cobas u 601 urinalysis test system

{0} 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY AND INSTRUMENT COMBINATION TEMPLATE A. 510(k) Number: k183432 B. Purpose for Submission: New device C. Measurands: Measurement of the following in urine: pH, leukocytes, nitrite, protein, glucose, ketones, urobilinogen, bilirubin, erythrocytes, color, and clarity D. Types of Test: Qualitative and semi-quantitative urinalysis E. Applicant: Roche Diagnostics F. Proprietary and Established Names: cobas u 601 urinalysis test system G. Regulatory Information: | Regulation | Classification | Product Code | Panel | | --- | --- | --- | --- | | 21 CFR §862.1340 Urinary glucose (nonquantitative) test system | II | JIL | Chemistry (75) | | 21 CFR §864.6550 Occult blood test | II | JIO | Hematology (81) | | 21 CFR §862.1785 Urinary urobilinogen (non-quantitative) test system | I | CDM | Chemistry (75) | | 21 CFR §862.1550 Urinary pH (nonquantitative) test system | I | CEN | Chemistry (75) | 1 {1} | Regulation | Classification | Product Code | Panel | | --- | --- | --- | --- | | 21 CFR §862.1435 Ketones (nonquantitative) test system | I | JIN | Chemistry (75) | | 21 CFR §862.1645 Urinary protein or albumin (nonquantitative) test system | I | JIR | Chemistry (75) | | 21 CFR §862.1115 Urinary bilirubin and its conjugates (nonquantitative) test system | I | JJB | Chemistry (75) | | 21 CFR §862.1510 Nitrite (nonquantitative) test system | I | JMT | Chemistry (75) | | 21 CFR §864.7675 Leukocyte peroxidase test | I | LJX | Hematology (81) | | 21 CFR §862.2900 Automated urinalysis system | I | KQO | Chemistry (75) | H. Intended Use: 1. Intended use: See indications for use. 2. Indications for use: The cobas u 601 urinalysis test system is comprised of the cobas u 601 urine analyzer and the cobas u pack. The cobas u 601 urine analyzer when used with the cobas u pack is a fully automated urinalysis system intended for the in vitro qualitative or semi-quantitative determination of urine analytes, including pH, leukocytes, nitrite, protein, glucose, ketones, urobilinogen, bilirubin, color, and erythrocytes, as well as clarity. These measurements are useful in the evaluation of renal, urinary, hepatic and metabolic disorders. This system is intended to be used by trained operators in clinical laboratories. The cobas u pack is a cassette loaded with cobas u 601 test strips for the in vitro qualitative or semi-quantitative determination of pH, leukocytes, nitrite, protein, glucose, ketones, urobilinogen, bilirubin, color, and erythrocytes in urine with the cobas u 601 urine analyzer. These measurements are useful in the evaluation of renal, urinary, hepatic and metabolic disorders. 3. Special conditions for use statement(s): Prescription use only The test strips are not for visual readings. {2} 4. Special instrument requirements: cobas u 601 urine analyzer I. Device Description: The cobas u 601 urinalysis test system is comprised of the cobas u 601 urine analyzer and the cobas u pack. The cobas u pack is a cassette which holds 400 test strips. Each cassette is identified by a unique radio frequency identification (RFID) tag. The RFID tag also contains information on expiration date and lot number. The cobas u 601 urine analyzer is a fully automated urine analysis system. The cobas u 601 analyzer consists of several major components: computer, rack transport system, liquid handling system, test strip cassette compartment, automated test strip processing area, test strip reflectance measuring unit, and physical measurement cell (PMC) for clarity and specific gravity. J. Substantial Equivalence Information: 1. Predicate device name: Cobas u 411 Test System 2. Predicate 510(k) number: k093555 3. Comparison with predicate: | Similarities and Differences | | | | --- | --- | --- | | Item | Candidate Device cobas u 601 urinalysis test system k183432 | Predicate Device Cobas u 411 Test System k093555 | | Intended use | For qualitative and semi-quantitative determination of pH, leukocytes, nitrite, protein, glucose, ketones, urobilinogen, bilirubin, color and erythrocytes in urine | Same | | Specimen type | Urine | Same | | Test strips | Cassette which holds 400 cobas u 601 Test Strips | Chemstrip 10 UA test strip | | Urine application | Automated dispense of urine onto each pad of test strip | Test strip manually dipped into urine sample | {3} K. Standard/Guidance Document Referenced: IEC 61010-1 Edition 3.0 2010-06 Safety requirements for electrical equipment for measurement, control, and laboratory use - Part 1: General requirements. L. Test Principles: cobas u pack pH: Color indicator method using methyl red, phenolphthalein and bromothymol blue. Leukocytes: The test reveals the presence of granulocyte esterases. The esterases cleave an indoxyl ester, and the indoxyl reacts with a diazonium salt to produce a violet dye. Nitrite: The test is based on the principle of the Griess test and is specific for nitrite. Nitrite reacts with an aromatic amine to give a diazonium salt, which by coupling with a further compound yields a red-violet azo dye. Protein: The detection of protein is based on the protein error of pH indicators method. When pH is held constant by a buffer, indicator dye (3',3",5',5"-tetrachlorophenol-3,4,5,6-tetrabromosulfophthalein) releases H⁺ ions based on the amount of protein present and change color from yellow to light green. Glucose: The glucose determination is based on the specific glucose-oxidase/peroxidase reaction. The reaction utilizes the glucose oxidase to catalyze the formation of gluconic acid and hydrogen peroxide from the oxidation of glucose. A second enzyme, peroxidase, catalyzes the reaction of hydrogen peroxide with the chromogen tetramethylbenzidine to form a green dye complex. Ketones: The detection of ketones in urine is based on a method where sodium nitroprusside and glycine react with acetoacetate and acetone in an alkaline medium to form a violet dye complex. Urobilinogen: Urobilinogen is coupled with 4-methoxybenzene-diazonium-tetrafluoroborate in an acid medium to form a red azo dye. Bilirubin: The detection of bilirubin is based on the coupling reaction of a diazonium salt of 2,6-dichlorobenzene-diazonium-tetrafluoroborate with bilirubin in an acid medium. The reaction yields a pink to red-violet color proportional to the total bilirubin concentration. Erythrocytes: The chemical detection of blood is based on the pseudo-peroxidase action of erythrocytes and hemoglobin. Hemoglobin and myoglobin, if present, catalyze the oxidation of the indicator by the organic peroxide to give a blue-green coloration. Intact erythrocytes are hemolyze on the test paper and liberate hemoglobin which produces a green dot. Scattered or compacted green dots on the yellow test paper are indicative of intact 4 {4} erythrocytes. A uniform green coloration of the test is indicative of free hemoglobin, myoglobin, or hemolyzed erythrocytes in the urine. Color: Urine color is measured in a white area on the test strip which is not impregnated with reagents. Urine color is reported as Pale Yellow, Yellow, Amber, Orange, Brown, Red, Green, or other. The urine color measurement is also used in this urinalysis system for a color correction algorithm to compensate for intrinsically colored urine samples when testing for Leukocytes, Nitrite, Glucose, Ketone bodies, Urobilinogen, Bilirubin, and Erythrocytes. The measurements of protein and pH are not compensated for urine color. cobas u 601 urine analyzer The analyzer photometer conducts reflectance measurements on each pad of the test strip. The analyzer PMC measures urine clarity and specific gravity. ## M. Performance Characteristics: ### 1. Analytical performance: #### a. Precision/Reproducibility: ##### All test strip analytes ###### Repeatability A repeatability study of the cobas u 601 urinalysis test system was conducted for the analytes measured from the test strip. Three controls and two human urine samples were used in the study. Control samples and human urine samples were measured in 2 runs with 21 replicates per run for a total of n=42 results per sample. A low positive control was measured in 1 run with 21 replicates. Control Level 1 | Analyte | Run 1 | | | Run 2 | | | | --- | --- | --- | --- | --- | --- | --- | | | Result | Exact Agreement (%) | Agreement ± 1 block (%) | Result | Exact Agreement (%) | Agreement ± 1 block (%) | | Bilirubin | Negative | 100 | 100 | Negative | 100 | 100 | | Erythrocytes | Negative | 100 | 100 | Negative | 100 | 100 | | Ketones | Negative | 100 | 100 | Negative | 100 | 100 | | Glucose | Normal | 100 | 100 | Normal | 100 | 100 | | Leukocytes | Negative | 100 | 100 | Negative | 100 | 100 | | Nitrite | Negative | 100 | 100 | Negative | 100 | 100 | | Protein | Negative | 100 | 100 | Negative | 100 | 100 | | Urobilinogen | Normal | 100 | 100 | Normal | 100 | 100 | | Color | Yellow | 100 | 100 | Yellow | 100 | 100 | | pH | 6 | 100 | 100 | 6 | 100 | 100 | {5} Control Level 2 | Analyte | Run 1 | | | Run 2 | | | | --- | --- | --- | --- | --- | --- | --- | | | Result | Exact Agreement (%) | Agreement ± 1 block (%) | Result | Exact Agreement (%) | Agreement ± 1 block (%) | | Bilirubin | 6 mg/dL | 100 | 100 | 6 mg/dL | 100 | 100 | | Erythrocytes | 250 Ery/μL | 100 | 100 | 250 Ery/μL | 100 | 100 | | Ketones | 150 mg/dL | 100 | 100 | 150 mg/dL | 100 | 100 | | Glucose | 1000 mg/dL | 100 | 100 | 1000 mg/dL | 100 | 100 | | Leukocytes | 500 Leu/μL | 100 | 100 | 500 Leu/μL | 100 | 100 | | Nitrite | Positive | 100 | 100 | Positive | 100 | 100 | | Protein | 100 mg/dL | 100 | 100 | 100 mg/dL | 100 | 100 | | Urobilinogen | 8 mg/dL | 100 | 100 | 8 mg/dL | 100 | 100 | | Color | Brown | 100 | 100 | Brown | 100 | 100 | | pH | 7 | 100 | 100 | 7 | 100 | 100 | Control Low positive | Analyte | Run 1 | | | | --- | --- | --- | --- | | | Result | Exact Agreement (%) | Agreement ± 1 block (%) | | Bilirubin | 1 mg/dL | 100 | 100 | | Erythrocytes | 10 Ery/μL | 100 | 100 | | Ketones | 5 mg/dL | 100 | 100 | | Glucose | 50 mg/dL | 100 | 100 | | Leukocytes | 25 Leu/μL | 100 | 100 | | Protein | 15 mg/dL | 100 | 100 | | Urobilinogen | 1 mg/dL | 100 | 100 | | Color | Amber | 100 | 100 | | pH | 6 | 100 | 100 | {6} Human Urine, Negative / Normal | Analyte | Run 1 | | | Run 2 | | | | --- | --- | --- | --- | --- | --- | --- | | | Result | Exact Agreement (%) | Agreement ± 1 block (%) | Result | Exact Agreement (%) | Agreement ± 1 block (%) | | Bilirubin | Negative | 100 | 100 | Negative | 100 | 100 | | Erythrocytes | Negative | 100 | 100 | Negative | 100 | 100 | | Ketones | Negative | 100 | 100 | Negative | 100 | 100 | | Glucose | Normal | 100 | 100 | Normal | 100 | 100 | | Leukocytes | Negative | 100 | 100 | Negative | 100 | 100 | | Nitrite | Negative | 100 | 100 | Negative | 100 | 100 | | Protein | Negative | 100 | 100 | Negative | 100 | 100 | | Urobilinogen | Normal | 100 | 100 | Normal | 100 | 100 | | Color | Yellow | 100 | 100 | Yellow | 100 | 100 | | pH | 6.5 | 90.5 | 100 | 6.5 | 100 | 100 | Human Urine, Positive | Analyte | Run 1 | | | Run 2 | | | | --- | --- | --- | --- | --- | --- | --- | | | Result | Exact Agreement (%) | Agreement ± 1 block (%) | Result | Exact Agreement (%) | Agreement ± 1 block (%) | | Bilirubin | 3 mg/dL | 100 | 100 | 3 mg/dL | 100 | 100 | | Erythrocytes | 250 Ery/μL | 100 | 100 | 250 Ery/μL | 100 | 100 | | Ketones | 50 mg/dL | 100 | 100 | 50 mg/dL | 100 | 100 | | Glucose | 1000 mg/dL | 100 | 100 | 1000 mg/dL | 100 | 100 | | Leukocytes | 500 Leu/μL | 100 | 100 | 500 Leu/μL | 100 | 100 | | Nitrite | Positive | 100 | 100 | Positive | 100 | 100 | | Protein | 100 mg/dL | 100 | 100 | 100 mg/dL | 100 | 100 | | Urobilinogen | 4 mg/dL | 95.2 | 100 | 4 mg/dL | 95.2 | 100 | | Color | Amber | 100 | 100 | Orange | 100 | 100 | | pH | 9 | 100 | 100 | 8 | 100 | 100 | Within-laboratory precision A within-laboratory precision study of the cobas u 601 urinalysis test system was conducted for the analytes measured from the test strip. Three controls and two human urine samples were used in the study. For each analyte three controls with different concentrations were measured over 21 days with 2 runs per day, and 2 replicates per run for a total of $n = 84$ results per sample. The result are given below. {7} Control level 1 | Analyte | Result | Exact Agreement (%) | Agreement ± 1 block (%) | | --- | --- | --- | --- | | Bilirubin | Negative | 100 | 100 | | Erythrocytes | Negative | 100 | 100 | | Ketones | Negative | 100 | 100 | | Glucose | Normal | 100 | 100 | | Leukocytes | Negative | 100 | 100 | | Nitrite | Negative | 100 | 100 | | Protein | Negative | 100 | 100 | | Urobilinogen | Normal | 100 | 100 | | Color | yellow | 100 | 100 | | pH | 6 | 100 | 100 | Control level 2 | Analyte | Result | Exact Agreement (%) | Agreement ± 1 block (%) | | --- | --- | --- | --- | | Bilirubin | 6 mg/dL | 100 | 100 | | Erythrocytes | 250 Ery/μL | 100 | 100 | | Ketones | 150 mg/dL | 100 | 100 | | Glucose | 1000 mg/dL | 100 | 100 | | Leukocytes | 500 Leu/μL | 95.2 | 100 | | Nitrite | Positive | 100 | 100 | | Protein | 100 mg/dL | 100 | 100 | | Urobilinogen | 8 mg/dL | 100 | 100 | | Color | Brown | 100 | 100 | | pH | 7 | 100 | 100 | Control low positive | Analyte | Result | Exact Agreement (%) | Agreement ± 1 block (%) | | --- | --- | --- | --- | | Bilirubin | 1 mg/dL | 100 | 100 | | Erythrocytes | 10 Ery/μL | 97.6 | 100 | | Ketones | 5 mg/dL | 100 | 100 | | Glucose | 50 mg/dL | 100 | 100 | | Leukocytes | 25 Leu/μL | 98.8 | 100 | | Protein | 15 mg/dL | 100 | 100 | | Urobilinogen | 1 mg/dL | 100 | 100 | | Color | Amber | 100 | 100 | {8} 9 # Urine Clarity ## Repeatability A repeatability study of the cobas u 601 urinalysis test system was conducted for the analyzer measured parameter of clarity. For the study, there were two controls and three human urine samples measured in 2 runs with 21 replicates per run for a total of n=42 results per control. Human urine samples were measured in 1 run with 21 replicates. The results are given as follows. | Sample | Result | Exact agreement (%) | Agreement ± 1 block (%) | | --- | --- | --- | --- | | Control 1 | Clear | 100 | 100 | | Control 2 | Clear | 100 | 100 | | Human urine sample | Light turbid | 100 | 100 | | Human urine sample | Turbid | 100 | 100 | | Human urine sample | Clear | 100 | 100 | ## Within-laboratory precision A within-laboratory precision study was conducted for the analyzer measured parameter of clarity. Two control samples were measured over 21 days with 2 runs per day and 2 replicates per run for a total of n = 84 results per control sample. | Sample | Result | Exact agreement (%) | Agreement ± 1 block (%) | | --- | --- | --- | --- | | Control level 1 | Clear | 100 | 100 | | Control level 2 | Clear | 100 | 100 | ## b. Linearity/assay reportable range: A study was conducted to evaluate the assay reportable range for each analyte of the cobas u pack and clarity. The reportable range was evaluated by measuring samples with known concentrations, and known clarity covering all measurement blocks. Samples were measured using 3 lots of cobas u pack cassettes and 3 analyzers in replicates of 21 per lot/analyzers for a total of 63 measurements per sample. The results are summarized below: | pH | | | | | --- | --- | --- | --- | | Test pH | Output | Exact match | ±1 color block match | | 5.0 | 5.0 | 100% | 100% | | 6.0 | 6.0 | 100% | 100% | | 6.5 | 6.5 | 100% | 100% | | 7.0 | 7.0 | 100% | 100% | | 8.0 | 8.0 | 100% | 100% | | 9.0 | 9.0 | 100% | 100% | {9} | Glucose | | | | | --- | --- | --- | --- | | Test concentration (mg/dL) | Output (mg/dL) | Exact match | ±1 color block match | | 0 | norm (norm) | 100% | 100% | | 45 | 50 (1+) | 100% | 100% | | 120 | 100 (2+) | 100% | 100% | | 250 | 250 (3+) | 100% | 100% | | 650 | 1000 (4+) | 100% | 100% | | Protein | | | | | --- | --- | --- | --- | | Test concentration (mg/dL) | Output (mg/dL) | Exact match | ±1 color block match | | 0 | neg (neg) | 100% | 100% | | 10 | 15 (1+) | 95% | 100% | | 25 | 30 (2+) | 100% | 100% | | 100 | 100 (3+) | 100% | 100% | | 400 | 500 (4+) | 100% | 100% | | Bilirubin | | | | | --- | --- | --- | --- | | Test concentration (mg/dL) | Output (mg/dL) | Exact match | ±1 color block match | | 0 | neg (neg) | 100% | 100% | | 1 | 1 (1+) | 100% | 100% | | 2 | 3 (2+) | 100% | 100% | | 6 | 6 (3+) | 100% | 100% | | Urobilinogen | | | | | --- | --- | --- | --- | | Test concentration (mg/dL) | Output (mg/dL) | Exact match | ±1 color block match | | 0 | norm (norm) | 100% | 100% | | 1.3 | 1 (1+) | 100% | 100% | | 3 | 4 (2+) | 100% | 100% | | 7 | 8 (3+) | 100% | 100% | | 12 | 12 (4+) | 99% | 100% | {10} | Erythrocytes | | | | | --- | --- | --- | --- | | Test concentration (ERY/μL) | Output (ERY/μL) | Exact match | ±1 color block match | | 0 | neg (neg) | 100% | 100% | | 10 | 10 (1+) | 100% | 100% | | 20 | 25 (2+) | 100% | 100% | | 40 | 50 (3+) | 100% | 100% | | 100 | 150 (4+) | 100% | 100% | | 400 | 250 (5+) | 100% | 100% | | Ketone | | | | | --- | --- | --- | --- | | Test concentration (mg/dL) | Output (mg/dL) | Exact match | ±1 color block match | | 0 | neg (neg) | 100% | 100% | | 5.5 | 5 (1+) | 100% | 100% | | 14 | 15 (2+) | 100% | 100% | | 45 | 50 (3+) | 100% | 100% | | 100 | 150 (4+) | 100% | 100% | | Nitrite | | | | | --- | --- | --- | --- | | Test concentration (mg/dL) | Output | Exact match | ±1 color block match | | 0 | neg | 100% | 100% | | 0.06 | pos | 100% | 100% | | Leukocytes | | | | | --- | --- | --- | --- | | Test concentration (Leu/μL) | Output (Leu/μL) | Exact match | ±1 color block match | | neg | neg (neg) | 100% | 100% | | 23 | 25 (1+) | 95% | 100% | | 112 | 100 (2+) | 99% | 100% | | 450 | 500 (3+) | 95% | 100% | | Clarity | | | | | --- | --- | --- | --- | | Test condition | Output | Exact match | ±1 color block match | | clear | clear | 100% | 100% | | light turbid | light turbid | 100% | 100% | | turbid | turbid | 100% | 100% | {11} The results of the assay reportable range studies support the following measurement ranges on the cobas u 601 urinalysis test system: | Analyte | Measurement range | | --- | --- | | pH | semi-quantitative: 5, 6, 6.5, 7, 8, 9 | | Erythrocytes | semi-quantitative: NEG, 10, 25, 50, 150, 250 Ery/μL qualitative: NEG, 1+, 2+, 3+, 4+ 5+ | | Leukocytes | semi-quantitative: NEG, 25, 100, 500 Leu/μL qualitative: NEG, 1+, 2+, 3+ | | Nitrite | qualitative: NEG, POS | | Protein | semi-quantitative: NEG, 15, 30, 100, 500 mg/dL qualitative: NEG, 1+, 2+, 3+, 4+ | | Glucose | semi-quantitative: NORM, 50, 100, 250, 1000 mg/dL qualitative: NEG, 1+, 2+, 3+, 4+ | | Ketones | semi-quantitative: NEG, 5, 15, 50, 150 mg/dL qualitative: NEG, 1+, 2+, 3+, 4+ | | Urobilinogen | semi-quantitative: NORM, 1, 4, 8, 12 mg/dL qualitative: NEG, 1+, 2+, 3+, 4+ | | Bilirubin | semi-quantitative: NEG, 1, 3, 6 mg/dL qualitative: NEG, 1+, 2+, 3+ | | Color | pale yellow, yellow, amber, brown, orange, red, green, other | | Clarity | clear, light turbid, turbid | c. Traceability, Stability, Expected values (controls, calibrators, or methods): Traceability The sponsor did not describe any traceability for the test system. d. Detection limit: Study 1 - Analytical sensitivity: The detection limit for each analyte on the test strip was established in an analytical sensitivity study which measured for each analyte the concentration which transitioned the lowest measurement block (negative or normal) to the next level measurement block (positive). The sponsor defined analytical sensitivity as the lowest analyte concentration where $\geq 90\%$ of the measurement results were positive. In the study, a negative native urine pool was spiked with the analyte to 5 to 7 concentration levels. Each concentration level was measured in replicates of 20 on each of the three analyzers using three lots of cobas u pack for a total of $n = 2820$ measurements across all analytes. The results are summarized in the following table: {12} 13 | Analyte | Analytical Sensitivity | | --- | --- | | Leukocytes (Subtilisin) | 10 Leu/μL | | Nitrite | 0.045 mg/dL | | Protein (albumin) | 9 mg/dL | | Glucose | 25 mg/dL | | Ketones (acetoacetate) | 4 mg/dL | | Bilirubin | 0.6 mg/dL | | Urobilinogen | 1.15 mg/dL | | Erythrocytes | 7 Ery/μL | ## Study 2 – Measurement block cut-off: Transition points studies were performed with the cobas u 601 urinalysis test system to determine the cut-off concentration between each semi-quantitative block. The cut-off concentration was defined as the lowest sample concentration at which $\geq 55\%$ of the test results are positive with respect to the transited from block. Samples were prepared from native negative urine spiked with the analyte to 5 concentrations spanning the expected cut-off concentration. Each concentration level was measured in replicates of 20 on each of the three analyzers using three lots of cobas u pack. The cut-off concentration between each measurement block is summarized in the table below where the block output is the transitioned to block. | pH | | | | --- | --- | --- | | Block output | Cut-off | % Positive | | 6.0 | 5.7 | 100% | | 6.5 | 6.2 | 100% | | 7.0 | 6.5 | 98% | | 8.0 | 7.2 | 68% | | 9.0 | 8.5 | 88% | | Glucose | | | | --- | --- | --- | | Block output | Cut-off, mg/dL | % Positive | | 100 (2+) | 60 | 100% | | 250 (3+) | 200 | 100% | | 1000 (4+) | 550 | 100% | | Protein | | | | --- | --- | --- | | Block output | Cut-off, mg/dL | % Positive | | 30 (2+) | 14.5 | 88% | | 100 (3+) | 45 | 95% | | 500 (4+) | 280 | 83% | {13} | Bilirubin | | | | --- | --- | --- | | Block output | Cut-off, mg/dL | % Positive | | 3 (2+) | 1.35 | 97% | | 6 (3+) | 2.75 | 82% | | Urobilinogen | | | | --- | --- | --- | | Block output | Cut-off, mg/dL | % Positive | | 4 (2+) | 1.85 | 85% | | 8 (3+) | 4.5 | 92% | | 12 (4+) | 9.5 | 100% | | Erythrocytes | | | | --- | --- | --- | | Block output | Cut-off, mg/dL | % Positive | | 25 (2+) | 12 | 75% | | 50 (3+) | 30 | 67% | | 150 (4+) | 110 | 70% | | 250 (5+) | 290 | 72% | | Ketones | | | | --- | --- | --- | | Block output | Cut-off, mg/dL | % Positive | | 15 (2+) | 8 | 93% | | 50 (3+) | 20 | 95% | | 150 (4+) | 62.5 | 82% | | Leukocytes | | | | --- | --- | --- | | Block output | Cut-off, mg/dL | % Positive | | 100 (2+) | 88 | 98% | | 500 (3+) | 400 | 83% | # e. Analytical specificity: Analytical specificity studies were conducted to assess for interfering effects of endogenous substances and therapeutic drugs on the cobas u 601 urinalysis test system (except color and clarity). In the study, samples were prepared from pooled analyte negative urine at two levels for each analyte (except pH which was tested at one normal level): (1) negative/normal range and (2) first positive range. Each of these samples was further aliquoted into three. Two of these were spiked at two different concentrations of interfering substance. A third aliquot was used as a reference without interfering substance. For therapeutic drug substances, the highest concentration tested was approximately 5 times the maximal daily dosage. For endogenous substances the highest concentration tested was approximately 5 times the highest pathological level. Each sample aliquot was tested in replicates of 10 across 2 analyzers and 2 cobas u pack lots. The sponsor defined no significant {14} interference if ≥90% (≥9 of 10 replicates) of the results were found in the correct block and 100% of results are within +/- 1 block of the correct block. No significant interference was observed for the following substances at that concentration, with certain exceptions as noted below: | Substance | Highest concentration at which no interference was observed unless noted below*** | | --- | --- | | **Therapeutic drugs** | | | Acetaminophen | 300 mg/dL | | Amoxicillin | 1333 mg/dL | | Ascorbic acid | 400 mg/dL | | Biotin | 100 mg/dL | | Cefoxitin | 1200 mg/dL | | Furosemide | 200 mg/dL | | Gabapentin | 1200 mg/dL | | Gentamycin Sulfate | 40 mg/dL | | Ibuprofen | 250 mg/dL | | Levodopa | 125 mg/dL | | Lisinopril | 27 mg/dL | | Metformin | 850 mg/dL | | Methyldopa | 200 mg/dL | | Methenamine + Methylene blue | 400 + 66.5 mg/dL | | N-Acetylcysteine | 20 mg/dL | | Ofloxacin | 90 mg/dL | | Phenazopyridine | 30 mg/dL | | Salicyluric acid | 600 mg/dL | | Tetracycline | 50 mg/dL | | **Endogenous substances** | | | 3-Hydroxybutyrate | 450 mg/dL | | Ammonium chloride | 2500 mg/dL | | Bilirubin conjugate | 80 mg/dL | | Calcium chloride | 300 mg/dL | | Creatinine | 1500 mg/dL | | Glucose | 10,000 mg/dL | | Lysed erythrocytes as hemoglobin | 83 mg/dL | | human IgG | 500 mg/dL | | Nitrite | 11 mg/dL | | Urea | 20,000 mg/dL | | Uric acid | 155mg/dL | | Urobilinogen | 300 mg/dL | *** Not all of the substances tested for interference demonstrated no significant interference for all analytes. For those substances that on initial screening where found to interfere with certain analytes, dose response testing was conducted to {15} establish the concentration limit below which no significant interference is expected. The results are given in the table below: | Analyte | Substance | Concentration limit with no significant interference | Effect when above the concentration limit | | --- | --- | --- | --- | | Urobilinogen | Acetaminophen | 24 mg/dL | At 42 mg/dL elevated from 1+ to 2+ | | | Bilirubin | 40 mg/dL | At 60 mg/dL decreased from 1+ to normal | | | Gabapentin | 1080 mg/dL | At 1200 mg/dL decreased from 1+ to normal | | | Methenamine + Methylene blue | 2.4 + 0.4 mg/dL | At 6.7 + 40 mg/dL elevated from 1+ to 2+ | | | Phenazopyridine | 12 mg/dL | At 30 mg/dL elevated from normal to 1+ and at 24 mg/dL elevated from 1+ to 2 | | | Nitrite | 0.7 mg/dL | At 1.4 mg/dL decreased from 1+ to normal | | Leukocytes | Amoxicillin | 1067 mg/dL | At 1200 mg/dL decrease from 1+ to negative | | | Bilirubin | 40 mg/dL | At 80 mg/dL increase from negative to 1+ | | | Ibuprofen | 20 mg/dL | At 125 mg/dL decreased from 1+ to negative | | | Methenamine + Methylene blue | 4 + 0.67 mg/dL | At 6.7 + 40 mg/dL elevated from negative to 1+ and at 6.7 + 40 mg/dL elevated from 1+ to 2+ | | | Calcium chloride | 243 mg/dL | At 300 mg/dL decreased from 1+ to negative | | | Glucose | 1000 mg/dL | At 2000 mg/dL decreased from 1+ to negative | | | Lysed erythrocytes as hemoglobin | 75 mg/dL | At 83 mg/dL increase from negative to 1+ | {16} | | Urobilinogen | 12 mg/dL | At 300 mg/dL elevated from 1+ to 2+ | | --- | --- | --- | --- | | Erythrocytes | Ascorbic Acid | 75 mg/dL | At 112 mg/dL decrease from 1+ to negative | | | Furosemide | 180 mg/dL | At 200 mg/dL decrease from 1+ to negative | | | Ibuprofen | 75 mg/dL | At 125 mg/dL decreased from 1+ to negative | | | Levodopa | 62 mg/dL | At 94 mg/dL elevated from negative to 1+ and elevated from 1+ to 2+ | | | Methyldopa | 80 mg/dL | At 200 mg/dL elevated from negative to 1+ and at 120 mg/dL elevated from 1+ to 2+ | | | Methenamine + Methylene blue | 0.8 + 0.13 mg/dL | At 2.7 + 16 mg/dL elevated from 1+ to 2+ | | | Calcium chloride | 243 mg/dL | At 300 mg/dL elevated from negative to 1+ | | | Nitrite | 4 mg/dL | At 8 mg/dL decreased from 1+ to negative | | | Urobilinogen | 48 mg/dL | At 120 mg/dL elevated from negative to positive and at 300 mg/dL elevated from 1+ to 2+ | | Nitrite | Ascorbic Acid | 150 mg/dL | At 200 mg/dL decreased from positive to negative | | | Bilirubin | 40 mg/dL | At 80 mg/dL decreased from positive to negative | | | Methenamine + Methylene blue | 2.8 + 0.47 mg/dL | At 6.7 + 40 mg/dL elevated from negative to positive | | | Phenazopyridine | 12 mg/dL | At 30 mg/dL elevated from negative to positive | | | Urobilinogen | 9 mg/dL | At 10 mg/dL elevated from negative to positive | | Glucose | Ascorbic Acid | 20 mg/dL | At 40 mg/dL decreased from 1+ to normal | {17} | | Bilirubin | 40 mg/dL | At 80 mg/dL decreased from 1+ to normal | | --- | --- | --- | --- | | | Methenamine + Methylene blue | 12 + 2 mg/dL | At 6.7 + 40 mg/dL decreased from 1+ to normal | | | Ammonium chloride | 1030 mg/dL | At 1520 mg/dL decreased from 1+ to normal | | | Urea | 8900 mg/dL | At 1260 mg/dL decreased from 1+ to normal | | | Urobilinogen | 125 mg/dL | At 300 mg/dL mg/dL decreased from 1+ to normal | | Bilirubin | Ascorbic Acid | 200 mg/dL | At 40 mg/dL decreased from 1+ to negative | | | Biotin | 80 mg/dL | At 100 mg/dL elevated from 1+ to 2+ | | | Methenamine + Methylene blue | 14 + 2.33 mg/dL | At 6.7 + 40 mg/dL decreased from 1+ to negative | | | Phenazopyridine | 12 mg/dL | At 30 mg/dL elevated from negative to 1+ and at 24 mg/dL elevated from 1+ to 2 | | | Nitrite | 0.7 mg/dL | At 1.4 mg/dL decreased from 1+ to negative | | | Urobilinogen | 6 mg/dL | At 12 mg/dL increased from negative to 2+ and 7 mg/dL increased from 1+ to 2+ | | Protein | Bilirubin | 40 mg/dL | At 60 mg/dL increase from negative to 1+ | | | Gabapentin | 240 mg/dL | At 360 mg/dL elevated from 1+ to 2+ | | | Ibuprofen | 225 | At 125 mg/dL decreased from 1+ to negative | | | Methenamine + Methylene blue | 0.4 + 0.067 mg/dL | At 6.7 + 40 mg/dL elevated from 1+ to 2+ | | | Phenazopyridine | 12 mg/dL | At 30 mg/dL elevated from negative to 1+ and at 24 mg/dL elevated from 1+ to 2+ | 18 {18} | | Ammonium chloride | 172 mg/dL | At 500 mg/dL decreased from 1+ to negative | | --- | --- | --- | --- | | | Calcium chloride | 243 mg/dL | At 300 mg/dL decreased from 1+ to negative | | | Creatinine | 285 mg/dL | At 1500 mg/dL elevated from negative to 1+ and at 420 mg/dL elevated from 1+ to 2+ | | | Lysed erythrocytes as hemoglobin | 6.6 mg/dL | At 30 mg/dL elevated from negative to 1+ and at 13 mg/dL elevated from 1+ to 2+ | | | Urea | 5200 mg/dL | At 8900 mg/dL elevated from negative to 1+ and at 8900 mg/dL elevated from 1+ to 2+ | | | Urobilinogen | 12 mg/dL | At 300 mg/dL elevated from negative to 1+ and at 300 mg/dL elevated from 1+ to 2+ | | Ketones | Bilirubin | 40 mg/dL | At 80 mg/dL decrease from 1+ to negative | | | Levodopa | 62 mg/dL | At 94 mg/dL elevated from 1+ to 2+ | | | Methyldopa | 120 mg/dL | At 200 mg/dL elevated from negative to 1+ and 160 mg/dL elevated from 1+ to 2+ | | | Methenamine + Methylene blue | 16 + 2.7 mg/dL | At 6.7 + 40 mg/dL decreased from 1+ to negative | | | N-Acetylcysteine | 3 mg/dL | At 10 mg/dL elevated from negative to 1+ and at 5 mg/dL elevated from 1+ to 2+ positive | | | Urobilinogen | 90 mg/dL | At 300 mg/dL decreased from 1+ to negative | {19} 20 ## Interference effect of urine pH Studies were conducted to assess the effect of urine pH on the test results. For all test strip analytes, except leukocytes there was no interference from pH across a range of 4.5 to 9.0. For leukocytes, urine pH values lower than 5.5 may yield a false negative result. ## Interference effect of intrinsic urine color The candidate device includes a feature that corrects for intrinsic urine color. Studies were conducted to verify that the test strip analytes of erythrocytes, leukocytes, nitrite, ketones, glucose, urobilinogen and bilirubin were insensitive to interference from red, orange, and brown colored urine samples. Other urine colors were not tested. The results demonstrated that red, orange, and brown urine do not significantly impact the results for those analytes tested since all results were within +/- 1 color block when testing red, orange and brown colored urine for these parameters. ## Interference effect of urine specific gravity Studies were conducted to assess the effect of urine specific gravity on the test results. For all test strip analytes, except leukocytes there was no interference from changes in specific gravity across a range of 1.015 (normal) to 1.050 (high) g/cm³. For leukocytes, false negative results were found at urine specific gravity values higher than 1.030 g/cm³. f. Assay cut-off: Not applicable. 2. Comparison studies: a. Method comparison with predicate device: The accuracy performance of the test system was assessed by method comparison for agreement to comparator devices for each analyte/parameter on the cobas u 601 urinalysis test system. ### Study #1 – All analytes except urine clarity A method comparison study for the test strip analytes was conducted at one clinical laboratory using left-over urine specimens from routine use and were measured within two hours from collection. All measurements were performed using native samples only - there were no contrived samples. Each sample was split in two aliquots and measured in one-fold determination on the candidate device and the predicate device (the cobas u 411 urinalysis test system.) The data are presented in concordance charts, as shown in the tables below. {20} | Erythrocytes | Comparator | | | | | | | --- | --- | --- | --- | --- | --- | --- | | cobas u 601 | neg | 10 Ery/μL | 25 Ery/μL | 50 Ery/μL | 150 Ery/μL | 250 Ery/μL | | Neg | 187 | 1 | 0 | 0 | 0 | 0 | | 10 Ery/μL | 2 | 25 | 1 | 0 | 0 | 0 | | 25 Ery/μL | 0 | 2 | 40 | 2 | 0 | 0 | | 50 Ery/μL | 0 | 0 | 6 | 30 | 0 | 0 | | 150 Ery/μL | 0 | 0 | 0 | 3 | 21 | 1 | | 250 Ery/μL | 0 | 0 | 0 | 0 | 0 | 21 | | | | | | | | | | Total | 189 | 28 | 47 | 35 | 21 | 22 | | Exact agreement % | 99% | 89% | 85% | 86% | 100% | 95% | | Agreement ± 1 block | 100% | 100% | 100% | 100% | 100% | 100% | | Leukocytes | Comparator | | | | | --- | --- | --- | --- | --- | | cobas u 601 | neg | 25 Leu/μL | 100 Leu/μL | 500 Leu/μL | | Neg | 185 | 3 | 0 | 0 | | 25 Leu/μL | 1 | 30 | 2 | 0 | | 100 Leu/μL | 0 | 1 | 30 | 2 | | 500 Leu/μL | 0 | 0 | 1 | 42 | | | | | | | | Total | 186 | 34 | 33 | 44 | | Exact agreement % | 99% | 88% | 91% | 95% | | Agreement ± 1 block | 100% | 100% | 100% | 100% | | Nitrite | Comparator | | | --- | --- | --- | | cobas u 601 | Neg | Pos | | Neg | 188 | 0 | | Pos | 2 | 40 | | | | | | Total | 190 | 40 | | Exact agreement % | 99% | 100% | {21} | Ketones | Comparator | | | | | | --- | --- | --- | --- | --- | --- | | cobas u 601 | Neg | 5 mg/dL | 15 mg/dL | 50 mg/dL | 150 mg/dL | | Neg | 189 | 3 | 0 | 0 | 0 | | 5 mg/dL | 1 | 21 | 2 | 0 | 0 | | 15 mg/dL | 0 | 0 | 21 | 1 | 0 | | 50 mg/dL | 0 | 0 | 0 | 20 | 2 | | 150 mg/dL | 0 | 0 | 0 | 0 | 20 | | | | | | | | | Total | 190 | 24 | 23 | 21 | 22 | | Exact agreement % | 99% | 88% | 91% | 95% | 91% | | Agreement ± 1 block | 100% | 100% | 100% | 100% | 100% | | Glucose | Comparator | | | | | | --- | --- | --- | --- | --- | --- | | cobas u 601 | Norm | 50 mg/dL | 100 mg/dL | 250 mg/dL | 1000 mg/dL | | Norm | 190 | 0 | 0 | 0 | 0 | | 50 mg/dL | 2 | 23 | 0 | 0 | 0 | | 100 mg/dL | 0 | 1 | 20 | 3 | 0 | | 250 mg/dL | 0 | 0 | 0 | 21 | 4 | | 1000 mg/dL | 0 | 0 | 0 | 0 | 25 | | | | | | | | | Total | 192 | 24 | 20 | 24 | 29 | | Exact agreement % | 99% | 96% | 100% | 88% | 86% | | Agreement ± 1 block | 100% | 100% | 100% | 100% | 100% | | Protein | Comparator | | | | | | --- | --- | --- | --- | --- | --- | | cobas u 601 | Norm | 15 mg/dL | 30 mg/dL | 100 mg/dL | 500 mg/dL | | Norm | 187 | 0 | 0 | 0 | 0 | | 15 mg/dL | 3 | 21 | 4 | 0 | 0 | | 30 mg/dL | 0 | 1 | 33 | 1 | 0 | | 100 mg/dL | 0 | 0 | 0 | 20 | 4 | | 500 mg/dL | 0 | 0 | 0 | 1 | 26 | | | | | | | | | Total | 190 | 22 | 37 | 22 | 30 | | Exact agreement % | 98% | 95% | 89% | 91% | 87% | | Agreement ± 1 block | 100% | 100% | 100% | 100% | 100% | {22} | Bilirubin | Comparator | | | | | --- | --- | --- | --- | --- | | cobas u 601 | neg | 1 mg/dL | 3 mg/dL | 6 mg/dL | | Neg | 188 | 2 | 0 | 0 | | 1 mg/dL | 0 | 21 | 1 | 0 | | 3 mg/dL | 0 | 0 | 33 | 2 | | 6 mg/dL | 0 | 0 | 0 | 20 | | | | | | | | Total | 188 | 23 | 34 | 22 | | Exact agreement % | 100% | 91% | 97% | 91% | | Agreement ± 1 block | 100% | 100% | 100% | 100% | | Urobilinogen | Comparator | | | | | | --- | --- | --- | --- | --- | --- | | cobas u 601 | Norm | 1 mg/dL | 4 mg/dL | 8 mg/dL | 12 mg/dL | | Norm | 189 | 3 | 0 | 0 | 0 | | 1 mg/dL | 1 | 26 | 5 | 0 | 0 | | 4 mg/dL | 0 | 1 | 44 | 2 | 0 | | 8 mg/dL | 0 | 0 | 1 | 21 | 1 | | 12 mg/dL | 0 | 0 | 0 | 0 | 30 | | | | | | | | | Total | 190 | 30 | 50 | 23 | 31 | | Exact agreement % | 99% | 87% | 88% | 91% | 97% | | Agreement ± 1 block | 100% | 100% | 100% | 100% | 100% | | pH | Comparator | | | | | | | --- | --- | --- | --- | --- | --- | --- | | cobas u 601 | pH 5 | pH 6 | pH 6.5 | pH 7 | pH 8 | pH 9 | | pH 5 | 44 | 6 | 0 | 0 | 0 | 0 | | pH 6 | 5 | 62 | 2 | 0 | 0 | 0 | | pH 6.5 | 0 | 3 | 14 | 1 | 0 | 0 | | pH 7 | 0 | 0 | 4 | 35 | 1 | 0 | | pH 8 | 0 | 0 | 0 | 1 | 28 | 4 | | pH 9 | 0 | 0 | 0 | 0 | 0 | 24 | | | | | | | | | | Total | 49 | 71 | 20 | 38 | 29 | 29 | | Exact agreement % | 90% | 87% | 70% | 95% | 97% | 86% | | Agreement ± 1 block | 100% | 100% | 100% | 100% | 100% | 100% | {23} | Color | Comparator | | | | | | | --- | --- | --- | --- | --- | --- | --- | | cobas u 601 | Pale yellow | Yellow | Amber | Brown | Orange | Red | | Pale yellow | 126 | 7 | 0 | 0 | 0 | 0 | | Yellow | 23 | 85 | 2 | 0 | 0 | 0 | | Amber | 1 | 29 | 58 | 0 | 0 | 0 | | Brown | 0 | 0 | 24 | 50 | 0 | 0 | | Orange | 5 | 0 | 5 | 7 | 15 | 3 | | Red | 0 | 0 | 0 | 0 | 7 | 31 | | | | | | | | | | Total | 155 | 121 | 89 | 57 | 22 | 34 | | Exact agreement % | 81% | 70% | 65% | 88% | 68% | 91% | ## Study #2 – Urine clarity A method comparison study for the analyzer measured parameter of clarity was conducted at three clinical laboratories using left-over urine specimens from routine use and were measured within two hours from collection. All measurements were performed using native samples only - there were no contrived samples. Urine samples were measured to cover the analytical measurement range of clarity. Each sample was split in two aliquots and measured in one-fold determination on the candidate device and on a comparator method. The data from each site was combined and analyzed in a concordance chart: | Clarity | Comparator | | | | --- | --- | --- | --- | | cobas u 601 | Clear | Light turbid | Turbid | | Clear | 921 | 23 | 0 | | Light turbid | 114 | 173 | 18 | | Turbid | 2 | 21 | 92 | | | | | | | total | 1037 | 217 | 110 | | Exact agreement % | 89% | 80% | 84% | | Agreement ± 1 block | 99.8% | 100% | 100% | ## b. Matrix comparison: Not applicable, the assays on the platform are only for testing human urine. ## 3. Clinical studies: ### a. Clinical Sensitivity: Not applicable. {24} b. Clinical specificity: Not applicable. c. Other clinical supportive data: Not applicable. 4. Clinical cut-off: Not applicable. 5. Expected values/Reference range: The following expected values are listed in the u pack cassette product labeling: | Analyte | Expected values | | --- | --- | | pH | 4.8 – 7.4 | | Erythrocytes | 0 – 5 Ery/μL | | Leukocytes | < 10 Leu/μL | | Nitrite | – | | Protein | < 10 mg/dL | | Glucose | < 30 mg/dL | | Ketones | < 5 mg/dL | | Urobilinogen | < 1 mg/dL | | Bilirubin | < 0.2 mg/dL | N. Instrument Name: cobas u 601 urine analyzer O. System Descriptions: 1. Modes of Operation: Does the applicant’s device contain the ability to transmit data to a computer, webserver, or mobile device? Yes ☐ X ☐ or No ☐ Does the applicant’s device transmit data to a computer, webserver, or mobile device using wireless transmission? Yes ☐ or No ☐ X ☐ {25} 2. Software: FDA has reviewed applicant’s Hazard Analysis and software development processes for this line of product types: Yes ☐ X ☐ or No ☐ 3. Specimen Identification (ID): A patient ID is entered either manually using the touch screen or scanned using the barcode reader. 4. Specimen Sampling and Handling: Samples tubes are manually placed into a rack, which is loaded into the analyzer. The rack is automatically moved within the analyzer fluid handling station using a rack conveyor. During a run, the urine sample is aspirated into the fluid system and pipetted onto test pads of a test strip. 5. Calibration: A calibration of the analyzer’s PMC is performed every 4 weeks by measuring the clarity and specific gravity of water. A calibration of the analyzer’s photometer unit is performed every 4 weeks by measuring the reflectance of a dedicated calibration strip; i.e. cobas u calibration strip. The results are compared against a reference plate built into the analyzer. There are no external calibrators for the test system. The analyzer reference plate is measured along with each test strip measurement, and the assay reflectance measurements are normalized to the reference plate when calculating the results. 6. Quality Control: The following quality controls are recommended: - qUAntify Plus Control - Liquichek Urinalysis Control P. Other Supportive Instrument Performance Characteristics Data Not Covered In The Performance Characteristics Section above: 1. Instrument / sample carryover Study #1 – all analytes, except urine clarity: The carryover on the cobas u 601 urine analyzer for all analytes measured by reflectance from the test strip was evaluated. Sample carry-over was assessed by alternatively measuring 5 high samples followed by 5 low samples, and repeating the cycle 4 times. The magnitude of the elevation of the low sample caused by carryover from the high 26 {26} sample was determined by comparison of low sample result to a reference run of negative samples with n=25 replicates. The carryover study was performed on one instrument. For all analytes, all negative/normal samples read as negative/normal, and therefore no significant carryover found in the study. For urine color, all pale yellow samples were measured in the same color range after pipetting of brown urine samples. | Analyte | Reference run | % Match | Carryover run | % Match | | --- | --- | --- | --- | --- | | BIL | Neg | 100 | Neg | 100 | | ERY | Neg | 100 | Neg | 100 | | GLU | Norm | 100 | Norm | 100 | | KET | Neg | 100 | Neg | 100 | | LEU | Neg | 100 | Neg | 100 | | NIT | Neg | 100 | Neg | 100 | | pH | 6 | 100 | 6 | 100 | | PRO | neg | 100 | neg | 100 | | UBG | norm | 100 | norm | 100 | | Color | Pale yellow | 100 | Pale yellow | 100 | Study #2 – Clarity: The PMC carryover on the cobas u 601 urine analyzer was evaluated in terms of urine clarity. Sample carry-over was assessed by alternatively measuring 5 high samples followed by 5 low samples, and repeating the cycle 4 times. The magnitude of the elevation of the low sample caused by carryover from the high sample was determined by comparison of low sample result to a reference run of negative samples with n=25 replicates. The carryover study was performed on one instrument. For urine clarity, the carryover was within the same color block, and therefore not significant. 2. Electromagnetic Compatibility (EMC) The sponsor provided documentation certifying that EMC testing was performed on the cobas u 601 urine analyzer and was found to be compliant of the requirements of the EMC specifications. 3. Electrical Safety The sponsor provided documentation certifying that electrical safety testing was performed on the cobas u 601 urine analyzer and that all requirements for electrical safety were met. 27 {27} Q. Proposed Labeling: The labeling is sufficient and it satisfies the requirements of 21 CFR Parts 801 and 809, as applicable. R. Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision. 28