Role of ICP-AES in Pharmaceutical Fields - Shimadzu … · 2016-04-28 · Role of ICP-AES in Pharmaceutical Fields ... (ICP- AES) and Inductively Coupled Plasma Mass ... using a different

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Role of ICP-AES in Pharmaceutical Fields

Shimadzu CorporationAnalytical and Measuring Instruments Division

Applications Development Center

LAAN-E-CP017

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Introduction To evaluate safety, pharmaceutical fields increasingly require analyzing the metal

content of pharmaceuticals. Guidelines on Impurities in New Drug Substances (Japanese Ministry of Health,

Labour, and Welfare Notice 1216001, December 2002, Pharmaceutical and Food Safety Bureau) requires that any metal catalyst residues be analyzed using a test method indicated by the Japanese Pharmacopoeia or other appropriate method and evaluated at the development stage.

The European Medicines Agency issued guidelines in 2008 that indicated that the content of residual catalyst metals in drug substances and drug products should be evaluated and restricted for safety and quality purposes.

The 2010 United States Pharmacopeia proposes limits for 16 types of elements in USP Elemental Impurities - Limits and corresponding test methods in USP Elemental Impurities - Procedures.

The 2010 USP Elemental Contaminants in Dietary Supplements proposes limits for 5 elements in dietary supplements.

The Japanese Pharmacopoeia Sixteenth Edition (notice scheduled for the end of March 2011) also is expected to include ICP optical emission spectrometry as a reference method.

Atomic absorption spectrometry is typically used, but Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES) and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) is useful in terms of speed and simplicity if multiple analytes must be analyzed.

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European Medicines Agency GuidelinesGuideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents

14 types of metals are classified into one of three classes - Class 1, 2 or 3, in terms of latent risk to human health.

Class 1 metals (metals that are known or suspect human carcinogens, or possible causative agents of other significant toxicity) are further classified into three sub-classes.

Allowable exposure levels for oral, parenteral, or inhalation exposure modes are specified for each class.

ICH Q3C (Impurities: Guideline for Residual Solvents) uses Permitted Daily Exposure (PDE, in terms of g/day units) values to indicate pharmaceutically maximum acceptable exposure to metals.

Concentration limits are calculated from each PDE value assuming a daily dose of 10 grams of the drug product. For daily doses greater than 10 g, limits are applied with respect to the active ingredients in the drug product, rather than being calculated for the drug product.

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European Medicines Agency Guidelines

Oral exposure Parenteral exposure Inhalationexposure

PDEg/day

Concentrationppm

PDE g/day

Concentrationppm

PDE g/day

Class 1A Pt, Pd 100 10 10 1 Pt: 70 *

Class 1B Ir, Rh, Ru, Os 100 ** 10 ** 10 ** 1 **

Class 1C Mo, Ni, Cr, V 250 25 25 2.5 Ni: 100Cr(VI): 10

Class 2 Cu, Mn 2500 250 250 25

Class 3 Fe, Zn 13000 1300 1300 130

Classifications and Respective Elemental Limits in European Medicines Agency Guidelines

* Pt at hexachloroplatinic acid** The total amount of listed metals should not exceed the indicated limit.

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USP (The United States Pharmacopeia) Elemental Impurities - Limits

Classifications and Respective Elemental Limits in USP Elemental Impurities - Limits

Limits are applied to drug substances, drug products, and excipients, which are classified into two groups, Class 1 and 2.

Class 1 includes four highly toxic elements (As, Cd, Pb, and Hg) and applies to all drug products.

Class 2 elements are subject to the same permitted daily exposure limits as metal catalysts indicated in the European Medicines Agency guidelines, but excludes Fe and Zn, due to their low toxicity.

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Element Component

Limit(g/g)

Oral Daily Dose PDE(g/day)

Parenteral Component

Limit(g/g)

Parenteral Dose PDE (g/day)

As 1.5 15 0.15 1.5

Cd 0.5 5 0.05 0.5

Pb 1 10 0.1 1Hg 1.5 15 0.15 1.5


Class 1 (elements that should be essentially absent or are known or strongly suspected human toxicants)

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Element Component

Limit(g/g)

Oral Daily Dose PDE

(g/day)

Parenteral Component

Limit(g/g)

Parenteral Dose PDE (g/day)

Cr, Mo, Ni, V 25 250 2.5 25Cu, Mn 250 2500 25 250Pd, Pt 10 100 1.0 10

Os, Rh, Ru, Ir10

(Combination not to exceed)

100(Combination not to exceed)

1.0(Combination not to exceed)

10(Combination not to exceed)


Class 2 (elements that should be limited, have a lower toxicity than Class 1, or deliberately added to an article)

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Procedure Proposed in USP (The United States Pharmacopeia) Elemental Impurities - Procedures

Materials soluble in aqueous or organic solvent are measured in that state, but insoluble materials are digested using a closed vessel microwave digestion apparatus.

Preparation Procedure Using Closed Vessel Microwave Digestion Apparatus

Dehydrate and predigest 0.5 g of primary sample in 5 mL of freshly prepared strong acid. Allow to sit loosely covered for 30 minutes in a fume hood. Add 10 mL more of strong acid and digest, using a closed vessel technique, until digestion or extraction is complete. Repeat if necessary by adding 5 mL more of strong acid. Fill to 50 mL and use as measurement solution. To measure Hg, add 0.1 ppm Au as a stabilizer.

Sample Preparation

Procedures are indicated for elements listed in Elemental Impurities - Limits

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Perform closed vessel microwave

digestion

Prepare samples

Is the compound soluble in aqueous

medium?

Yes

Is the compound soluble in organic

solvent?

No No

Yes

Prepare sample and check standard solutions according to sample preparation procedure

Perform analysis

Did the check standard recover to

within 20 %

Perform analysis using element-specific method

No

Report result

Yes

Perform solid-state analysis

Yes

No

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Validation of Lower Limit TestPerform validation at measurement precision of spiked sample. If digesting with a closed vessel microwave digestion apparatus,

spike with appropriate reference materials before digesting. Perform repeatability test with 6 independent samples of the material andmaximum 20 % RSD (relative standard deviation).

Validation of Quantitative ProceduresGiven limit value J, confirm the accuracy (recovery rate of 80 % to

150 %) and repeatability of 0.5 J, 1.0 J, and 1.5 J control samples and spiked samples.

Perform repeatability test with 6 independent samples of the material and maximum 20 % RSD (relative standard deviation).

If digesting with a closed vessel microwave digestion apparatus,spike with appropriate reference materials before digesting.

Perform an intermediate precision test (n = 12) on a different day, using a different instrument, or using a different analyst. Maximum RSD allowed is 25 %.

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Spike-and-Recovery Test

Spike-and-Recovery Test Recovery Rate (%) = (C1 - C2) / B 100

Spike Sample After DigestingPDS (Post Digestion Spike Sample)

Evaluate recovery test of additives and level of non-spectral interference after digestion

Spike After Digesting

Analytical Sample

Adjustment Solution

Quantitation Value C2

Quantitation Value C1Prepare

Sample

Analyze

Measurement Solution A

Additive Concentration B

Measurement Solution B

Analyze

Spike Before Digesting

Analyze

Additive Concentration B


Analyze

Measurement Solution A

PrepareSample


Measurement Solution B

Analytical Sample

PrepareSample

Spike Sample Before DigestingMS (Matrix Spike Sample)

Evaluate before digesting, including recovery rate of additives and sample preparation

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Analytical Procedure Using ICP-AESUse 2 J, 0.1 J, and blank samples as calibration

curve samples, where J is the limit value given the same acid concentration value as the measurement sample.

For the check sample, use a 1 ppm sample with the same acid concentration and confirm that the value is within 20 % of the adjusted value.

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Procedure Proposed in USP (The United States Pharmacopeia) Elemental Contaminants in Dietary Supplements

For dietary supplements and nutrients, five highly toxic substances, including four elements, are specified - As (inorganic), Cd, Pb, Hg, and methylmercury, in stead of USP Heavy Metal).

Arsenic is specified as inorganic arsenic, but the inorganic form is measured only if the total arsenic concentration exceeds the permitted limit value.

If total mercury does not exceed permitted limit for methylmercury, then measurement of methylmercury is not required.

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Element Individual

Component Limit(g/g)

PDE(g/day)

As (inorganic) 1.5 15Cd 0.5 5Pb 1.0 10

Hg (total) 1.5 15

Methylmecury (as Hg) 0.2 2

Allowable Limits of Elemental Contaminants in Elemental Contaminants in Dietary Supplements

Procedure Proposed in USP (The United States Pharmacopeia) Elemental Contaminants in Dietary Supplements

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Analysis of Drug SubstancesAnalysis of Drug Substances Using Dilute Organic Solvent (DMSO) Sample: A commercial research grade reagent was used as a model for

drug substances Sample Preparation

DMSO (dimethyl sulfoxide), which is able to dissolve many samples, was used as the sample solvent.

0.5 g of the sample was dissolved in DMSO and diluted (by 10 times) to make 5 mL. 0.1 mg/L of Y (yttrium) was added as an internal standard element.

The 14 elements specified in the European Medicines Agency guidelines were measured as residual metal catalysts in the drug substance.

Instrument Used: Shimadzu ICPE-9000 Multitype ICP Emission Spectrometer

ICPE-9000 (multitype)

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Results of Analyzing Drug Substances (3 types)

Element Cr Cu Fe Ir Mn Mo NiTosufloxacin Tosilate 0.11 0.05 4.37 < 0.03

Role of ICP-AES in Pharmaceutical Fields - Shimadzu … · 2016-04-28 · Role of ICP-AES in Pharmaceutical Fields ... (ICP- AES) and Inductively Coupled Plasma Mass ... using a different

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