HITACHI CLINICAL ANALYZER S TEST REAGENT CARTRIDGE GLUCOSE (GLU)

K120369 · Hitachi Chemical Diagnostics, Inc. · CFR · May 10, 2012 · Clinical Chemistry

Device Facts

• Record ID: K120369
• Device Name: HITACHI CLINICAL ANALYZER S TEST REAGENT CARTRIDGE GLUCOSE (GLU)
• Applicant: Hitachi Chemical Diagnostics, Inc.
• Product Code: CFR · Clinical Chemistry
• Decision Date: May 10, 2012
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1345
• Device Class: Class 2

Intended Use

The S TEST reagent cartridge for glucose is intended for the quantitative measurement of glucose in serum, lithium heparin plasma, K3 EDTA plasma, and sodium citrate plasma on the Hitachi Clinical Analyzer. The test system is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus and idiopathic hypoglycemia.

Device Story

The Hitachi Clinical Analyzer is a bench-top, automated wet chemistry system for clinical or physician office laboratories. It utilizes single-use plastic reagent cartridges containing two reagents (R1 and R2) and a reaction cell. The operator places sample cups and reagent cartridges into the analyzer carousels. The system automatically pipettes samples and reagents, mixes them, and incubates the reaction. A multi-wavelength photometer measures absorbance at 340/450 nm. The device uses an enzymatic hexokinase method: glucose is phosphorylated to glucose-6-phosphate, which is then converted to 6-phosphogluconic acid by G6PD, reducing NADP to NADPH. The resulting change in absorbance at 340 nm is proportional to glucose concentration. The analyzer calculates and displays results in approximately 15 minutes. The output assists clinicians in diagnosing and managing carbohydrate metabolism disorders. Reagent cartridges include a dot code label containing chemistry parameters and calibration factors.

Clinical Evidence

Clinical performance was evaluated at three external physician office laboratory (POL) sites. The study assessed precision and accuracy (method comparison) using 50-53 blinded serum samples per site compared against the Roche cobas 6000. Accuracy results showed high correlation (r=0.99) with slopes ranging from 0.97 to 1.05. Precision studies (n=30 results per level) demonstrated within-run %CVs ranging from 0.8% to 4.5% and total %CVs from 1.1% to 4.6% across low, intermediate, and high concentration samples.

Technological Characteristics

Bench-top wet chemistry analyzer. Reagent cartridges: plastic, 13.5mm x 28mm x 20.2mm. Sensing: multi-wavelength photometer (340/450 nm). Energy: electrical. Connectivity: dot code label for parameter/calibration data. Sterilization: N/A. Software: embedded firmware for analyzer control and photometric data processing.

Indications for Use

Indicated for quantitative glucose measurement in serum, lithium heparin, K3 EDTA, and sodium citrate plasma for patients requiring diagnosis or treatment of carbohydrate metabolism disorders, including diabetes mellitus and idiopathic hypoglycemia. For use in clinical or physician office laboratories.

Regulatory Classification

Identification

A glucose test system is a device intended to measure glucose quantitatively in blood and other body fluids. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma.

Special Controls

*Classification.* Class II (special controls). The device, when it is solely intended for use as a drink to test glucose tolerance, is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9.

Predicate Devices

• Roche/Hitachi cobas 8000 (c502 module) (K100853)
• Alfa Wasserman S40 system (K072140)

Submission Summary (Full Text)

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510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION
DECISION SUMMARY
ASSAY

A. 510(k) Number:
k120369

B. Purpose for Submission:
New device

C. Measurand:
Glucose

D. Type of Test:
Quantitative Photometric

E. Applicant:
Hitachi Chemical Diagnostics, Inc

F. Proprietary and Established Names:
Hitachi Clinical Analyzer S TEST Reagent Cartridge for Glucose

G. Regulatory Information:
1. Regulation section:
21 CFR § 862.1345- glucose test system
2. Classification:
Class II
3. Product code:
CFR
4. Panel:
Chemistry (75)

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H. Intended Use:

1. Intended use(s):

See indications for use below

2. Indication(s) for use:

The S TEST reagent cartridge for glucose is intended for the quantitative measurement of glucose in serum, lithium heparin plasma, K3 EDTA plasma, and sodium citrate plasma on the Hitachi Clinical Analyzer. The test system is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus and idiopathic hypoglycemia.

3. Special conditions for use statement(s):

Prescription use only

4. Special instrument requirements:

Hitachi Clinical Analyzer (previously cleared in k111753)

I. Device Description:

The Hitachi Clinical Analyzer is an automatic, bench-top, wet chemistry system intended for use in clinical laboratories or physician office laboratories. The analyzer unit includes a single probe, an incubation rotor, carousels for sample cups and reagent cartridges, and a multi-wavelength photometer. The single-use reagent cartridges may be placed in any configuration on the carousel, allowing the user to develop any test panel where the reagent cartridges are available.

The S TEST reagent cartridges are made of plastic and include two small reservoirs capable of holding two separate reagents (R1 and R2), separated by a reaction cell/photometric cuvette. The cartridges also include a dot code label that contains all chemistry parameters, calibration factors, and other production-related information, e.g., expiration dating. The dimensions of the reagent cartridges are: 13.5 mm (W) × 28 mm (D) × 20.2 mm (H).

GLU Reagent (1):

- Hexokinase (Yeast) 4.0 U/mL
- Nicotinamide adenine dinucleotide phosphate (oxidized form) 3.0 g/L
- Glucose-6-phosphate dehydrogenase (E.coli) 2.0 U/mL
- 2-Amino-2-hydroxymethyl-1,3-propanediol Buffer (pH7.2) 0.1 mol/L

GLU Reagent (2):

- 2'-Deoxyadenosine-5'-triphosphate sodium salt 5.0 mmol/L
- 2-Amino-2-hydroxymethyl-1,3-propanediol Buffer (pH8.4) 0.1 mol/L

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J. Substantial Equivalence Information:

1. Predicate device name(s):
Roche cobas 8000

2. Predicate 510(k) number(s):
k100853

3. Comparison with predicate:

| Characteristic | Hitachi S TEST Systems | PREDICATE(S) |
| --- | --- | --- |
| Glucose Test System | K number- k120369 | Roche K number- k100853 |
| Intended Use | Quantitative determination of glucose | Same |
| Testing Environment | Physician office or clinical lab | Clinical lab- cobas |
| Test Principle | Enzymatic method (Hexokinase method) | UV Test- enzymatic reference method with hexokinase |
| Specimen Type | Human serum or plasma | Human serum, plasma, CSF, or urine |
| Reportable Range | 5 to 500 mg/dL | 2 to 750 mg/dL |
| Detection Wavelength | 340/450 nm | 700/340 nm |
| Detection Limit | 5 mg/dL | 2 mg/dL |
| Linearity | 5 to 500 mg/dL | 2 to 750 mg/dL |
| Precision | %CVs ranged from 2.1% to 3.9% | %CVs range from 0.7% to 1.3%
(from product labeling) |

K. Standard/Guidance Document Referenced (if applicable):
CLSI - Protocols for Determination of Limits of Detection and Limits of Quantitation - EP17-A
CLSI - Evaluation of Precision Performance of Clinical Chemistry Devices - EP05-A2
CLSI - Interference Testing in Clinical Chemistry - EP07-A2

L. Test Principle:
Glucose is phosphorylated to glucose-6-phosphate by hexokinase (HK) in the presence of ATP. When the glucose-6-phosphate is converted into 6-phosphogluconic acid by glucose-6-phosphate dehydrogenase (G6PD), NADP is converted into NADPH with an increase in absorbance at 340 nm. The concentration of glucose can be determined by measuring the amount of change in absorbance of NADPH.

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# M. Performance Characteristics (if/when applicable):

# 1. Analytical performance:

# a. Precision/Reproducibility:

Three levels of serum samples (low, middle, and high levels of GLU) were tested in duplicate with 2 cartridges, twice a day, for 20 days, for a total of 80 results per level to assess in-house precision. The precision estimates are described below.

GLU- Low, Level 1, Summary

| GLU | Within-Run | Total |
| --- | --- | --- |
| Mean (mg/L) | 73.0 | 73.0 |
| SD (mg/L) | 2.86 | 2.88 |
| %CV | 3.9% | 3.9% |

GLU- Middle, Level 2, Summary

| GLU | Within-Run | Total |
| --- | --- | --- |
| Mean (mg/dL) | 213.8 | 213.8 |
| SD (mg/dL) | 3.11 | 4.49 |
| %CV | 1.5% | 2.1% |

GLU- High, Level 3, Summary

| GLU | Within-Run | Total |
| --- | --- | --- |
| Mean (mg/L) | 306.1 | 306.1 |
| SD (mg/L) | 3.33 | 9.20 |
| %CV | 1.1% | 3.0% |

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Three levels of serum samples (A= low, B= medium, and C= high) were tested at three POL sites, six times a day for five days. The precision estimates are described below.

Glucose (mg/dL)
n = 30 replicates per sample per site

| Site | Sample | Mean | Within-run Precision | | Total Precision | |
| --- | --- | --- | --- | --- | --- | --- |
| | | | SD (mg/dL) | %CV | SD (mg/dL) | %CV |
| Site 1 | A | 59.3 | 2.6 | 4.5% | 2.8 | 4.6% |
| Site 2 | A | 59.1 | 0.7 | 1.1% | 1.0 | 1.7% |
| Site 3 | A | 59.1 | 1.2 | 2.1% | 1.4 | 2.3% |
| | | | | | | |
| Site 1 | B | 117.3 | 4.0 | 3.4% | 4.4 | 3.7% |
| Site 2 | B | 117.7 | 0.9 | 0.8% | 1.3 | 1.1% |
| Site 3 | B | 114.9 | 1.6 | 1.4% | 1.7 | 1.7% |
| | | | | | | |
| Site 1 | C | 358.7 | 11.5 | 3.2% | 12.8 | 3.6% |
| Site 2 | C | 354.8 | 3.5 | 1.0% | 6.8 | 1.9% |
| Site 3 | C | 343.9 | 7.1 | 2.1% | 10.2 | 3.0% |

b. Linearity/assay reportable range:

11 serum samples (0, 1.5, 4.0, 6.5, 8.0, 15.0, 29.0, 132, 251, 468, 690 mg/dL) were assigned their reference values arithmetically and were tested in duplicate by the Hitachi Clinical Analyzer, and the mean Hitachi results (y-axis) were plotted against the assigned values (x-axis).

| | Linearity (assigned) | Regression analysis | reportable range (within linearity) |
| --- | --- | --- | --- |
| GLU | 2 mg/dL and 655 mg/dL | y = 1.038x-0.4173
R² = 0.9992 | 5 mg/dL and 500 mg/dL |

The data supported the sponsor's claimed range of the device (5-500 mg/dL).

c. Traceability, Stability, Expected values (controls, calibrators, or methods):

Glucose S Test cartridge lot is calibrated using standard material traceable to ReCCS (Reference Material Institute for Clinical Chemistry Standards) standard serum JCCRM 521.

Shelf life/ stability of the cartridge:

Real-time, shelf-life stability studies for the GLU reagent cartridge were performed. A two-level control set, (92 and 212 mg/dL, respectively) was tested in replicates of

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five with three lots of cartridges across six analyzers according to standard procedure.

Testing occurred at Time 0 (baseline), and again at approximately, 6, 9, 11, 12 and 13 months; the storage condition was refrigerated (2 to 8 °C). The studies supported the sponsor’s claimed shelf life of 12 months at 2 to 8 °C.

d. Detection limit:

Per CLSI EP17-A, blank samples for each reagent system were assayed 20 times per day for three days for a total of 60 replicate results to determine LOB and LOD. Low samples were assayed 20 times with the specific reagent cartridges to determine the detection limit below:

LoD for GLU: 0.3 mg/dL

LoB for Glu: (mean of the 57th and 58 point) -0.28

LoQ study was performed as follows: three clinical samples were diluted to target 5.5 mg/dL glucose. Each sample was tested with one lot of cartridges 6x/day on 3 different days with three different analyzers for a total of 54 replicate results per sample. From these data, the means, standard deviations (SDs), and percent coefficients of variation (%CVs) were calculated. The % CVs ranged from 14.5 to 17.5 % with all three < 20 %. The data supported the sponsor’s claimed LoQ of 5 mg/dL.

e. Analytical specificity:

The studies followed CLSI EP7-A2. The data demonstrated that GLU was not affected by the following substances at the levels noted below. No significant interference is defined by the sponsor as the highest level of interferent that is within 10% of the neat sample.

The interference studies demonstrated that the S TEST for GLU was resistant to high levels of ascorbic acid (up to 50 mg/dL), hemoglobin up to 500 mg/dL for low (50 mg/dL) glucose levels and 1000 mg/dL for high (200 mg/dL) glucose levels, unconjugated bilirubin up to 6.25 mg/dL for low (50 mg/dL) glucose levels and 50 mg/dL for high (50 mg/dL) glucose levels, and triglycerides (up to 800 mg/dL).

f. Assay cut-off:

Not applicable

2. Comparison studies:

a. Method comparison with predicate device:

The in-house method comparison study evaluated 100 serum samples; matched aliquots

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were assayed with both the Hitachi Clinical Analyzer with S TEST GLU reagent cartridge and the Roche/Hitachi cobas 6000. The data were analyzed by least squares linear regression (Hitachi = y-axis), and the results were as follows:

## Glucose (mg/dL)

n= 100

y= 0.99x -2.7

correlation coefficient (r) = 0.999

95% confidence interval of the slope = 0.98 to 1.02; 95% confidence interval of the y-intercept = -5.5 to 0.8

Range (serum) = 12 to 441 mg/dL

Method comparison at POL sites:

| Site # | n | Range (mg/dL) | Regression equation | CI slope | CI intercept | r |
| --- | --- | --- | --- | --- | --- | --- |
| 1 | 53 | 75 to 375 | y = 1.01x - 1.1 | 0.99 to 1.02 | -2.7 to 0.6 | 0.99 |
| 2 | 52 | 69 to 361 | y = 0.97x -0.1 | 0.96 to 0.99 | -2.1 to 1.9 | 0.99 |
| 3 | 51 | 75 to 399 | y = 1.05x - 2.5 | 1.03 to 1.07 | 1.03 to 1.07 | 0.99 |

## b. Matrix comparison:

Serum/Plasma Comparison Study

A study was performed to validate the use of sodium citrate (Na citrate), lithium heparinized, and K3 EDTA plasma as alternatives to serum for the Hitachi Clinical Analyzer with S TEST GLU reagent cartridges Thirty-eight (38) matched serum/plasma samples that spanned the glucose dynamic range were assayed in singleton and the results were compared using least squares liner regression (plasma = y-axis). The performance characteristics were as follows.

N = 38

Range (serum) = 12 to 441 mg/dL

| | Na Citrate Plasma | Heparinized Plasma | K3 EDTA Plasma |
| --- | --- | --- | --- |
| Slope (95% CIs) | 0.98 (0.96 to 1.00) | 1.00 (0.98 to 1.02) | 1.00 (0.99 to 1.02) |
| y-intercept (95% CIs) | -4.6 (-8.2 to -0.8) | -2.1 (-5.8 to 1.6) | -0.3 (-3.1 to 2.6) |
| r | 0.99 | 0.99 | 0.99 |

## 3. Clinical studies:

a. Clinical Sensitivity:

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Not Applicable

b. Clinical specificity:

Not Applicable

c. Other clinical supportive data (when a. and b. are not applicable):

None

4. Clinical cut-off:
Not applicable

5. Expected values/Reference range:
Reportable range: 5 - 500 mg/dL
Reference range (US, fasting serum): 60 – 95 mg/dL*
It is recommended that each laboratory determine the expected values for its particular population.

* Tietz, Tietz Fundamentals of Clinical Chemistry, 4th Edition, WB Saunders Company, (1996

N. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

O. Conclusion

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.