BS-480 CHEMISTRY ANALYZER, BS-490 CHEMISTRY ANALYZER, CLC720I CHEMISTRY ANALYZER

{0} 1 # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY AND INSTRUMENT COMBINATION TEMPLATE A. 510(k) Number: k140690 B. Purpose for Submission: Adding previously cleared assays on new instrument platforms (BS-480 / BS-490 / CLC720i Chemistry Analyzers) C. Measurand: Sodium, Potassium, Chloride, and Urea Nitrogen D. Type of Test: Quantitative Photometric and Ion Selective Electrodes E. Applicant: Shenzhen Mindray Bio-Medical Electronics Co., Ltd F. Proprietary and Established Names: BS-480 Chemistry Analyzer BS-490 Chemistry Analyzer CLC720i Chemistry Analyzer G. Regulatory Information: | Product Code | Regulation Name | Classification | Regulation Section | Panel | | --- | --- | --- | --- | --- | | CDQ | Urea Nitrogen test system | II | 21 CFR 862.1770 | Chemistry (75) | | JGS | Sodium test system | II | 21 CFR 862.1665 | Chemistry (75) | | CEM | Potassium test system | II | 21 CFR 862.1600 | Chemistry (75) | | CGZ | Chloride test system | II | 21 CFR 862.1170 | Chemistry (75) | | JJE | Discrete photometric chemistry analyzer for clinical use | I, exempt | 21 CFR 862.2160 | Chemistry (75) | {1} H. Intended Use: 1. Intended use(s): See indication(s) for use below 2. Indication(s) for use: The BS-480 / BS-490 / CLC720i Chemistry Analyzer is designed for clinical chemistry laboratory use, making direct quantitative measurements of Na⁺(sodium), K⁺ (potassium), Cl⁻ (chloride) in serum, plasma and urine samples, and Urea Nitrogen in serum samples. Additionally, other various chemistry tests may be adaptable to the analyzer depending on the reagent used to induce a photometric reaction. Sodium measurements monitor electrolyte balance and in the diagnosis and treatment of diseases involving electrolyte imbalance. Potassium measurements monitor electrolyte balance and 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. Urea Nitrogen (BUN) measurements are used to aid in the determination of liver and kidney function and other diseases associated with protein catabolism. 3. Special conditions for use statement(s): For prescription use only 4. Special instrument requirements: BS-480 Chemistry Analyzer, BS-490 Chemistry Analyzer, and CLC720i Chemistry Analyzer I. Device Description: The BS-480, BS-490, and CLC720i are automated chemistry analyzers containing an automated reagent probe, sample probe, mixers, reagent carousel, reaction carousel, wash station for in vitro diagnostic use in clinical laboratories, and designed for in vitro quantitative determination of clinical chemistries in serum, plasma, and urine samples. The devices are composed of a photometric module and an Ion Selective Electrode module for measuring sodium, potassium, and chloride. All three analyzers are the exact same analyzer except for the model names. The Urea Nitrogen reagent is a previously cleared (k971309) liquid ready to use reagent {2} composed of Urease (jack bean), 30,000 U/L, GLDH (bovine liver), 200 U/L, α-KG, 9.5 mmol/L, NADH (yeast), 0.28 mmol/L, buffer, and stabilizer. The ISE module is the same module as the one cleared on the BS-200 analyzer k072018) and consists of ion selective electrodes for sodium, potassium, chloride, and reference electrodes along with pump, tubes, connectors, and accessory reagents. ## J. Substantial Equivalence Information: 1. Predicate device name(s): Shenzhen Mindray Bio-Medical Electronics BS-400/CLC 720 Chemistry Analyzer, ISE Derma Media Lab Urea Nitrogen 2. Predicate 510(k) number(s): k112377 k971309 3. Comparison with predicate: BS-480 Chemistry Analyzer/ISE | Similarities / Differences | | | | --- | --- | --- | | Item | BS-480 Chemistry Analyzer k140690 (Candidate Device) | BS-400 Chemistry Analyzer k112377 (Predicate Device) | | Intended use | The BS-480 Chemistry Analyzer is an automated chemistry analyzer for in vitro diagnostic use in clinical laboratories. The analyzer is designed for the in vitro quantitative determination of clinical chemistries in serum, plasma or urine sample | The BS-400 Chemistry Analyzer is an automated chemistry analyzer for in vitro diagnostic use in clinical laboratories. The analyzer is designed for the in vitro quantitative determination of clinical chemistries in serum, plasma, urine, or cerebral spinal fluid samples. | | System Function | | | | System Control | Automatic computer control | Same | | LIS external connectivity capability | Yes | Same | | Calibration/QC | Automatic and Manual calibration/QC | Same | | Barcode | Yes | Same | | Throughput (Max) | 400 photometric test per hour | Same | | Configuration | Analytical unit, Operational Unit | Same | | Principle of Analysis | | | | Mode of detection | Photometric | Same | {3} | Similarities / Differences | | | | --- | --- | --- | | Item | BS-480 Chemistry Analyzer k140690 (Candidate Device) | BS-400 Chemistry Analyzer k112377 (Predicate Device) | | Analytical methods | Endpoint Fixed-time Kinetic | Same | | Calibration methods | Linear calibration and nonlinear calibration | Same | | Optical Measurement Unit | | | | Measurement Modes | Absorbance | Same | | Optical Modes | Monochromatic, Bichromatic | Same | | Photometer | Multi-wavelength, diffraction grating spectrophotometer | Same | | Wavelength | 340nm, 380nm, 412nm, 450nm, 505nm, 546nm, 570nm, 605nm, 660nm, 700nm, 740nm, and 800nm | Same | | Linear absorbance | 0 – 3.3 absorbance | 0 – 3.0 absorbance | | Light Source | Tungsten halogen lamp | Same | | Detector | Photodiode | Same | | Reaction Unit | | | | Reaction cuvettes | Glass 90 non-disposable | Plastic or Glass 90 non-disposable | | Reaction Volume | 120 ~ 360 μL | 150 ~ 360 μL | | Path length | 5mm | Same | | Reaction temperature | 37°C | Same | | Sample and Reagent System | | | | Sample disk | 90 positions, 30 positions respectively for inner, middle, and outer circles. | Same | | Reagent disk | 80 positions, 40 positions respectively for inner and outer circles. | Same | | Pipettor System | Positive displacement stepper motor driven | Same | | Refrigerator temperature | 2 - 10°C | Same | | Sample Dispense | 1.5μL - 45μL | 2μL - 45μL | | Reagent Dispense | 10μL - 350μL | 20μL - 350μL | | Power | | | | Input | 110/115V~, 60Hz | Same | | Operational environment conditions | | | | Temperature | 15°C - 30°C | Same | {4} | Similarities / Differences | | | | --- | --- | --- | | Item | BS-480 Chemistry Analyzer k140690 (Candidate Device) | BS-400 Chemistry Analyzer k112377 (Predicate Device) | | Humidity | 35% - 85% non-condensing | Same | | ISE Module | | | | Principle | ISE (ion selective electrode) | Same | | Sample type | Serum, plasma, or diluted urine | Same | | Test | Na+, K+, Cl- | Same | | Sample Size | 70μL Serum, plasma mode; 140μL Urine mode | Same | | ISE Calibration | Two-point and single-point calibrations | Same | BUN | Similarities / Differences | | | | --- | --- | --- | | Item | Shenzhen-Mindray BUN Reagent (Candidate Device) | Derma Media Lab BUN (k971309) (Predicate Device) | | Intended Use | Measurements are used to aid in the determination of liver and kidney functions and other diseases associated with protein catabolism. | Same | | Sample type | Serum | Same | | Assay method | Photometric | Same | | Reagent format | Liquid, ready to use | Same | | Calibration frequency | Every 14 days | Same | | Instrument platform | BS 480 chemistry analyzer | Olympus Chemistry Analyzer. | # K. Standard/Guidance Document Referenced (if applicable): CLSI-Evaluation of Precision Performance of Clinical Chemistry Devices-EP05-A2 CLSI-Evaluation of Linearity of Quantitative Analytical Methods-EP06-A CLSI-Interference Testing in Clinical Chemistry-EP07-A2 CLSI-Method Comparison and Bias estimation Using Patients Samples-EP09-A2 CLSI-Protocols for Determination of Limits of Detection and Limits of Quantitation-EP17-A {5} L. Test Principle: BUN-Urea is converted to ammonia and $\mathrm{CO}_{2}$ by the enzyme urease. The ammonia produced is utilized by glutamate dehydrogenase (GLDH) to convert alpha-ketoglutarate ($\alpha$-KG) to glutamic acid, with the concomitant conversion of NADH to NAD which is measured bichromatically at $340/380\,\mathrm{nm}$, and is proportional to the amount of BUN present. ISE- The ion selective electrodes develop a voltage that varies with the concentration of the ion $(\mathrm{Na}^{+},\mathrm{K}^{+},\mathrm{Cl}^{-})$ to which they are specific. The relationship between the voltage developed and the concentration of the sensed ion is logarithmic and calculated by the Nernst equation. M. Performance Characteristics (if/when applicable): The BS-480, BS-490 and CLC720i Chemistry analyzers are identical except for the model names. The sponsor conducted all the performance testing on the BS-480 model only. 1. Analytical performance: a. Precision/Reproducibility: Repeatability and total precision of serum BUN, serum ISE and urine ISE were demonstrated by analyzing three aliquots of serum based control material and two aliquots of urine based control material on the BS-480 Chemistry Analyzer. The control pools were analyzed in duplicate, two runs per day over twenty days, as described in CLSI document EP5-A2, Evaluation of Precision Performance of Quantitative Measurement Methods. | Analyte | Unit | Sample | n | Mean | Repeatability | | Total (Within Device) Precision | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | SD | CV% | SD | CV% | | Serum BUN | mg/dL | Control pool 1 | 80 | 16 | 0.12 | 0.7% | 0.28 | 1.7% | | | | Control pool 2 | 80 | 41 | 0.18 | 0.4% | 0.70 | 1.7% | | | | Control pool 3 | 80 | 66 | 0.30 | 0.5% | 1.18 | 1.8% | | Serum Na+ | mmol/L | Control pool 1 | 80 | 142 | 0.51 | 0.4% | 1.15 | 0.8% | | | | Control pool 2 | 80 | 160 | 0.35 | 0.2% | 1.02 | 0.6% | | | | Control pool 3 | 80 | 119 | 0.25 | 0.2% | 0.81 | 0.7% | | Serum K+ | mmol/L | Control pool 1 | 80 | 3.7 | 0.01 | 0.4% | 0.03 | 0.9% | | | | Control pool 2 | 80 | 5.6 | 0.02 | 0.3% | 0.04 | 0.7% | | | | Control pool 3 | 80 | 3 | 0.01 | 0.4% | 0.02 | 0.8% | | Serum CL- | mmol/L | Control pool 1 | 80 | 103 | 0.53 | 0.5% | 0.93 | 0.9% | | | | Control pool 2 | 80 | 125 | 0.43 | 0.3% | 0.86 | 0.7% | | | | Control pool 3 | 80 | 82 | 0.40 | 0.5% | 0.67 | 0.8% | | Urine Na+ | mmol/L | Control pool 1 | 80 | 75 | 1.29 | 1.7% | 2.21 | 2.9% | | | | Control pool 2 | 80 | 165 | 1.75 | 1.1% | 2.93 | 1.8% | {6} | Urine K+ | mmol/L | Control pool 1 | 80 | 34 | 0.16 | 0.5% | 0.49 | 1.5% | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | Control pool 2 | 80 | 97 | 0.34 | 0.3% | 0.77 | 0.8% | | Urine CL- | mmol/L | Control pool 1 | 80 | 76 | 0.89 | 1.2% | 2.02 | 2.7% | | | | Control pool 2 | 80 | 202 | 1.20 | 0.6% | 2.32 | 1.1% | # b. Linearity/assay reportable range: Linearity claims are validated using CLSI document EP6-A. For the linearity of BUN the low concentration serum pool containing $5.1\mathrm{mg / dL}$ BUN was collected from hospitals, a concentrated solution of BUN is used to supplement the high concentration serum pool. For serum ISE, the low concentration serum pool was obtained by diluting with $5\%$ BSA, the high concentration serum pool is obtained by spiking with a concentrated solution of NaCl or KCl. For Urine ISE, the low concentration urine pool was obtained by diluting with urine diluent; the high concentration urine pool was obtained by spiking with a concentrated solution of NaCl or KCl. Next, 11 equally spaced samples across the linear range are prepared by using the high and low sample pool. These samples were assayed on the BS-480 chemistry analyzer randomly, and each analyzer was assayed in 4 replicates. The summary of the results are presented in the table below. | Analyte | Unit | Slope | Intercept | Correlation Coefficient | Sample Range Tested | Claimed Measuring Range | | --- | --- | --- | --- | --- | --- | --- | | Serum BUN | mg/dL | 1.0000 | -0.0109 | 0.9992 | 5 – 165 | 6 – 152 | | Serum Na+ | mmol/L | 1.0001 | 0.9999 | 0.9999 | 69 – 250 | 100 – 200 | | Serum K+ | mmol/L | 1.0001 | 0.9998 | 0.9998 | 0.85 – 9.76 | 1 – 8 | | Serum Cl- | mmol/L | 0.9999 | 0.9999 | 0.9999 | 44.7 – 186 | 50 – 150 | | Urine Na+ | mmol/L | 1.0001 | 1.0000 | 1.0000 | 10.0 – 614.0 | 10 – 500 | | Urine K+ | mmol/L | 1.0005 | 0.9997 | 0.9997 | 4.0 – 230 | 5 – 200 | | Urine Cl- | mmol/L | 1.0000 | 0.9996 | 0.9996 | 6.8 – 452.0 | 15 - 400 | # c. Traceability, Stability, Expected values (controls, calibrators, or methods): The BUN calibrators were previously cleared in k070207 and are traceable to NIST; no modification was made. The ISE modules, including the calibrators, were previously cleared in k072018; no modification was made. # d. Detection limit: The limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) evaluations followed CLSI t EP17-A2. For the determination of LoB, two reagent lots and five blank samples were prepared. All samples were assayed in four {7} replicates per reagent lot per day for three days on the BS-480 chemistry analyzer for each analyte. A total of 60 measurements were obtained per reagent lot. For the determination of LoD, five samples with low analyte concentrations were measured. In total 60 measurements were obtained per reagent lot. For the determination of LoQ, five low level samples of known measurand concentration were prepared. The BUN concentrations were obtained from dilution calculation with a serum sample whose measurand concentration was determined by a reference method. The ISE concentrations were obtained from dilution calculation with salt solution whose measurand concentration was determined by theoretical spike. All samples were assayed in four replicates per reagent lot per day for three days. Results from the detection limit studies are summarized in the table below. | Analyte | Unit | LoB | LoD | LoQ | | --- | --- | --- | --- | --- | | Serum BUN | mg/dL | 0.2 | 0.3 | 4.8 | | Serum Na+ | mmol/L | 3.7 | 5.1 | 48.0 | | Serum K+ | mmol/L | 0.21 | 0.24 | 0.69 | | Serum Cl- | mmol/L | 1.2 | 3.7 | 36.6 | | Urine Na+ | mmol/L | 3 | 4.5 | 10 | | Urine K+ | mmol/L | 1 | 1.2 | 3.3 | | Urine Cl- | mmol/L | 1 | 2.6 | 6.3 | # e. Analytical specificity: The effects of potentially interfering substances were determined by using 2 sample pools (normal and abnormal) according to CLSI document EP7-A2. Bilirubin, hemoglobin, lipemia (Intralipid, $20\%$ emulsion, used to emulate extremely turbid samples), and ascorbic acid were tested as potential interfering substances. For each tested substance, a series of five samples with increasing interferent concentrations were prepared. Each series of pools were assayed 3 times. The bias between the control pool and test pool were calculated. The sponsor defines non-significant interference as $\leq + / - 10\%$ bias) when the concentrations of interference materials is below the ones in the following table. | Item | Highest Concentration Tested that showed no significant interference | | | | | --- | --- | --- | --- | --- | | | Total Bilirubin (mg/dL) | Hemoglobin (mg/dL) | Lipemia (mg/dL) | Ascorbic Acid (mg/dL) | | Serum BUN | 40 | 500 | 1000 | 30 | | Serum Na+ | 40 | 500 | 1000 | 30 | | Serum K+ | 40 | * | 1000 | 30 | | Serum Cl- | 40 | 500 | 1000 | 30 | | Urine Na+ | 40 | 500 | 1000 | 30 | | Urine K+ | 40 | 125 | 1000 | 30 | | Urine Cl- | 40 | 250 | 1000 | 30 | {8} * Hemolysis can lead to falsely elevated $\mathrm{K}+$ values; the sponsor has put the following limitation in the labeling: "Hemolyzed samples should not be tested for potassium." The sponsor also tested the effects of potentially interfering exogenous substances. Testing for each analyte was performed at two concentration levels (low and high). For each potential exogenous interfering substance, a series of five samples with increasing interferent concentrations were prepared. Each series of pools were assayed 3 times. The bias between the control pool and test pool were calculated. There was non-significant interference with $\mathrm{Na^{+}}$ , $\mathrm{K^{+}}$ , and $\mathrm{Cl^-}$ by the following drugs at the concentration ranges indicated below: (Sponsor defines non-significant interference as $\leq \pm 10\%$ ) | Drug interferents | Drug level tested (mg/dL) | | --- | --- | | Imipramine | 0.15 | | Procainamide | 15 | | Nortriptyline | 0.23 | | Hydroxytyramine | 50.4 | | Valproic acid | 75.5 | | Chlorpromazine | 6 | | Salicylic acid | 70.5 | | Acetylsalicylic acid | 1201 | | Erythromycin | 7.1 | | Ethosximide | 30.5 | | Acetaminophen | 242 | | Ampicillin | 6 | There was significant interference for Ibuprofen, Benzalkonium Chloride, and Potassium Thiocyanate, when these analytes and interferents were tested in the concentration ranges indicated below: (Sponsor defines significant interference as $\geq \pm$ $10\%$ ). | Drug interferents | ISE application | Drug level tested (mg/dL) | Effect | | --- | --- | --- | --- | | Ibuprofen | Serum K+ | 506 | Decrease Potassium by 0.5 mmol/L at the concentration of 3.25 mmol/L and by 0.59 mmol/L at the concentration of 5.39 mmol/L. | | | Serum CL- | 380 | Increases Chloride by 15.4 mmol/L at the concentration of 99 mmol/L and by 14.6 mmol/l at the concentration of 119.3 mmol/L | | Benzalkonium Chloride | Serum Na+ | 7.7 | Increases Sodium by 21.5 mmol/L at the concentration of 130.5 mmol/L and by 17.4 mmol/L at the concentration of 146.1 mmol/L | | | Serum K+ | 5.2 | Increases Potassium by 0.38 | {9} The sponsor cites the following reference for exogenous interference of BUN in the labeling. Young DS. Effects of Drugs on Clinical Laboratory Tests, 5th ed. AACC Press, 2000 f. Assay cut-off: Not Applicable 2. Comparison studies: a. Method comparison with predicate device: Method comparison was performed according to CLSI document EP9-A2, 120- 132 samples for each analyte were assayed in duplicate on the BS-480 Chemistry Analyzer and the BS-400 Chemistry Analyzer (predicate device). The first of the duplicate results from the BS-480 chemistry analyzer were compared against the predicate's results. The slope, intercept, and correlation coefficient were obtained using Passing-Bablok analysis. The total numbers of altered (spiked and diluted) samples were no more than 19% of the total samples tested. Statistical results are shown in the table below. | Analyte | Unit | Sample Range Tested | n | Slope | Intercept | Correlation Coefficient | | --- | --- | --- | --- | --- | --- | --- | | Serum BUN | mg/dL | 6.0– 147 | 120 | 0.9912 | 0.0494 | 1.000 | | Serum Na+ | mmol/L | 100–200 | 132 | 0.9613 | 3.243 | 0.998 | | Serum K+ | mmol/L | 1.4 – 7.3 | 120 | 0.9570 | 0.0914 | 1.000 | | Serum Cl- | mmol/L | 55 – 147.0 | 125 | 0.9537 | 4.216 | 0.998 | | Urine Na+ | mmol/L | 12 – 473 | 120 | 0.9925 | -0.9291 | 1.000 | {10} | Urine K+ | mmol/L | 5 – 192 | 120 | 0.9677 | 0.6774 | 1.000 | | --- | --- | --- | --- | --- | --- | --- | | Urine Cl- | mmol/L | 16 - 396 | 120 | 1.006 | 2.704 | 1.000 | b. Matrix comparison : A Matrix comparison study was conducted following CLSI document EP-9-A2. Samples were tested on the The BS-480 analyzer. The study was conducted using 67 paired serum and lithium heparin plasma samples drawn from the same individuals. Statistical results using Passing-Bablok analysis are shown in the table below. | Analyte | Unit | N | Sample range | Slope | Intercept | Correlation Coefficient | | --- | --- | --- | --- | --- | --- | --- | | Na+ | mmol/L | 67 | 103. – 186 | 0.971 | 2.9 | 0.995 | | K+ | mmol/L | 67 | 1.2 – 6.9 | 0974 | -0.17 | 0.992 | | Cl- | mmol/L | 67 | 70 – 143 | 1.005 | -0.1 | 0.995 | The sponsor concluded that Lithium heparin plasma is acceptable to be used with their ISE $(\mathrm{Na}^{+},\mathrm{K}^{+}$ and Cl-) assay. 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 4. Clinical cut-off: Not Applicable 5. Expected values/Reference range: BUN - serum: 7-18 mg/dL Sodium - serum: 136-145 mmol/L, 24-hour urine: 40-220 mmol/L Potassium - serum: 3.5-5.1 mmol/L, 24-hour urine: 25-125 mmol/L Chloride - serum: 98-107 mmol/L, 24-hour urine: 110-250 mmol/L {11} References: Tietz, N.W., Fundamentals of clinical chemistry, 6th Edition, W.B. Saunders Co., Philadelphia, PA, 2008 N. Instrument Name: BS-480 Chemistry Analyzer, BS-490 Chemistry Analyzer, and CLC720i Chemistry Analyzer O. System Descriptions: 1. Modes of Operation: Random access instrument with optional ISE module 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: Manual or sample barcode option 4. Specimen Sampling and Handling: Random access and stat mode operation. Samples are loaded on a sample wheel. 5. Calibration: The sponsor recommends BUN calibration every 14 days. The recommended calibrators are provided in the labeling. The sponsor recommends that the user perform an ISE two-point calibration every 8 hours. If the user is running more than 50 serum samples a day; both cleaning and two-point calibration must be performed after every 50 samples to ensure reliable operation of the ISE Module. 6. Quality Control: In the labeling, the sponsor recommends the controls should be run at least with every working shift in which BUN assays are performed. It is recommended that each laboratory establish its own frequency of control determination. The recommended control materials are provided in the labeling. The sponsor recommends the QC materials should be run after each calibration of the ISE module. 12 {12} P. Proposed Labeling: The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10. Q. Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision. 13