiked with appropriate reference
spiked with appropriate reference materials at
sample of material under test, materials for the Target Elements at the
80% of the Target Concentration for the Target
solubilized or digested in the Target Concentration, solubilized or
Elements, solubilized or digested as described in
same manner as the Sample digested as described in Sample
Sample Preparation.
solutions) Preparation.

Acceptance Criteria

- Non-instrumental equivalent to or greater than the


less than the Spiked sample solution 1
procedures Standard solution
(NLT the Unspiked sample solution)
(signal/intensity) (NLT the Unspiked sample solution)

- Instrumental within ±15% of the value obtained for the must provide a signal intensity or value less than
procedures replicates of Standard solution (corrected that of the Standard solution (corrected using
(ave. of replicates) using Unspiked sample solution) Unspiked sample solution)
Other Limit Procedures
Precision for Instrumental Methods (Repeatability)

- 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: RSD = NMT 20% for each Target Element

- Non-instrumental precision is demonstrated by meeting the Detectability requirement

Specificity

- The procedure must be able to unequivocally assess each Target Element in the presence of
components that may be expected to be present, including other Target Elements, and matrix
components.
Quantitative Procedures
a. Accuracy

b. Precision

c. Specificity
Quantitative Procedures
Test Samples Acceptance Criteria

Accuracy Prepare samples of the material under test spiked


Standard solutions: Prepare with appropriate reference materials before any Spike recovery: 70%–150% for
solutions containing the Target sample the mean of three replicate
Elements at concentrations ranging preparation steps (digestion or solubilization) at preparations at each
from 50% to 150% of J, using concentrations ranging from 50% to 150% of J for concentration
appropriate reference materials. each Target Element.

Precision

Six independent samples of material under test


(taken from the same lot) spiked with appropriate RSD: NMT 20% for each Target
- Repeatability reference materials for the Target Element(s) at the Element
indicated level.

Similar to Repeatability analysis, but over three


independent events:
RSD: NMT 25% for each Target
- Ruggedness 1. on different days;
Element
2. with different instrumentation; or
3. with different analysts.
Other Quantitative Procedures
Specificity

- The procedure must be able to unequivocally assess 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.


Applications

- Analysis of groundwater, wastewater, soil, and solid waste

- Formulation of new drugs

- Risk Assessment
THANK YOU!
References
United States Pharmacopoeial Convention. (2015). The United States
Pharmacopoeia 38th Revision and The National Formulary 33rd Edition. Rockville,
Maryland: USP Convention.

Reddy, M.M., Reddy, K.H., and Reddy, M.U. (2016). Harmonized Guideline on Limit
and Testing of Elemental Impurities in Pharmaceutical Substances: A Review.
Pharmaceutical Regulatory Affairs, 5:168. doi: 10.4172/2167-7689.1000168

U.S. Department of Health and Human Services. (2016). Elemental Impurities in


Drug Products: Guidance for Industry (Draft Guidance). Federal Register, 15505.

You might also like