COBAS 8000 ISE INDIRECT NA, K, CI FOR GEN. 2

K123726 · Roche Diagnostics · JGS · May 21, 2013 · Clinical Chemistry

Device Facts

• Record ID: K123726
• Device Name: COBAS 8000 ISE INDIRECT NA, K, CI FOR GEN. 2
• Applicant: Roche Diagnostics
• Product Code: JGS · Clinical Chemistry
• Decision Date: May 21, 2013
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1665
• Device Class: Class 2

Indications for Use

The cobas 8000 ISE module is a fully automated ion-specific analyzer intended for the in vitro potentiometric determination of chloride, potassium, and sodium in serum, plasma, and urine using ion-selective electrodes. Measurements obtained by this device are used in the diagnosis and treatment of diseases or conditions involving electrolyte imbalance.

Device Story

The cobas 8000 ISE module is a fully automated clinical chemistry analyzer component; it utilizes ion-selective electrodes (ISE) to measure sodium, potassium, and chloride concentrations in serum, plasma, and urine. The system operates by measuring the electrical potential (electromotive force, EMF) generated across selective membrane materials in contact with test and internal filling solutions; the EMF difference correlates to ion concentration via the Nernst equation. The device is operated by laboratory personnel in clinical settings. Output is provided as quantitative electrolyte concentrations, which clinicians use to diagnose and manage conditions related to electrolyte imbalance. This submission specifically expands the sample type capability to include urine.

Clinical Evidence

Bench testing only. Precision studies (within-run and total) performed using human urine and controls. Linearity validated across reportable ranges (Sodium 60-350, Potassium 3-100, Chloride 60-350 mmol/L). Method comparison against predicate (n=100 for Na/K, n=59 for Cl) showed high correlation (r ≥ 0.999). Interference studies confirmed no significant impact from common drugs, pH, or protein; hemolysis noted to interfere with potassium at >400 mg/dL in normal urine.

Technological Characteristics

Quantitative indirect potentiometric measurement using ion-selective electrodes. System includes sodium, potassium, chloride, and reference electrodes with open liquid junction membranes. Automated 1:46 sample dilution. Operates as a module within the cobas 8000 Modular Analyzer Series. Traceable to flame photometry and coulometry. Standards: CLSI EP5-A2, EP6-A, EP17-A.

Indications for Use

Indicated for in vitro potentiometric determination of sodium, potassium, and chloride in serum, plasma, and urine for patients requiring diagnosis or treatment of electrolyte imbalance.

Regulatory Classification

Identification

A sodium test system is a device intended to measure sodium in serum, plasma, and urine. Measurements obtained by this device are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of large amounts of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance.

Predicate Devices

• COBAS INTEGRA ISE System (k963627)

Submission Summary (Full Text)

{0}

1

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE

A. 510(k) Number:
k123726

B. Purpose for Submission:
Addition of urine sample type to the already cleared device (k100853)

C. Measurand:
Sodium, Potassium, and Chloride

D. Type of Test:
Quantitative, indirect potentiometric measurement with ion-selective electrodes

E. Applicant:
Roche Diagnostics

F. Proprietary and Established Names:
cobas 8000 ISE Indirect Na, K, Cl for Gen. 2.

G. Regulatory Information:

1. Regulation section:
21CFR 862.1665: Ion Specific Electrode, Sodium
21CFR 862.1600: Ion Specific Electrode, Potassium
21CFR 862.1170: Ion Specific Electrode, Chloride

2. Classification:
Class II

3. Product code:
JGS
CEM
CGZ

4. Panel:
75 (Clinical Chemistry)

H. Intended Use:

1. Intended use(s):
See Indication(s) for use below.

{1}

2. Indication(s) for use:
The cobas 8000 ISE module is a fully automated ion-specific analyzer intended for the in vitro potentiometric determination of chloride, potassium, and sodium in serum, plasma, and urine using ion-selective electrodes. Measurements obtained by this device are used in the diagnosis and treatment of diseases or conditions involving electrolyte imbalance.

3. Special conditions for use statement(s):
For in vitro diagnostic use only.
For prescription use.

4. Special instrument requirements:
cobas 8000 ISE Modular Analyzer

I. Device Description:

The cobas 8000 Modular Analyzer Series is a fully automated system for clinical chemistry analysis intended for the in vitro quantitative/qualitative determination of analytes in body fluids. It is optimized for high throughput workloads using a combination of ion selective electrodes (cobas 8000 ISE module) and photometric analysis modules (cobas c 701 and c 502 modules). The cobas 8000 ISE module and the ISE Gen 2 reagents were previously cleared for serum and plasma sample types under k100853. The ISE module includes a sodium electrode, a chloride electrode, a potassium electrode, a reference electrode, an ISE diluent, an ISE internal standard, an ISE reference electrolyte, an ISE calibrator and an ISE Compensator (calibrator). The ISE standard calibrators (S1, S2, and S3) were cleared under k053165 and ISE Compensator cleared under k052193.

J. Substantial Equivalence Information:

1. Predicate device name(s):
COBAS INTEGRA ISE System

2. Predicate 510(k) number(s):
k963627

3. Comparison with predicate:

| Similarities and Differences | | |
| --- | --- | --- |
| Item | Predicate device COBAS INTEGRA ISE k963627 | Candidate device cobas 8000 ISE Module |
| Intended Use | The COBAS INTEGRA ISE module applications are intended | Same (only for sodium, potassium and chloride, no |

{2}

| | for use for the quantitative determination of sodium, potassium, chloride, and lithium in serum, plasma or urine using ion-selective electrodes. | lithium) |
| --- | --- | --- |
| Specimen Type | Serum, Plasma, Urine | Same |
| Measurement Principle | ISE Potentiometry | Same |
| Reagent container | Plastic bottles closed via screw caps | Same |
| Onboard storage temperature | Room Temperature | Same |
| ISE Module | Integrated into Integra analyzer | Separate ISE module connected to Core cobas 8000 module |
| Ion Selective Electrodes (ISEs) | Potentiometric chloride, potassium, sodium and reference electrodes | Same |
| Sample Dilution | 1:6 | 1:46 |
| Throughput | Max 600 tests/hour | Max 1800 tests/hour |
| Detection Limits - Chloride | Not Determined | LOB = 10 mmol/L
LOD = 10 mmol/L
LOQ = 60 mmol/L |
| Reportable Range - Chloride | 20-350 mmol/L | 60-350 mmol/L |
| Detection Limits - Potassium | Not Determined | LOB = 1 mmol/L
LOD = 1 mmol/L
LOQ = 3 mmol/L |
| Reportable Range - Potassium | 1-150 mmol/L | 3-100 mmol/L |
| Detection Limits - Sodium | Not Determined | LOB = 10 mmol/L
LOD = 10 mmol/L
LOQ = 60 mmol/L |
| Reportable Range - Sodium | 20-350 mmol/L | 60-350 mmol/L |

# K. Standard/Guidance Document Referenced (if applicable):

- CLSI EP5-A2: Evaluation of Precision Performance of Clinical Chemistry

{3}

Devices

- CLSI EP6-A: Evaluation of Linearity of Quantitative Analytical Methods
- CLSI EP17-A: Protocols for Determination of Limits of Detection
- CLSI EP17-A: Protocols for Determination of Limits of Detection

# L. Test Principle:

Sodium, Potassium and Chloride are measured using ion-selective electrodes utilizing an indirect (diluted) method where urine samples are automatically diluted at 1:46 ratio using ISE diluent. Each of the electrodes (Sodium, Potassium and Chloride) has membrane with an open liquid junction that is ion-selective. The reference electrode uses the same design of the ion-electrodes and it is exclusively used as a reference for every measurement. The difference of all voltages between the reference electrode and any ion-selective electrode is a measure for the concentration of individual ions. For every test, the voltages of both ISE internal standard and diluted sample solution are measured for each type of ions (Sodium, Potassium and Chloride). The measurement of all electrodes is performed in parallel. The resulting voltages are converted into operator readable results.

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

# 1. Analytical performance:

# a. Precision/Reproducibility:

Precision studies were performed using human urine samples and control material. Within-run precision was determined using 21 replicates for each sample type (3 urine samples and 2 controls) by one operator on one instrument. Total precision was determined using 3 samples (Low, Medium and High) over 21 days in 2 runs with one operator on one instrument. The following results were obtained:

Sodium

| Sodium | Within-run precision | | | Total precision | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Mean mmol/L | SD mmol/L | CV % | Mean mmol/L | SD mmol/L | CV % |
| Urine low | 66.4 | 0.4 | 0.6 | 68.6 | 1.1 | 1.6 |
| Urine medium | 178.9 | 0.9 | 0.5 | 180.3 | 1.0 | 0.6 |
| Urine high | 321.7 | 0.7 | 02 | 318.0 | 2.1 | 0.7 |
| Liquichek 1 | 81.1 | 0.3 | 0.4 | 82.7 | 1.2 | 1.4 |
| Liquichek 2 | 170.6 | 0.5 | 0.3 | 171.3 | 1.0 | 0.6 |

{4}

# Potassium

| Potassium | Within-run precision | | | Total precision | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Mean mmol/L | SD mmol/L | CV % | Mean mmol/L | SD mmol/L | CV % |
| Urine low | 3.65 | 0.00 | 1.2 | 3.75 | 0.06 | 1.7 |
| Urine medium | 51.10 | 0.30 | 0.6 | 49.48 | 0.65 | 1.3 |
| Urine high | 83.78 | 0.66 | 0.8 | 80.60 | 1.32 | 1.6 |
| Liquichek 1 | 32.19 | 0.19 | 0.6 | 31.32 | 0.37 | 1.2 |
| Liquichek 2 | 69.47 | 0.39 | 0.6 | 67.49 | 1.17 | 1.7 |

# Chloride

| Chloride | Within-run precision | | | Total precision | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Mean mmol/L | SD mmol/L | CV % | Mean mmol/L | SD mmol/L | CV % |
| Urine low | 63.6 | 0.5 | 0.7 | 64.7 | 1.1 | 1.7 |
| Urine medium | 180.8 | 0.9 | 0.5 | 179.7 | 12 | 0.7 |
| Urine high | 341.7 | 1.1 | 0.3 | 336.5 | 3.5 | 1.0 |
| Liquichek 1 | 92.3 | 0.4 | 0.5 | 92.6 | 1.1 | 1.2 |
| Liquichek 2 | 189.6 | 0.6 | 0.3 | 187.9 | 1.6 | 0.9 |

# b. Linearity/assay reportable range:

Linearity studies were performed according to CLSI EP6-A. Dilution series of 11 concentrations were prepared using low and high human urine sample pools for each of the analytes and tested in triplicates. Linear regression summary results of the study are presented in the table below:

| Analyte | Slope | Intercept | r2 | Range Tested |
| --- | --- | --- | --- | --- |
| Sodium | 0.9914 | 3.1424 | 0.999957 | 54.6 – 368.8 |
| Potassium | 1.0389 | 0.1518 | 0.999597 | 2.9 – 101.7 |
| Chloride | 0.9425 | 2.7004 | 0.999499 | 48 – 384.5 |

{5}

The results of the study support the sponsor's claims that the urine Sodium is linear from 60 - 350 mmol/L, urine Potassium is linear from 3-100 mmol/L, and urine Chloride is linear form 60-350 mmol/L.

c. Traceability, Stability, Expected values (controls, calibrators, or methods): Aqueous ISE standard calibrators (S1, S2, and S3) were previously cleared under k053165 and ISE Compensator (calibrator) under k052193. The ISE Compensator is traceable to Flame Photometry (Sodium, Potassium) and Coulometry (Chloride).

d. Detection limit:

Studies were carried out in accordance with CLSI Guidance Document EP17-A for Sodium, Potassium and Chloride analytes. For determination of LoB one analyte free sample was measured in 5 replicates, 6 runs, 3 days, on 2 cobas 8000 ISE analyzers. Total of 60 measurements were obtained per analyzer. For determination of LoD, five samples (one replicate) with low-analyte concentration were measured in 6 runs for 3 days on 2 cobas 8000 ISE analyzer modules. In total 60 measurements were obtained per analyzer. For LoQ studies a low level sample set was prepared by diluting 3 human urine samples with an analyte free diluent (ISE Diluent). The low level sample set was tested in single replicate for 3 days in 2 runs per day on two cobas 8000 ISE analyzers. LoQ is defined as the concentration where total error is less than 20%. Results from the detection limit studies are summarized in the table below:

| | LoB (mmol/L) | LoD (mmol/L) | LOQ (mmol/L) | Claimed measuring range (mmol/L) |
| --- | --- | --- | --- | --- |
| Sodium | 10 | 10 | 60 | 60-350 |
| Potassium | 1 | 1 | 3 | 3-100 |
| Chloride | 10 | 10 | 60 | 60-350 |

e. Analytical specificity:

Urine interference studies were performed in according to CLSI EP7-A2 for sodium, potassium, and chloride analytes using 2 levels of analytes (normal and abnormal). The effect of pH (3.8 - 8.2), total protein (14 - 280 mg/L), and hemoglobin (0 - 1,000 mg/dL) on analyte recovery was evaluated in these studies. Different concentrations of potential interference substances were spiked into pooled urine samples. The sponsor's definitions of non-significant interference is <10% difference between the spiked and unspiked samples. There was no significant interference for sodium, potassium, and chloride

{6}

when these analytes and interferents were tested in the concentration ranges indicated below:

**Drug interferents:**

Acetaminophen (paracetamol) 3000 mg/L

Ascorbic acid 4000 mg/L

Ca-Dobesilate 1000 mg/L

Gentamycin sulfate 400 mg/L

Ibuprofen 4000 mg/L

L-Dopa 1000 mg/L

Methyldopa 2000 mg/L

Na-Cefoxitin 12000 mg/L

N-Acetylcysteine 10 mg/L

Ofloxacine 900 mg/L

Phenazopyridine 300 mg/L

Salicyluric acid 6000 mg/L

Tetracycline (Doxycycline) 300 mg/L

**Hemolysis:**

**Sodium and Chloride**

Hemoglobin in urine samples does not interfere in the tested concentration range up to 1000 mg/dL (621 umol/L) hemoglobin (approximate H index 1000).

**Potassium**

Hemoglobin levels higher than 400 mg/dL in normal human urine samples increase the apparent potassium concentrations significantly.

Hemoglobin in pathological urine samples does not interfere in the tested concentration range up to 1000 mg/dl (621 umol/L).

Avoid hemolyzed specimens.

**Icterus:**

Bilirubin (conjugated) in urine samples does not interfere in the tested concentration range up to 60 mg/dl (1026 umol/L) bilirubin (approximate I index 60).

| Sample | pH | Sodium | | Potassium | | Chloride | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | Result (mmol/L) | % of Reference | Result (mmol/L) | % of Reference | Result (mmol/L) | % of Reference |
| Reference | 6 | 74.4 | - | 27.32 | - | 70.0 | - |
| Acidic | 3.8 | 74.2 | 99.7 | 26.77 | 97.99 | 72.6 | 103.7 |
| Alkaline | 8.2 | 74.8 | 100.5 | 26.95 | 98.65 | 67.3 | 96.1 |

f. Assay cut-off: Not applicable

{7}

8

2. Comparison studies:

a. Method comparison with predicate device:
Method comparison studies were conducted for sodium, potassium and chloride on the candidate device (cobas 8000 ISE module) (y) and the results were compared to those determined with the predicate device analyzer (x). The lowest concentration and the highest concentration are diluted and spiked in order to cover hard-to-find sample range for each analyte. Results from the method comparison studies are summarized in tables below:

Sodium

| Instruments | No. Samples | Range Tested (mmol/L) | Passing Bablok | R |
| --- | --- | --- | --- | --- |
| x:cobas INTEGRA ISE
y:cobas 8000 ISE | 100 | 62.2 – 340 | y = 1.041x – 4.477 | 1.000 |

Potassium

| Instruments | No. Samples | Range Tested (mmol/L) | Passing Bablok | R |
| --- | --- | --- | --- | --- |
| x:cobas INTEGRA ISE
y:cobas 8000 ISE | 100 | 3.4 – 100 | y = 0.937x + 0.429 | 1.000 |

Chloride

| Instruments | No. Samples | Range Tested (mmol/L) | Passing Bablok | R |
| --- | --- | --- | --- | --- |
| x:cobas INTEGRA ISE
y:cobas 8000 ISE | 59 | 61.1 – 344.3 | y = 0.971x – 2.787 | 0.999 |

b. Matrix comparison:
Not applicable

3. Clinical studies:

a. Clinical Sensitivity:
Not applicable

b. Clinical specificity:
Not applicable

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

{8}

4. Clinical cut-off:
Not Applicable

5. Expected values¹/Reference range:
The expected values for adult based on 24 hours urine out-put are cited from the literature:

Na+ 40-220 mmol/24 h
K+ 25-125 mmol/24 h
Cl- 110-250 mmol/24 h

References:
1. Tietz Fundamentals of Clinical Chemistry, Fifth Edition, Edited by Carl A. Burtis and Edward R. Ashwood, W.B. Saunders Company, 2001: 970, 1004, 1009 (ISBN 0-7216-8634-6).

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.

9