Elecsys TSH assay, cobas e 801 Immunoassay analyzer

{0} 1 # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY AND INSTRUMENT COMBINATION TEMPLATE A. 510(k) Number: k162606 B. Purpose for Submission: Adding a previously cleared assay on a new a instrument platform. C. Measurand: Thyroid-stimulating hormone (TSH) D. Type of Test: Quantitative, electrochemiluminescence immunoassay E. Applicant: Roche Diagnostics Corp F. Proprietary and Established Names: Elecsys TSH assay Cobas e 801 Immunoassay analyzer G. Regulatory Information: | Product Code | Regulation Name | Classification | Regulation Section | Panel | | --- | --- | --- | --- | --- | | JLW | Thyroid stimulating hormone test system | Class II | 21 CFR § 862.1690 | Chemistry 75 | | JJE | Discrete photometric chemistry analyzer for clinical use | Class I | 21 CFR § 862.2160 | Chemistry 75 | H. Intended Use: 1. Intended use(s): See indications for use {1} 2. Indication(s) for use: cobas e 801 immunoassay analyzer is intended for the in-vitro determination of analytes in body fluids. Elecsys TSH immunoassay is intended for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in diagnosis of thyroid or pituitary disorders. The Elecsys TSH immunoassay is an electrochemiluminescence immunoassay "ECLIA", which is in intended for use on the cobas e immunoassay analyzers. 3. Special conditions for use statement(s): For prescription use. 4. Special instrument requirements: Cobas e 801 Immunoassay analyzer I. Device Description: The cobas e 801 immunoassay analyzer is a fully automated, software controlled analyzer system for in vitro determination of analytes in human body fluids. It is part of the cobas 8000 modular analyzer series cleared under k100853. It uses electrochemiluminescent technology for signal generation and measurement. It is a modified version of the cobas e 601 analyzer module, part of the cobas 6000 modular analyzer. The Roche Elecsys TSH assay contains the following reagents: The Elecsys TSH assay employs monoclonal antibodies specifically directed against human TSH. The antibodies labeled with ruthenium complex a) consist of a chimeric construct from human and mouse-specific components. The reagents include: M Streptavidin-coated microparticles, 1 bottle, 14.1 mL: Streptavidin-coated microparticles 0.72 mg/mL, preservative. R1 Anti-TSH-Ab~biotin, 1 bottle, 15.8 mL: Biotinylated monoclonal anti-TSH antibody (mouse) 2.0 mg/L; phosphate buffer 100 mmol/L, pH 7.2; preservative. R2 Anti-TSH-Ab~Ru(bpy), 1 bottle, 13.9 mL: Monoclonal anti-TSH antibody (mouse/human) labeled with ruthenium complex 1.2 mg/L; phosphate buffer 100 mmol/L, pH 7.2; preservative. Total duration of the assay is 18 min, sandwich principle. 2 {2} J. Substantial Equivalence Information: 1. Predicate device name(s): Elecsys 2010 Elecsys TSH assay 2. Predicate 510(k) number(s): k961491 3. Comparison with predicate: | Similarities- Analyzer | | | | --- | --- | --- | | Item | Candidate Device: cobas e801 analyzer (k162606) | Predicate device: Elecsys 2010 (k961491) | | Intended Use | Same | Fully automated immunoassay analyzer intended for the in vitro determination of analytes in body fluids. | | Measurement principle | Same | Electrochemiluminescence immunoassay method (ECLIA) | | Workflow principle | Same | Batch or random access | | Temp. control | Same | Incubation at 37°C. | | Probe cleaning | Same | Automatic for reagent probe | | Functions performed | Same | Data input, sample processing, result calculation, result reporting, quality control | | Differences- Analyzer | | | | --- | --- | --- | | Item | Candidate Device: cobas e801 analyzer (k162606) | Predicate device: Elecsys 2010 (k961491) | | Throughput | 300 tests/hour/module | 86 tests/hour/module | | Typical sample volumes | 4-60 μL | 10-50μL | | Sample handling system | Input and transport of samples using universal sample racks, modular sample buffer input, core/transportation unit and STAT port. | Via sample disk or racks | {3} | Differences- Analyzer | | | | --- | --- | --- | | Item | Candidate Device: cobas e801 analyzer (k162606) | Predicate device: Elecsys 2010 (k961491) | | Sample capacity on board | 300 | Disc:30; rack: 75 | | Reagent volume | 6-60 μL | 10-190 μL | | Reagent container | Plastic bottles with changes in materials, geometry and volume | Plastic bottles closed via snap caps | | Onboard storage temperature | 5-10 °C | 18-22 °C | | Reagent bottle/Cassette identification | RFID | 2-d Barcode | | Software | cobas 8000 modular System Software | Elecsys 2010 Software | | Configuration | One PC and one core in combination with several e-modules or c analytical modules | Stand alone | | Similarities and Differences- Reagent | | | | --- | --- | --- | | Item | Candidate Device: Elecsys TSH on cobas e801 analyzer (k162606) | Predicate Device: Elecsys TSH on Elecsys 2010 (k961491) | | Intended Use | same | Immunoassay for the in vitro quantitative determination of thyroid stimulating hormone in human serum and plasma | | Antibody/ Reagents | Same | Biotinylated monoclonal anti-TSH antibody (mouse)Monoclonal anti-TSH antibody (mouse/human) labeled with ruthenium complexStreptavidin -coated microparticles | | Measuring Range | same | 0.005-100 μIU/mL | | Measurement principle | same | Electrochemiluminescence immunoassay (ECLIA) method | | Sample size | 50 μL of sample | 30μL of sample | | Sample Types | Serum, serum with separating gel, Li-heparin, K2EDTA, and K3EDTA | Serum, serum with separating gel, Li-heparin, K2EDTA, K3EDTA, Sodium citrate and NaF/K oxalate | {4} K. Standard/Guidance Document Referenced (if applicable): CLSI EP5, Evaluation of Precision Performance of Quantitative Measurement Method, Version A2, 2005. CLSI EP6, Evaluation of the Linearity of Quantitative Measurement Procedures, Version A, 2009. CLSI EP9, Method Comparison and Bias Estimation using patient samples, Version A3, 2010. CLSI EP17, Evaluation of Detection Capability of Clinical Laboratory Measurement Procedures, Version A2, 2012. IEC 61010-2-101, Safety requirements for electrical equipment for measurement, control and laboratory use- Part 2-101: Particular requirements for in vitro diagnostic (IVD) medical equipment, 2015. L. Test Principle: Incubation of sample, a biotinylated monoclonal TSH-specific antibody and a monoclonal TSH-specific antibody labeled with a ruthenium complex react to form a sandwich complex (first incubation). After streptavidin-coated magnetic microparticles are added to the incubate the sandwich complexes are bound in the second incubation step to the solid phase via interaction of biotin and streptavidin. The reaction mixture is then aspirated into the measuring cell where the microparticles are magnetically captured on the surface of the electrode. Unbound substances are removed by washing with ProCell II M. Application of a voltage to the electrode then induces chemiluminescent emission which is measured and amplified by a photomultiplier. M. Performance Characteristics (if/when applicable): 1. Analytical performance: a. Precision/Reproducibility: Precision of the Elecsys TSH assay was evaluated on cobas e801 immunoassay analyzer according to CLSI document EP5-A3. Three serum based controls and 11 levels of serum samples (Serum 1 to 5 and 11 were pooled samples, serum 6-10 were spiked pooled samples). The samples were tested in duplicate, twice per day for 21 days (N=84). Results are summarized in the tables below: {5} | Sample | n | Mean μIU/mL | Within-run | | Total | | | --- | --- | --- | --- | --- | --- | --- | | | | | SD μIU/mL | CV% | SD μIU/mL | CV% | | PC Universal 1 | 84 | 1.41 | 0.0197 | 1.4 | 0.0301 | 2.1 | | PC Universal 2 | 84 | 8.18 | 0.132 | 1.6 | 0.207 | 2.5 | | PreciControl TS | 84 | 0.184 | 0.00325 | 1.8 | 0.00417 | 2.3 | | Serum 1 | 84 | 0.00851 | 0.000600 | 7.1 | 0.000962 | 11.3 | | Serum 2 | 84 | 0.209 | 0.00338 | 1.6 | 0.00520 | 2.5 | | Serum3 | 84 | 1.88 | 0.0264 | 1.4 | 0.0432 | 2.3 | | Serum 4 | 84 | 51.8 | 0.653 | 1.3 | 1.05 | 2.0 | | Serum 5 | 84 | 90.0 | 1.24 | 1.4 | 1.75 | 1.9 | # b. Linearity/assay reportable range: Linearity of the Elecsys TSH assay was assessed on the cobas e 801 Immunoassay Analyzer using 3 different lot reagents according to CLSI EP6-A. A high serum sample was serially diluted into 10 concentrations with the TSH specimen diluent (Diluent MultiAssay) to obtain a total of 12 TSH samples (0.00, 0.004, 0.203, 0.678, 2.03, 5.09, 10.2, 25.4, 33.9, 50.9, 72.7, 102 $\mu$ IU/mL) ranging from 0-102 $\mu$ IU/mL throughout the measuring range. All 12 samples were assayed in triplicate. The results from 3 lots of reagent yielded similar results. One representative lot is summarized in the table below. The measured values were plotted against the target values and the regression results support the sponsor's claim. | Linear Regression Equation and Correlation Coefficient | | | --- | --- | | Slope | 0.952 | | Intercept | -0.00272 | | r | 0.9986 | The sponsor claims a measuring range of 0.005-100 $\mu$ IU/mL for the Elecsys TSH assay. c. Traceability, Stability, Expected values (controls, calibrators, or methods): Traceability: This method is traceable to the $2^{\mathrm{nd}}$ IRP WHO Reference Standard 80/558. Controls and Calibrator: PreciControl Universal (cleared under k090541) and PreciControl TS (cleared under k140534) are the recommended controls to be used with the Elecsys TSH assay. {6} The Roche Elecsys TSH CalSet (cleared under k060754) is the recommended calibrator to be used with the Elecsys TSH assay. ## Reagent Stability: The sponsor provided new real time stability study protocol and acceptance criteria, and these were reviewed and found to be acceptable. The reagent is stable when stored unopened at +2°C to +8°C or onboard (5-10°C) for 16 weeks. ## d. Detection limit: The Limit of Blank (LoB) of the Elecsys TSH assay on the cobas e 801 Immunoassay Analyzer was determined according to CLSI EP17-A2 as the 95th percentile of measurements of blank samples on the cobas e 801 analyzer. One blank serum sample with no detectable levels of TSH were assayed per day, 10 replicates per run, using three lots of reagent over six days for a total of 60 replicates. The LoB was calculated to be 0.0025 μIU/mL. The Limit of Detection (LoD) of the Elecsys TSH assay was determined as recommended in CLSI EP17-A2 by using five low-level TSH native serum samples (0.000967- 0.00112 μIU/mL). All samples were assayed in duplicate, one run per day over six days, for a total of 20 runs using three lots of reagents (n=60) on the cobas e 801 instrument. The LoD was calculated to be 0.005 μIU/mL using the following equation: LoD = LoB + 1.653 SD. The Limit of Quantitation (LoQ) was determined using functional sensitivity for five low-level native TSH serum samples (0.0078 to 0.064 μIU/mL). All samples were assayed in five replicates, one run per day, for over five days, on the cobas e 801 instrument, using three reagent lots (n=75). Functional sensitivity was based on the within lab precision of 20% CV and was determined to be 0.005 μIU/mL. The results of the detection limits are summarized in the table below: | LoB | LoD | LoQ | | --- | --- | --- | | 0.0025 μIU/mL | 0.005 μIU/mL | 0.005 μIU/mL | This study supports the claimed assay measuring range of 0.005 to 100 μIU/mL. ## e. Analytical specificity: An interference study was conducted to evaluate the effect of endogenous interfering substances using the Elecsys TSH on the cobas e 801 Immunoassay analyzer. Three serum samples containing low (pooled sera), medium (pooled spiked sera), and high (pooled spiked sera) concentrations of TSH were tested. {7} The spiked sample (interference pool) was then diluted in 10% increments. The recovery was determined by testing a control sample without the interferent and comparing it to the value obtained from a test sample in which the potential interferent had been added. The sponsor defined significant interference as follows: Sample with concentration of 0.005 to 0.2 µIU/mL: &gt; ± 0.02 µIU/mL Sample with concentration of &gt; 0.2 to 100 µIU/mL: &gt; ± 10% No significant interference was observed for the substances and concentrations listed below: | Potential interfering endogenous substances | Highest interferent concentration tested at which no significant interference was observed | | --- | --- | | Intralipid (Lipemia) | 2000 mg/dL | | Biotin | 56.0 ng/mL | | Bilirubin | 66.0 mg/dL | | Hemoglobin | 1000 mg/dL | | Rheumatic Factor | 1500 IU/mL | | Human IgG | 2.80g/dL | | Human IgM | 0.500 g/dL | In addition, the sponsor states the following in the limitation section in the package insert: "Samples should not be taken from patients receiving therapy with high biotin doses (i.e. &gt;5 mg/day) until at least 8 hours following the last biotin administration." ## Drug interference: The effect on quantitation of analyte in the presence of drugs was determined by comparing values obtained from samples spiked with 29 pharmaceutical compounds spiked into two human serum samples (pooled serum samples, native) and tested on the Elecsys TSH assay on the cobas e 801 Immunoassay Analyzer. The analyte concentrations of the samples were approximately 0.3 and 8 µIU/mL. The sponsor defined non-significant interference as recovery within ±10%. | Potential interfering exogenous substances | Highest interferent concentration tested at which no significant interference was observed | | --- | --- | | Acetylcystein | 553 mg/dL | | Ampicillin-Na | 1000 mg/dL | | Ascorbic acid | 300 mg/dL | | Cyclosporine | 5 mg/dL | | Cefoxitin | 2500 mg/dL | | Heparin | 5000 U | {8} | Potential interfering exogenous substances | Highest interferent concentration tested at which no significant interference was observed | | --- | --- | | Levodopa | 20 mg/dL | | Methyldopa +1.5 | 20 mg/dL | | Metronidazole | 200 mg/dL | | Phenylbutazone | 400 mg/dL | | Doxycycline | 50 mg/dL | | Acetylsalicylic Acid | 1000 mg/dL | | Rifampicin | 60 mg/dL | | Acetaminophen | 200 mg/dL | | Ibuprofen | 500 mg/dL | | Theophylline | 100 mg/dL | | Amiodarone | 200 mg/L | | Carbimazole | 30 mg/L | | Fluocortolone | 100 mg/L | | Hydrocortisone | 200 mg/L | | Iodide | 0.2 mg/L | | Levothyroxine | 0.25 mg/L | | Liothyronine | 0.015 mg/L | | Methimazole | 80 mg/L | | Octreotide | 0.3 mg/L | | Prednisolone | 100 mg/L | | Propanolol | 240 mg/L | | Propylthiouracil | 60 mg/L | | Perchlorate | 2000 mg/L | A cross-reactivity study was conducted according to CLSI-EP7-A2 to evaluate the potential cross-reactivity of the assay. The potential cross-reactants were added at defined concentrations to native human sera with approximate concentrations of 0, 12.5, 25, 50 and 100 µIU/mL and analyzed with Elecsys TSH on the cobas e 801 analyzer. Results from these spiked serum samples were matched against the unspiked references and the % cross-reactivity was calculated as follows: % cross-reactivity = (mean concentration of spiked sample – mean concentration of unspiked sample/spiked concentration) x 100 The following cross-reactivities were found, tested with TSH concentrations of 0.3 µIU/mL and 8 µIU/mL. {9} | Cross-reactant | Concentration Tested mU/mL | Cross-reactivity % | | --- | --- | --- | | LH | 10,000 | <0.038 | | FSH | 10,000 | <0.080 | | hGH | 1,000 | 0.00 | | hCG | 50,000 | 0.00 | Hook effect: High dose hook effect of the Elecsys TSH was assessed on the cobas e 801 analyzer with three serum samples. The samples were spiked with analyte to achieve high TSH concentration. The hook concentration reported corresponds to the highest analyte concentration that generates a signal $\geq 10\%$ above the upper limit of the measuring range. There was no high dose effect observed at TSH concentrations equal or higher than $(\geq)$ $1,000~\mu \mathrm{IU / mL}$ . f. Assay cut-off: Not applicable # 2. Comparison studies: a. Method comparison with predicate device: A method comparison study was performed to compare TSH on the Elecsys 2010 analyzer (predicate) and the cobas e 801 analyzer. A total of 130 samples were measures with the Elecsys TSH immunoassay on the analyzer in singlicate covering the meaning range; mean values ranged from $0.009 - 92.6\mu \mathrm{IU} / \mathrm{mL}$ . Two out of 130 were spiked. Passing/Bablok and Linear regression analyses were performed according to CLSI EP09-A3. The data is summarized in the table below: | n | Passing/Bablok Regression | Linear Regression | Pearson Correlation Coefficient | Sample Range On Elecsys 2010 (μIU/mL) | | --- | --- | --- | --- | --- | | 130 | y = 0.936x - 0.003 | y = 0.958x - 0.052 | 0.999 | 0.005 - 85.9 | b. Matrix comparison: The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys TSH Immunoassay was determined by comparing values obtained from samples (single donors, native as well as spiked) drawn into Serum, Li-Heparin, K2-EDTA and K3-EDTA plasma tubes. A total of 56 serum/plasma pairs were tested in singleton with one reagent lot on one cobas e 801 immunoassay analyzer. {10} Data were evaluated using a regression analysis according to Passing/Bablok. The data and regression analysis are summarized below: | | Lithium Heparin | K2-EDTA | K3-EDTA | | --- | --- | --- | --- | | n | 56 | 56 | 56 | | Sample Range Tested | 0.0147 – 92.5 μIU/mL | 0.0147 – 92.5 μIU/mL | 0.0147 – 92.5 μIU/mL | | Slope | 1.001 | 0.994 | 0.983 | | Y-Intercept (μIU/mL) | -0.00634 | -0.00600 | -0.0229 | | Correlation Coefficient | 0.999 | 0.999 | 0.999 | The results of this study support the use of samples drawn into serum, Li-Heparin, K2-EDTA and K3-EDTA plasma tubes with the Elecsys TSH 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: 0.270-4.20 μIU/mL These values correspond to the $2.5^{\text{th}}$ and $97.5^{\text{th}}$ percentiles of results obtained from a total of 516 healthy test subjects examined. Each laboratory should investigate the transferability of the expected values to its own patient population and if necessary determine its own reference ranges. {11} 12 N. Instrument Name: Cobas e801 Chemistry 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 ☐ 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: Barcode 4. Specimen Sampling and Handling: Input and transport of samples using universal sample racks, modular sample buffer input, core/transportation unit and STAT port. 5. Calibration: It is recommended to perform calibration once per reagent lot using fresh reagent (i.e. not more than 24 hours since the cobas e pack was registered on the analyzer). Renewed calibration is recommended after 12 weeks when using the same reagent lot, after 28 days when using the same cobas e pack on the analyzer and as required: e.g. quality control findings outside the defined limits. 6. Quality Control: The sponsor recommends running various concentrations of controls at least once every 24 hours when the test is in use, once per cobas e pack. Values obtained should fall {12} within the defined limits. Each laboratory should establish corrective measures to be taken if values fall outside the defined limits. P. Other Supportive Instrument Performance Characteristics Data Not Covered In The "Performance Characteristics" Section above: The software documentations were reviewed and found to be acceptable. The firm provided documentation to support the devices was designed, developed and is under good software lifecycle processes. Q. Proposed Labeling: The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10. R. Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision. 13