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Elemental Scientific prepFAST ICP-OES: USP <232><233> Inhalation UndilutedAutomated Inline Calibration and Sample Spiking

Brief

The prepFAST inline autodilution system with ICP-OES fully automates USP <233> J based calibrations protocols. The prepFAST provides 1) autocalibration, 2) auto sample injection, and 3) autospike addition, eliminating manual sample preparation.

Features

• Autocalibration from a single J stock standard

• Auto J spiking

• Pour sample in tube and run

• Daily walk-up and analyze ICP-OES instrument for USP

• Perfect for laboratories new to ICP-OES

• Automate labor intensive steps to significantly reduce notebook entries

Figure 1. Autocalibration of Arsenic at 0.5 and 2J using inline J spiking. Arsenic, having the lowest PDE level of 0.125 mg/L (Figure 3), is easily calibrated using ICP-OES.

As 188.979

R2 = 0.999985

As Calibration

0.5J

2J

Authors: Kyle Uhlmeyer and Paul Field (field@icpms.com)

Elemental Scientific

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Figure 2. The prepFAST system schematic illustrating a two-step process of loading sample into a loop and injecting sample while performing inline dilution.

Abstract

USP <233> outlines specific validation protocols that require standardization, precision and spike recovery to be based on a target (J) value. Saline (0.9%) solution is a common excipient for many inhalation drugs that can be analyzed directly by prepFAST ICP-OES, thereby fully automating all J based protocols. High Total Dissolved Solids (TDS) tolerance of ICP-OES eliminates the need for sample dilution freeing one prepFAST syringe for the inline addition of a J spike solution. The prepFAST fully automates inline, 1) J based calibration, 2) unspiked sample injection, and 3) sample spiking at any J level (USP <233> 0.8 and 1.0 for validation tests). This capability of the prepFAST ICP-OES requires only a blank solution and samples be placed in the autosampler. The seamlessly integrated prepFAST ICP-OES system easily surpasses USP <233> validation criteria of, 1) stability < ± 5% (USP limit ± 20%), 2) repeatability < ± 5% (USP limit ± 20%), 3) ruggedness < ± 5% (USP limit ± 25%) and 4) accuracy < ±10% (USP limit ± 20%). Automating the J based calibration and J spiking process removes human error and reduces note book entries simplifying compliance with FDA’s 21 CFR Part 11 record integrity regulation .

S4:J Spike

S3:Diluent

S2:Carrier

Sample

Vacuum

V2:P7+ LoadFill Loop

Carrier

Waste

To ICPMS

V1:P6 Load

Carrier

S4:J Spike

S3:Diluent

S2:Carrier

Sample

Vacuum

V2:P7+ InjectDilute Sample

Waste

To ICPMS

V1:P6 Load

S4:J Spike

S3:Diluent

S2:Carrier

Rinse

Vacuum

V2:P7+ LoadInject SampleClean V2

Carrier

Waste

To ICPMS

S4:J Spike

S3:Diluent

S1:Carrier

Sample

Vacuum

V2:P7+ InjectClean V1

Waste

V1:P6 Load

S4:J Spike

S3:Diluent

S2:Carrier

Sample

Vacuum

V2:P7+ LoadTune

Tune

Waste

To ICPMS

V1:P6 Load

Carrier

To ICPMS

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USP <232> <233> Definition:

Figure 3. USP <232><233> defined calculation of J for As in albuterol solution with 12 mL/day daily dose and no dilution factor.

Introduction

Inhalation drugs absorbed through the lungs can be delivered with very rapid action, low metabolism and high bioavailability. As a result this pathway has the minimum Permissible Daily Exposure (PDE) of all categories defined in USP <232>. Delivered through inhalation, albuterol is used to prevent and treat wheezing, difficulty breathing and chest tightness. The active ingredient albuterol (0.083%) is prescribed in a 0.9% saline solution for nebulization. prepFAST ICP-OES eliminates the need for dilution while providing sufficient signal for the determination of elements with the lowest USP <232> defined PDEs. The prepFAST ICP-OES system calibrates, injects samples and spikes samples inline, eliminating manual sample and standard preparation, surpassing all USP <233> acceptance criteria.

Table 1. The USP Chapter <232> defined PDE (µg/day) values for inhalation drugs are used (Figure 3) to calculate target values (J). USP <233> requires a calibration curve and a series of QC validation protocols including repeatability, ruggedness and spike recovery be based on the J value. NOTE: Cr is regulated in inhalation drugs.

Table 1. Maximum Permissible Daily Exposure - PDE

Element Inhalation Daily Dose PDE (µg/day)

LVP Component Limit (µg/g)

Cd 2 0.2

Pb 5 0.5

As 2 0.2

Hg 1 0.1

Co 3 0.3

V 1 0.1

Ni 5 0.5

Tl 8 0.8

Au 1 0.1

Pd 1 0.1

Ir 1 0.1

Os 1 0.1

Rh 1 0.1

Ru 1 0.1

Se 130 13

Ag 7 0.7

Pt 1 0.1

Li 25 2.5

Sb 20 2

Ba 300 30

Mo 10 1

Cu 30 3

Sn 60 6

Cr 3 0.3

undiluted

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0.9995 

0.9996 

0.9997 

0.9998 

0.9999 

1.0000 

As  Cd  Cr  Cu  Hg  Ir  Mo  Ni  Os  Pb  Pd  Pt  Rh  Ru  V 

Calibra'on Coefficient 

LVP Calibration Coefficients

Figure 5. Fully automated inline dilutions from a single stock standard generate linear (>0.9999) calibration curves for all USP elements (Cr added for inhalation pathway).

Figure 4. Autocalibration of Cr at 0.5J and 2J using inline J spiking.

Cr Calibration

0.5J

2J

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Cu Washout

Figure 6. Copper has the highest PDE and therefore J spike concentration. A blank solution analyzed immediately after a J spiked sample returns to baseline. prepFAST > 10000 fold washout indicates no detectable carryover when performing inline spiking.

Figure 7. Stability is assessed (at 0.8J spike) throughout one analytical day. The long-term stability of the method is illustrated in a 8 hr run of 15 analytes from 160 analyses of saline solution. A drift of ± 2.4% RSD surpasses the USP acceptance criteria (± 20%) by nearly a factor of 10.

Stability

USP <233> Definition:

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prepFAST - ICP-OESRSD < 4.0%

Figure 9. The ruggedness of the method demonstrated on 3 separate days yields accuracy (recoveries) of < ± 10% and reproducibility of < ± 4%. The USP acceptance criteria is defined as < ± 25% RSD for each target analyte.

RuggednessUSP <233> Definition:

Figure 8. Repeatability for all USP <232> defined analytes of interest of < ± 3% at 1J spike in albuterol is significantly below the USP <233> accepted criteria of < ± 20% RSD.

Repeatability

USP <233> Definition:

prepFAST - ICP-OESRSD < 3.0%

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prepFAST - ICP-OESRecovery Range for All Elements: 92% to 108%

Figure 10. Excellent spike recovery (± 10%) for 1J spike to albuterol indicates the method is accurate to levels that are significantly better than the USP threshold (70-150%).

USP <233> Definition:

Spike Recovery

Table 2. Results for albuterol, all significantly below USP PDE values.

Table 2. Inhalant Results

Element Target Value (ppm)

Detected Concentration

(ppm)As 0.125 -Cd 0.125 -Cr 2.083 -Cu 5.833 -Hg 0.125 -Ir 0.125 -Mo 20.833 -Ni 0.125 0.063Os 0.125 -Pb 0.417 -Pd 0.125 -Pt 0.125 -Rh 0.125 -Ru 0.125 -V 2.500 -

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Benefits

• prepFAST: autocalibration - Single multi-element standard for all J values

• prepFAST: auto inline J spiking - Eliminate final manual J spiking step

• Run undiluted samples up to 1% TDS

• Easy-to-use automated system for USP protocols

• Pre-developed fully automated methods

• Exceeds all USP validation criteria: Stability, Repeatability, Ruggedness, and Accuracy

• Well-suited to the demands of a high throughput pharmaceutical laboratory

7277 World Communications Drive | Omaha, NE 68122 USA

Phone: 1.402.991.7800 | Fax: 1.402.991.7799

Email: prepFAST@icpms.com

Web: www.prepFAST.com | www.icpms.com Elemental Scientific

SC-2 DX prepFAST System

14058