ISE indirect K for Gen.2; ISE indirect Na for Gen.2; ISE indirect Cl for Gen.2; cobas pro integrated solutions
Device Facts
| Record ID | K253491 |
|---|---|
| Device Name | ISE indirect K for Gen.2; ISE indirect Na for Gen.2; ISE indirect Cl for Gen.2; cobas pro integrated solutions |
| Applicant | Roche Diagnostics |
| Product Code | CEM · Clinical Chemistry |
| Decision Date | Feb 12, 2026 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1600 |
| Device Class | Class 2 |
| Attributes | Pediatric |
Indications for Use
cobas pro integrated solutions is an automated analyzer, intended for running qualitative, semiquantitative, and quantitative clinical chemistry and immunochemistry assays as well as ion-selective measurements. The ISE analytical unit of the cobas c systems is intended for the quantitative determination of sodium, potassium and chloride in serum, plasma or urine using ion-selective electrodes. Sodium measurements 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. Potassium measurements are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels. Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such as cystic fibrosis and diabetic acidosis.
Device Story
Automated, random-access, software-controlled clinical chemistry analyzer; cobas pro integrated solutions platform; incorporates cobas ISE neo analytical unit. Input: serum, plasma, or urine samples in barcoded tubes. Operation: Ion-Selective Electrode (ISE) technology; membrane potential (EMF) measured against internal filling solution; concentration calculated via Nernst equation. Output: quantitative electrolyte concentrations (Na, K, Cl). Used in clinical laboratories; operated by trained personnel. Output displayed to clinicians for diagnosis/monitoring of electrolyte imbalances and metabolic disorders. Benefits: high-throughput (900 tests/hour) automated electrolyte analysis; improved diagnostic efficiency.
Clinical Evidence
Bench testing only. Precision (repeatability/intermediate) evaluated per CLSI EP05-A3 (n=84). Analytical sensitivity (LoB, LoD, LoQ) per CLSI EP17-A2. Linearity per CLSI EP06-Ed2. Interference studies (endogenous/exogenous) confirmed no significant impact. Method comparison (cobas c 703 vs c 503) showed high correlation (r=1.000 for serum/plasma/urine/CSF). Methadone II method comparison vs GC-MS demonstrated clinical performance at 300 ng/mL cutoff.
Technological Characteristics
Ion-selective electrode (ISE) technology; Nernst equation-based measurement. Reagents: HEPES buffer, triethanolamine, potassium chloride, sodium hydroxide, sodium hypochlorite. Throughput: up to 900 tests/hour. Connectivity: automated barcode scanning, software-controlled. Safety: IEC 61010-1 compliant. Sterilization: N/A (reagent-based).
Indications for Use
Indicated for quantitative determination of sodium, potassium, and chloride in serum, plasma, or urine for patients requiring electrolyte monitoring or diagnosis of metabolic/electrolyte disorders (e.g., aldosteronism, diabetes insipidus, cystic fibrosis, diabetic acidosis). For prescription use only.
Regulatory Classification
Identification
A potassium test system is a device intended to measure potassium in serum, plasma, and urine. Measurements obtained by this device are used to monitor electrolyte balance in the diagnosis and treatment of diseases conditions characterized by low or high blood potassium levels.
Predicate Devices
- cobas c 503 in cobas pro integrated solutions (K191899)
- ONLINE DAT Methadone II on Roche/Hitachi Family (K021505)
Submission Summary (Full Text)
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FDA
U.S. FOOD & DRUG
ADMINISTRATION
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
ASSAY AND INSTRUMENT
## I Background Information:
A 510(k) Number
K253491
B Applicant
Roche Diagnostics
C Proprietary and Established Names
ISE indirect K for Gen.2; ISE indirect Na for Gen.2; ISE indirect Cl for Gen.2; cobas pro integrated solutions
D Regulatory Information
| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| CEM | II | 21 CFR 862.1600 - Potassium Test System | CH - Clinical Chemistry |
| JGS | II | 21 CFR 862.1665 - Sodium Test System | CH - Clinical Chemistry |
| CGZ | II | 21 CFR 862.1170 - Chloride Test System | CH - Clinical Chemistry |
| JJE | I | 21 CFR 862.2160 - Discrete photometric chemistry analyzer for clinical use | CH - Clinical Chemistry |
## II Submission/Device Overview:
A Purpose for Submission:
Addition of previously cleared assays to a modified instrument platform
B Measurand:
Potassium, Sodium, Chloride
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
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C Type of Test:
Quantitative, ion selective electrode
III Intended Use/Indications for Use:
A Intended Use(s):
See Indications for Use below.
B Indication(s) for Use:
cobas pro integrated solutions is an automated analyzer, intended for running qualitative, semiquantitative, and quantitative clinical chemistry and immunochemistry assays as well as ion-selective measurements.
The ISE analytical unit of the cobas c systems is intended for the quantitative determination of sodium, potassium and chloride in serum, plasma or urine using ion-selective electrodes.
Sodium measurements 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.
Potassium measurements are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels.
Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such as cystic fibrosis and diabetic acidosis.
C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
D Special Instrument Requirements:
cobas pro integrated solutions
IV Device/System Characteristics:
A Device Description:
cobas pro integrated solutions
The cobas pro integrated solutions is a fully automated, random-access, software-controlled system intended for in vitro quantitative and qualitative analysis of analytes in body fluids. The quantitative analysis also includes semi-quantitative. The cobas ISE neo, with a throughput of up to 900 tests per hour, is being added to the cobas pro integrated solutions.
ISE indirect Na for Gen.2, ISE indirect K for Gen.2 and ISE indirect Cl for Gen.2
ISE auxiliary reagents include:
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- ISE Reference Electrolyte: 1 mol/L potassium chloride
- ISE Diluent: HEPES buffer: 10 mmol/L; Triethanolamine: 7 mmol/L; Preservative
- ISE Internal Standard: HEPES buffer: 10 mmol/L; Triethanolamine: 7 mmol/L; Sodium chloride: 3.06 mmol/L; Sodium acetate: 1.45 mmol/L; Potassium chloride: 0.16 mmol/L; Preservatives
- ISE Cleaning Solution: Sodium hydroxide solution: 3 mol/L with sodium hypochlorite solution < 2 % active Cl
- Deproteinizer and ISE Deproteinizer: The Deproteinizer and ISE Deproteinizer are aqueous sodium hypochlorite solutions.
- Electrodes: Sodium, Potassium, Chloride, Reference
## B Principle of Operation:
An Ion-Selective Electrode (ISE) makes use of the unique properties of an ion-selective membrane to develop an electrical potential (electromotive force, EMF) for the measurements of ions in solution. The selective membrane is in contact with both the test solution and an internal filling solution. Due to the selectivity of the membrane, only the ions to be measured contribute to the EMF. The membrane EMF is determined by the difference in concentration of the test ion in the test solution and the internal filling solution. The EMF develops and ion concentration is determined according to the Nernst equation.
## C Instrument Description Information:
1. Instrument Name:
cobas pro integrated solutions
2. Specimen Identification:
The specimen is in a tube with a barcode label. The system identifies specimens by scanning the barcode. This is the primary use case for sample identification. The system also supports manual entry of sample IDs to support the needs of the customer.
3. Specimen Sampling and Handling:
Specimen sampling and handling procedures are analyte specific and documented in the respective reagent method sheets.
4. Calibration:
The software automatically recommends calibration for all tests requiring calibration. Calibration may also be ordered manually at any time. Calibration methods and procedures are analyte specific and documented in the respective reagent method sheets.
5. Quality Control:
The method sheet for each assay used on the system contains QC recommendations for the specific application.
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V Substantial Equivalence Information:
A Predicate Device Name(s):
ISE indirect K for Gen.2; ISE indirect Cl for Gen.2; cobas 6000 Series System
ISE indirect Na for Gen.2; cobas pro integrated solutions
B Predicate 510(k) Number(s):
K060373, K191899
C Comparison with Predicate(s):
Comparison of ISE indirect K for Gen.2 and ISE indirect Cl for Gen.2
| Device & Predicate Device(s): | K253491 | K060373 |
| --- | --- | --- |
| Device Trade Name | ISE indirect K for Gen.2; ISE indirect Cl for Gen.2 | ISE indirect K for Gen.2; ISE indirect Cl for Gen.2 |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | Intended for quantitative determination of potassium and chloride in serum, plasma or urine using ion-selective electrodes. | Same |
| General Device Characteristic Differences | | |
| Analyzer Units | cobas ISE neo | cobas c 501 module (comprises a photometric unit and an ISE unit) |
Comparison of ISE indirect Na for Gen.2
| Device & Predicate Device(s): | K253491 | K191899 |
| --- | --- | --- |
| Device Trade Name | ISE indirect Na for Gen.2 | ISE indirect Na for Gen.2 |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | Intended for quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. | Same |
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Comparison of the cobas pro integrated solution and cobas 6000 Series system
| Device & Predicate Device(s): | K253491 | K060373 |
| --- | --- | --- |
| Device Trade Name | cobas pro integrated solutions | cobas 6000 Series System |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | Intended for automated running of quantitative ion-selective measurements | Same |
| General Device Characteristic Differences | | |
| Analyzer Units | cobas ISE neo | cobas c 501 module (comprises a photometric unit and an ISE unit) |
## VI Standards/Guidance Documents Referenced:
- Clinical and Laboratory Standards Institute (CLSI EP05-A3). Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline – Third Edition.
- CLSI EP06 2nd Edition. Evaluation of the Linearity of Quantitative Measurement Procedures.
- CLSI EP17-A2. Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline – Second Edition.
- IEC 61010-1 Edition 3.1 2017-01 consolidated version. Safety requirements for electrical equipment for measurement, control, and laboratory use – Part 1: General Requirements (including: Corrigendum 1).
## VII Performance Characteristics (if/when applicable):
### A Analytical Performance:
1. Precision/Reproducibility:
Precision studies were performed in accordance with CLSI guideline EP05-A3. The protocol consisted of testing two sample replicates per run, two runs per day for ≥ 21 days on the candidate device. The protocol was repeated for each application in serum, plasma and urine. Repeatability and within-laboratory precision estimates were calculated. The samples were randomized in each run separately. Pooled samples were used for each level. Samples 1 and
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5 were diluted or spiked, samples 2-4 were native. The results are summarized in the tables below.
Summary of Precision Results – ISE Indirect Na for Gen.2
| Sample | N | Mean (mmol/L) | Repeatability | | Mean (mmol/L) | Within-Laboratory Precision | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD (mmol/L) | CV (%) | | SD (mmol/L) | CV (%) |
| Serum Control 1 | 84 | 116 | 0.714 | 0.6 | 116 | 1.40 | 1.2 |
| Serum Control 1 | 84 | 140 | 0.658 | 0.5 | 140 | 1.41 | 1.0 |
| Serum 1 | 84 | 87.0 | 0.404 | 0.5 | 87.0 | 0.947 | 1.1 |
| Serum 2 | 84 | 133 | 0.609 | 0.5 | 133 | 1.05 | 0.8 |
| Serum 3 | 84 | 137 | 0.675 | 0.5 | 137 | 0.984 | 0.7 |
| Serum 4 | 84 | 159 | 0.797 | 0.5 | 159 | 1.24 | 0.8 |
| Serum 5 | 84 | 176 | 0.811 | 0.5 | 176 | 1.29 | 0.7 |
| Plasma Control 1 | 84 | 115 | 0.529 | 0.5 | 115 | 1.11 | 1.0 |
| Plasma Control 1 | 84 | 139 | 0.543 | 0.4 | 139 | 1.34 | 1.0 |
| Plasma 1 | 84 | 87.3 | 0.367 | 0.4 | 87.3 | 1.05 | 1.2 |
| Plasma 2 | 84 | 131 | 0.815 | 0.6 | 131 | 0.999 | 0.8 |
| Plasma 3 | 84 | 136 | 0.734 | 0.5 | 136 | 1.01 | 0.7 |
| Plasma 4 | 84 | 156 | 0.742 | 0.5 | 156 | 1.09 | 0.7 |
| Plasma 5 | 84 | 173 | 0.818 | 0.5 | 173 | 1.13 | 0.7 |
| Urine Control 1 | 84 | 81.1 | 0.380 | 0.5 | 81.1 | 1.17 | 1.4 |
| Urine Control 2 | 84 | 171 | 0.947 | 0.6 | 171 | 1.72 | 1.0 |
| Urine 1 | 84 | 27.0 | 0.295 | 1.1 | 26.1 | 1.20 | 4.6 |
| Urine 2 | 84 | 135 | 0.492 | 0.4 | 135 | 1.33 | 1.0 |
| Urine 3 | 84 | 111 | 0.432 | 0.4 | 111 | 1.02 | 0.9 |
| Urine 4 | 84 | 198 | 0.847 | 0.4 | 198 | 2.04 | 1.0 |
| Urine 5 | 84 | 237 | 1.02 | 0.4 | 237 | 2.84 | 1.2 |
Summary of Precision Results – ISE Indirect K for Gen.2
| Sample | N | Mean (mmol/L) | Repeatability | | Mean (mmol/L) | Within-Laboratory Precision | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD (mmol/L) | CV (%) | | SD (mmol/L) | CV (%) |
| Serum Control 1 | 84 | 3.65 | 0.0240 | 0.7 | 3.65 | 0.0553 | 1.5 |
| Serum Control 1 | 84 | 7.44 | 0.0405 | 0.5 | 7.48 | 0.0942 | 1.3 |
| Serum 1 | 84 | 1.76 | 0.0105 | 0.6 | 1.76 | 0.0556 | 3.2 |
| Serum 2 | 84 | 5.08 | 0.0279 | 0.6 | 5.12 | 0.0674 | 1.3 |
| Serum 3 | 84 | 3.64 | 0.0187 | 0.5 | 3.64 | 0.0432 | 1.2 |
| Serum 4 | 84 | 5.65 | 0.0286 | 0.5 | 5.65 | 0.0583 | 1.0 |
| Serum 5 | 84 | 9.70 | 0.0505 | 0.5 | 9.76 | 0.0815 | 0.8 |
| Plasma Control 1 | 84 | 3.62 | 0.0194 | 0.5 | 3.65 | 0.0556 | 1.5 |
| Plasma Control 1 | 84 | 7.44 | 0.0327 | 0.4 | 7.49 | 0.0947 | 1.3 |
| Plasma 1 | 84 | 1.69 | 0.0126 | 0.7 | 1.69 | 0.0592 | 3.5 |
| Plasma 2 | 84 | 5.56 | 0.0253 | 0.5 | 5.06 | 0.0561 | 1.1 |
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| Sample | N | Mean (mmol/L) | Repeatability | | Mean (mmol/L) | Within-Laboratory Precision | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD (mmol/L) | CV (%) | | SD (mmol/L) | CV (%) |
| Plasma 3 | 84 | 3.50 | 0.0221 | 0.6 | 3.52 | 0.0485 | 1.4 |
| Plasma 4 | 84 | 5.56 | 0.0253 | 0.5 | 5.56 | 0.0579 | 1.0 |
| Plasma 5 | 84 | 9.70 | 0.0527 | 0.5 | 9.77 | 0.0866 | 0.9 |
| Urine Control 1 | 84 | 30.3 | 0.208 | 0.7 | 30.3 | 0.597 | 2.0 |
| Urine Control 2 | 84 | 71.7 | 0.673 | 0.9 | 71.7 | 2.00 | 2.8 |
| Urine 1 | 84 | 3.51 | 0.0611 | 1.7 | 3.51 | 0.0611 | 1.7 |
| Urine 2 | 84 | 48.5 | 0.394 | 0.8 | 48.5 | 1.22 | 2.5 |
| Urine 3 | 84 | 29.3 | 0.239 | 0.8 | 29.3 | 0.510 | 1.7 |
| Urine 4 | 84 | 75.2 | 0.609 | 0.8 | 75.2 | 2.09 | 2.8 |
| Urine 5 | 84 | 88.3 | 0.772 | 0.9 | 88.3 | 2.67 | 3.0 |
Summary of Precision Results – ISE Indirect Cl for Gen.2
| Sample | N | Mean (mmol/L) | Repeatability | | Mean (mmol/L) | Within-Laboratory Precision | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD (mmol/L) | CV (%) | | SD (mmol/L) | CV (%) |
| Serum Control 1 | 84 | 85.9 | 0.560 | 0.7 | 85.9 | 1.21 | 1.4 |
| Serum Control 1 | 84 | 107 | 0.652 | 0.6 | 107 | 1.27 | 1.2 |
| Serum 1 | 84 | 68.0 | 0.322 | 0.5 | 68.0 | 1.07 | 1.6 |
| Serum 2 | 84 | 104 | 0.463 | 0.4 | 104 | 0.938 | 0.9 |
| Serum 3 | 84 | 97.8 | 0.461 | 0.5 | 97.8 | 0.935 | 1.0 |
| Serum 4 | 84 | 114 | 0.613 | 0.5 | 114 | 1.05 | 0.9 |
| Serum 5 | 84 | 138 | 0.651 | 0.5 | 138 | 1.11 | 0.8 |
| Plasma Control 1 | 84 | 86.2 | 0.454 | 0.5 | 85.9 | 1.20 | 1.4 |
| Plasma Control 1 | 84 | 107 | 0.455 | 0.4 | 107 | 1.34 | 1.3 |
| Plasma 1 | 84 | 65.0 | 0.301 | 0.5 | 65.2 | 1.20 | 1.8 |
| Plasma 2 | 84 | 101 | 0.632 | 0.6 | 101 | 1.07 | 1.1 |
| Plasma 3 | 84 | 94.5 | 0.541 | 0.6 | 94.4 | 1.02 | 1.1 |
| Plasma 4 | 84 | 110 | 0.497 | 0.5 | 110 | 1.14 | 1.0 |
| Plasma 5 | 84 | 135 | 0.735 | 0.5 | 135 | 1.28 | 0.9 |
| Urine Control 1 | 84 | 82.3 | 0.402 | 0.5 | 82.0 | 0.985 | 1.2 |
| Urine Control 2 | 84 | 193 | 1.14 | 0.6 | 193 | 2.12 | 1.1 |
| Urine 1 | 84 | 23.5 | 0.535 | 2.3 | 23.5 | 1.63 | 7.0 |
| Urine 2 | 84 | 132 | 0.571 | 0.4 | 132 | 1.33 | 1.0 |
| Urine 3 | 84 | 105 | 0.656 | 0.6 | 106 | 1.10 | 1.0 |
| Urine 4 | 84 | 201 | 0.925 | 0.5 | 202 | 2.01 | 1.0 |
| Urine 5 | 84 | 247 | 1.02 | 0.4 | 247 | 3.51 | 1.4 |
2. Linearity:
The linearity studies were conducted to demonstrate that measurements across the claimed measuring range for each parameter are linear. The studies were performed according to
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CLSI guideline EP06-Ed2. Testing for each sample type was completed with three reagent lots, in one run each, 4 replicates per sample on the candidate device. Dilution series (12 concentrations for each sample type) were prepared using human sample pools with analyte concentration above the upper limit of the linearity interval and human sample pools with analyte concentration below the lower limit of the linearity interval.
## ISE Indirect Na for Gen.2
The results demonstrated that the deviation from linearity did not exceed 0.4% for serum and plasma samples, and 0.6% for urine samples within the measuring range. Linear regression results are summarized in the table below.
| Sample | Linear Regression | Correlation Coefficient (r2) |
| --- | --- | --- |
| Serum | y = 1.0017x - 0.0971 | 1.0000 |
| Plasma | y = 1.0044x - 0.4425 | 1.0000 |
| Urine | y = 1.0013x + 0.0028 | 0.9999 |
## ISE Indirect K for Gen.2
The results demonstrated that the deviation from linearity did not exceed 1.5% for serum and plasma samples, and 10% for urine samples within the measuring range. Linear regression results are summarized in the table below.
| Sample | Linear Regression | Correlation Coefficient (r2) |
| --- | --- | --- |
| Serum | y = 0.9966x + 0.0146 | 0.9999 |
| Plasma | y = 1.0008x - 0.0118 | 1.0000 |
| Urine | y = 1.0429x + 0.2021 | 0.9991 |
## ISE Indirect Cl for Gen.2
The results demonstrated that the deviation from linearity did not exceed 0.4% for serum and plasma samples, and 2% for urine samples within the measuring range.
| Sample | Linear Regression | Correlation Coefficient (r2) |
| --- | --- | --- |
| Serum | y = 1.0009x - 0.3864 | 0.9999 |
| Plasma | y = 1.0032x - 0.6441 | 1.0000 |
| Urine | y = 0.9752x - 0.9047 | 0.9999 |
Results support the following measuring ranges:
- Serum/Plasma:
- Sodium: 80 - 180 mmol/L
- Potassium: 1.5 - 10.0 mmol/L
- Chloride: 60 - 140 mmol/L
- Urine:
- Sodium: 20 - 250 mmol/L
- Potassium: 3 - 100 mmol/L
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O Chloride: 20 - 250 mmol/L
## Dilution Recovery Studies
ISE indirect K for Gen. 2, ISE indirect Na for Gen. 2, and ISE indirect Cl for Gen. 2: A dilution study was performed by diluting five high concentration urine samples with water in a 1:46 ratio. The data support the 1:46 dilution claim in the Method Sheet.
## 3. Analytical Specificity/Interference:
### Endogenous Interference
The effects on quantitation of analyte in the presence of potentially interfering endogenous substances using the ISE indirect Na for Gen.2, ISE indirect K for Gen.2 and ISE indirect Cl for Gen.2 on the candidate device were determined using two levels of pooled human serum, plasma and urine. Sodium levels of approximately 112 and 148 mmol/L for serum and plasma and at 65 and 183 mmol/L for urine; potassium levels of approximately 3.4 and 6.4 mmol/L for serum and plasma and at 23 and 85 mmol/L for urine, and chloride levels of approximately 80 and 110 mmol/L for serum and plasma and at 66 and 191 mmol/L for urine were tested. Substances with ≤ 10% were considered to have no interference with the assay.
ISE Indirect Na for Gen.2
| Potential Interferent | | Highest Concentration Tested Without Significant Interference |
| --- | --- | --- |
| Serum and Plasma | Conjugated Bilirubin | 70 mg/dL |
| | Unconjugated Bilirubin | 77 mg/dL |
| | Hemolysis | 1771 mg/dL |
| | Lipemia | 2279 mg/dL |
| Urine | Hemolysis | 1227 mg/dL |
ISE Indirect K for Gen.2
| Potential Interferent | | Highest Concentration Tested Without Significant Interference |
| --- | --- | --- |
| Serum and Plasma | Conjugated Bilirubin | 70 mg/dL |
| | Unconjugated Bilirubin | 77 mg/dL |
| | Hemolysis | 23 mg/dL |
| | Lipemia | 2279 mg/dL |
| Urine | Hemolysis | 23 mg/dL |
ISE Indirect Cl for Gen.2
| Potential Interferent | | Highest Concentration Tested Without Significant Interference |
| --- | --- | --- |
| | Conjugated Bilirubin | 70 mg/dL |
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| Potential Interferent | | Highest Concentration Tested Without Significant Interference |
| --- | --- | --- |
| Serum and Plasma | Unconjugated Bilirubin | 77 mg/dL |
| | Hemolysis | 1771 mg/dL |
| | Lipemia | 2279 mg/dL |
| Urine | Hemolysis | 1227 mg/dL |
## Exogenous Interference
Exogenous drug Interference studies were conducted to evaluate drugs for potential interference with ISE indirect Na for Gen.2, ISE indirect K for Gen.2 and ISE indirect Cl for Gen.2 on the candidate device using human serum, plasma, and urine samples. Sodium levels of approximately 125 and 155 mmol/L for serum and plasma and at 30 and 195 mmol/L for urine; potassium levels of approximately 2.5 and 6.5 mmol/L for serum and plasma and at 19.5 and 78 mmol/L for urine, and chloride levels of approximately 86 and 117 mmol/L for serum and plasma and at 27 and 202 mmol/L for urine were tested. Substances with ≤ 10% bias were considered to have no interference with the assay.
| Potential Interferent | | Highest concentration tested that showed no interference (mg/L) |
| --- | --- | --- |
| Serum and Plasma | N-Acetylcysteine | 1660 |
| | Ampicillin-Na | 1000 |
| | Ascorbic acid | 300 |
| | Cyclosporine | 5 |
| | Cefoxitin | 2500 |
| | Heparin | 5000 |
| | Intralipid | 10000 |
| | Levodopa | 20 |
| | Methyldopa + 1.5 | 20 |
| | Metronidazole | 200 |
| | Phenylbutazone | 400 |
| | Doxycyclin | 50 |
| | Acetylsalicylic acid | 1000 |
| | Rifampicin | 60 |
| | Acetaminophen | 200 |
| | Ibuprofen | 500 |
| | Theophylline | 100 |
| Urine | Acetaminophen | 3000 |
| | N-Acetylcysteine | 10 |
| | Salicyluric acid | 6000 |
| | Ascorbic acid | 4000 |
| | Cefoxitin | 12000 |
| | Gentamycine sulfate | 400 |
| | Ibuprofen | 4000 |
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| Potential Interferent | | Highest concentration tested that showed no interference (mg/L) |
| --- | --- | --- |
| | Levodopa | 1000 |
| | Methyldopa | 2000 |
| | Ofloxacine | 900 |
| | Phenazopyridine | 300 |
| | Tetracycline | 300 |
## 4. Detection Limit and Assay Reportable Range:
The Limit of Blank (LoB), Limit of Detection (LoD) and Limit of Quantitation (LoQ) were determined in accordance with the CLSI EP17-A2 requirements.
The LoB of the ISE indirect Na for Gen.2, ISE indirect K for Gen.2 and ISE indirect Cl for Gen.2 on the cobas ISE neo analytical unit of cobas pro integrated solutions system were determined as the 95th percentile of measurements of blank samples. For determination of the LoB, one analyte-free sample was measured with three reagent lots in six runs, distributed over three days, 10 replicates per run, on one candidate device. In total, 60 determinations of analyte free samples were obtained. Data analysis was based on determination of the 95th percentile of the 60 measured values. In this design (n=60) the 95th percentile was the average of the 57th and 58th value.
The LoD of the ISE indirect Na for Gen.2, ISE indirect K for Gen.2 and ISE indirect Cl for Gen.2 on the cobas candidate device were determined as the lowest amount of analyte in a sample that can be detected with a 95% probability. Data analysis was based on determination of the 60 measured values of the five low analyte samples. For determination of the LoD, five samples with low analyte content were measured using three reagent lots with two-fold determination per run on one candidate device. Six runs distributed over ≥ three days on one instrument were performed. The LoD is defined as the concentration, at which there is a 95% probability that a sample contains analyte. $\mathrm{LoD} = \mathrm{LoB} + 1.653 \times \mathrm{SD}_{\text{total}}$.
The LoQ of the ISE indirect Na for Gen.2, ISE indirect K for Gen.2 and ISE indirect Cl for Gen.2 on the candidate device were determined as the lowest concentration of analyte which can be quantified with a total error of no more than 30%. For determination of the LoQ, five samples with low analyte concentration were measured using three reagent lots on one cobas ISE neo analytical unit. These samples were tested in two runs per day over three days, two replicates per run for each LoQ sample (n=12 per sample).
Detection limit results are summarized in the tables below.
| Sodium | |
| --- | --- |
| Limit of Blank | 5.70 mmol/L |
| Limit of Detection | 6.17 mmol/L |
| Limit of Quantitation | 14.5 mmol/L |
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| Potassium | |
| --- | --- |
| Limit of Blank | 0.195 mmol/L |
| Limit of Detection | 0.224 mmol/L |
| Limit of Quantitation | 0.891 mmol/L |
| Chloride | |
| --- | --- |
| Limit of Blank | 2.70 mmol/L |
| Limit of Detection | 3.42 mmol/L |
| Limit of Quantitation | 10.3 mmol/L |
5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
Traceability: All three assays are standardized against primary calibrators prepared gravimetrically from purified salts.
6. Assay Cut-Off:
Not applicable.
B Comparison Studies:
1. Method Comparison with Predicate Device:
Method Comparison experiments were performed for all sample types. Less than 12% of these samples were spiked or diluted to cover the measuring range. The results of the candidate device were compared to the results of the predicate device. Additionally, the results of the candidate device were compared against flame photometry (Sodium and Potassium) or coulometry (Chloride). The results were evaluated using Passing-Bablok. A summary of results is presented in the table below.
ISE indirect Na for Gen.2
| Candidate vs. | Sample Type | N | Sample Concentration Range (mmol/L) | Passing-Bablok Regression |
| --- | --- | --- | --- | --- |
| Flame photometer | Plasma | 118 | 79.5-177 | y = 0.967x + 5.07; r= 0.987 |
| Predicate | Plasma | 119 | 80.5-176 | y = 1.000x + 0.500; r= 0.999 |
| Flame photometer | Serum | 117 | 85.4-182 | y = 0.950x + 5.83; r= 0.989 |
| Predicate | Serum | 119 | 80.7-178 | y = 1.002x + 0.393; r= 0.999 |
| Flame photometer | Urine | 100 | 25.4-238 | y = 1.009x + 0.529; r= 0.999 |
| Predicate | Urine | 118 | 20.9-239 | y = 1.010x - 0.555; r= 1.000 |
ISE indirect K for Gen.2
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| Candidate vs. | Sample Type | N | Sample Concentration Range (mmol/L) | Passing-Bablok Regression |
| --- | --- | --- | --- | --- |
| Flame photometer | Plasma | 106 | 1.59-10.1 | y = 1.027x - 0.0254; r= 0.998 |
| Predicate | Plasma | 116 | 1.64-9.69 | y = 1.000x - 0.0400; r= 0.999 |
| Flame photometer | Serum | 101 | 1.59-9.69 | y = 1.009x + 0.0155; r= 0.998 |
| Predicate | Serum | 118 | 1.62-9.93 | y = 1.000x - 0.0400; r= 1.000 |
| Flame photometer | Urine | 106 | 3.20-95.6 | y = 1.042x - 0.0282; r= 0.999 |
| Predicate | Urine | 113 | 3.41-93.4 | y = 1.056x - 0.777; r= 1.000 |
ISE indirect Cl for Gen.2
| Candidate vs. | Sample Type | N | Sample Concentration Range (mmol/L) | Passing-Bablok Regression |
| --- | --- | --- | --- | --- |
| Coulometer | Plasma | 117 | 66.0-138 | y = 0.992x + 1.16; r= 0.988 |
| Predicate | Plasma | 119 | 62.4-137 | y = 1.010x + 0.152; r= 0.999 |
| Coulometer | Serum | 108 | 63.0-132 | y = 0.950x + 5.82; r= 0.986 |
| Predicate | Serum | 115 | 63.1-139 | y = 1.021x - 1.41; r= 0.998 |
| Coulometer | Urine | 117 | 21.0-240 | y = 1.033x - 3.12; r= 0.999 |
| Predicate | Urine | 118 | 22.6-248 | y = 1.004x - 1.20; r= 1.000 |
A method comparison study was also provided comparing Li-heparin plasma on flame photometry to the candidate device for potassium. The results supported the accuracy of potassium in lithium heparin samples.
2. Matrix Comparison:
To support the use of the ISE indirect Na for Gen.2 Test, ISE indirect K for Gen.2 Test, and ISE indirect Cl for Gen.2. Test on the candidate device with different sample matrices, a matrix comparison study was conducted by comparing values obtained from samples drawn into serum and plasma collection tubes. Two replicates were processed for each sample, the first replicate results were evaluated. The results were evaluated using Passing-Bablok regression analysis. A summary of results is presented in the table below.
| ISE indirect Na for Gen.2 | N | Slope | Intercept | Coefficient r |
| --- | --- | --- | --- | --- |
| Serum vs. Serum w/Gel Separation Tube | 106 | 1.009 | -1.41 | 0.995 |
| Serum vs. Li-Heparin Plasma | 104 | 1.00 | -0.300 | 0.998 |
| ISE indirect K for Gen.2 | N | Slope | Intercept | Coefficient r |
| --- | --- | --- | --- | --- |
| Serum vs. Serum w/Gel Separation Tube | 101 | 0.996 | 0.016 | 0.997 |
| ISE indirect Cl for Gen.2 | N | Slope | Intercept | Coefficient r |
| --- | --- | --- | --- | --- |
| Serum vs. Serum w/Gel Separation Tube | 102 | 1.000 | -0.050 | 0.991 |
| Serum vs. Li-Heparin Plasma | 100 | 0.997 | -0.014 | 0.995 |
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C Clinical Studies:
1. Clinical Sensitivity:
Not applicable.
2. Clinical Specificity:
Not applicable.
3. Clinical Cut-Off
Not applicable.
4. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):
D Expected Values/Reference Range:
The sponsor provides the following information for expected values in the labeling:
| Expected Values | | Reference Range | | |
| --- | --- | --- | --- | --- |
| Sample Type | | Sodium | Potassium | Chloride |
| Serum | Adults | 136-145 mmol/L | 3.5-5.1 mmol/L | 98-107 mmol/L |
| Plasma | Adults | 136-145 mmol/L | 3.4-4.5 mmol/L | 98-107 mmol/L |
| Urine | 24 hours | 40-220 mmol/24 h | 25-125 mmol/24 h | 110-250 mmol/24 h |
Reference: Tietz NW. Fundamentals of Clinical Chemistry, 5th ed. Burtis CA, Ashwood ER, eds. WB Saunders Co 2001:970,1004,1009.
E Other Supportive Instrument Performance Characteristics Data:
1. Carryover Study: Carryover studies was reviewed and found to be acceptable.
2. Electrical safety and electromagnetic compatibility (EMC) testing were performed, and the results were found to be acceptable.
3. Software and cybersecurity documentation was reviewed and found to be acceptable.
VIII Proposed Labeling:
The labeling supports the finding of substantial equivalence for this device.
IX Conclusion:
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The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
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