Access TSH (3rd IS) Assay, DxI 9000 Access Immunoassay Analyzer

{0} 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY AND INSTRUMENT I Background Information: A 510(k) Number K221225 B Applicant Beckman Coulter, Inc. C Proprietary and Established Names Access TSH (3rd IS) Assay, DxI 9000 Access Immunoassay Analyzer D Regulatory Information | Product Code(s) | Classification | Regulation Section | Panel | | --- | --- | --- | --- | | JLW | Class II | 21 CFR 862.1690 - Thyroid Stimulating Hormone Test System | CH - Clinical Chemistry | | JJE | Class I | 21 CFR 862.2160 - Discrete photometric chemistry analyzer for clinical use | CH - Clinical Chemistry | II Submission/Device Overview: A Purpose for Submission: New Device B Measurand: Thyroid Stimulating Hormone (TSH) C Type of Test: Quantitative chemiluminescent immunoassay {1} III Intended Use/Indications for Use: A Intended Use(s): See Indications for Use below. B Indication(s) for Use: The Access TSH (3rd IS) assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of human thyroid-stimulating hormone (thyrotropin, TSH, hTSH) levels in human serum and plasma using the Access Immunoassay Systems. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders. This assay is capable of providing 3rd generation TSH results. The DxI 9000 Access Immunoassay Analyzer is an in vitro diagnostic device used for the quantitative, semi-quantitative, or qualitative determination of various analyte concentrations found in human body fluids. C Special Conditions for Use Statement(s): Rx - For Prescription Use Only D Special Instrument Requirements: DxI 9000 Access Immunoassay Analyzer IV Device/System Characteristics: A Device Description: The DxI 9000 Access Immunoassay Analyzer is an in vitro diagnostic device used for the quantitative, semi-quantitative, or qualitative determination of various analyte concentrations found in human body fluids. The analyzer subsystems include the luminometer, and components for handling fluids, compressed air, samples, and consumables. The DxI 9000 Access Immunoassay Analyzer provides automated, continuous, random-access processing. The Access TSH (3rd IS) reagent pack is ready to use and consists of the following reagents: - R1a: Paramagnetic particles coated with mouse monoclonal anti-human TSH antibody suspended in TRIS buffered saline, with surfactant, bovine serum albumin (BSA), <0.1% sodium azide, and 0.1% ProClin 300. - R1b: TRIS buffered saline with surfactant, BSA, protein (murine), < 0.1% sodium azide, and 0.1% ProClin 300. - R1c: Mouse monoclonal anti-human TSH alkaline phosphatase conjugate in ACES buffered saline, with surfactant, BSA matrix, protein (murine), < 0.1% sodium azide, and 0.25% ProClin 300. - R1d: Mouse monoclonal anti-human TSH alkaline phosphatase conjugate in ACES buffered saline, with surfactant, BSA matrix, protein (murine), < 0.1% sodium azide, {2} and 0.25\% ProClin 300. Reagent packs are made in two configurations to contain enough materials for 100 or 200 tests. Materials needed but not supplied with reagent kit include Access TSH (3rd IS) Calibrators, Quality Control (QC) materials, Access Wash Buffer II and Access Substrate (Lumi-Phos PRO). ## B Principle of Operation: The Access TSH (3rd IS) assay is a two-site immunoenzymatic (“sandwich”) assay. A sample is added to a reaction vessel with mouse anti-hTSH-alkaline phosphatase conjugate, buffered protein solution and paramagnetic particles coated with immobilized mouse monoclonal anti-hTSH antibody. The hTSH binds to the immobilized monoclonal anti-hTSH antibody on the solid phase while the mouse anti-hTSH-alkaline phosphatase conjugate reacts with a different antigenic site on the hTSH. After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then, the chemiluminescent substrate is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of analyte in the sample. Analyte concentration is automatically determined from a stored multi-point calibration curve. ## C Instrument Description Information: 1. Instrument Name: DxI 9000 Access Immunoassay Analyzer 2. Specimen Identification: Specimen identification can be done by a barcode or by manual entry. Barcode labels are read by the analyzer. Orders that are entered manually include the rack ID and position, so bar code labels are not necessary for sample identification. 3. Specimen Sampling and Handling: Specimen sampling and handling procedures are analyte-specific and are documented in the specific reagent Instructions for Use (IFU). 4. Calibration: Calibrators are packaged in sets and are dedicated to particular assays. The number of calibrators required is defined by the assay protocol file. Specific information is provided on a calibration card included with each calibrator set. This data can be entered into the system configuration using a virtual keyboard or the external barcode gun. Assay calibration can be performed when prompted by the DxI 9000 analyzer or when requested by the operator. Assay calibration data are automatically evaluated by the system, using acceptance criteria defined by the assay protocol file (APF). The calibration acceptance criteria are automatically applied to the data and acceptance or rejection of data occurs without operator intervention. A current (or active) assay calibration is required for each assay that is to be performed. {3} The DxI 9000 analyzer provides three types of assay calibrations. - Quantitative calibrator results provide a multipoint calibration curve that is used to calculate the concentration of an analyte in a patient sample or control. A calibration curve is used to convert raw measurements in RLUs to specific analyte concentrations. Results are then expressed as numerical units. - Semiquantitative calibrator results provide a multipoint calibration curve to which patient samples are compared in order to calculate a concentration value and categorize them into qualitative classes for the analyte such as reactive, non-reactive, or equivocal. - Qualitative calibrator results provide a cutoff determined by a predefined formula defined in the APF. The analyzer compares a result to the cutoff and then expresses the result as reactive or non-reactive for the analyte. ## 5. Quality Control: The labeling recommends that at least two levels of an appropriate quality control material be tested a minimum of once a day. The labeling also recommends that quality control testing should be performed in accordance with laboratory accreditation requirements, applicable laws and good laboratory practices. ## V Substantial Equivalence Information: ### A Predicate Device Name(s): Access TSH (3rd IS) Assay Access 2 Immunoassay System ### B Predicate 510(k) Number(s): K153651 K121214 ### C Comparison with Predicate(s): | Device & Predicate Device(s): | K221225 | K153651 | | --- | --- | --- | | Device Trade Name | Access TSH (3rd IS) Assay | Access TSH (3rd IS) Assay | | General Device Characteristic Similarities | | | | Intended Use/Indications For Use | The Access TSH (3rd IS) assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of human | Same | {4} | | thyroid-stimulating hormone (thyrotropin, TSH, hTSH) levels in human serum and plasma using the Access Immunoassay Systems. This assay is capable of providing 3rd generation TSH results. | | | --- | --- | --- | | Analyte Measured | Human thyroid-stimulating hormone (thyrotropin, TSH, hTSH) | Same | | Traceability | WHO 3rd International Reference Preparation Thyroid Stimulating Hormone, Human (NIBSC Coded 81/565) | Same | | Technology | Sandwich immunoassay | Same | | Format | Chemiluminescent | Same | | Calibration | Utilizes a stored calibration curve | Same | | Sample Type | Serum or plasma | Same | | Sample Volume | Use 30 μL of sample for each determination in addition to the sample container and system dead volumes. Use 50 μL of sample in addition to the sample container and system dead volumes for each determination run with the automated dilution feature. | Same | | Measuring Range | 0.01 – 50.0 μIU/mL | Same | | General Device Characteristic Differences | | | | Instrument | DxI 9000 Access Immunoassay Analyzer | UniCel DxI 800 Immunoassay System | | Substrate | Lumi-Phos PRO substrate | Access Substrate | {5} | Reagent Configurations | Two Configurations:1) 200 determinations, 2packs, 100 tests/pack(for predicate andcandidate instrument)2) 400 determinations, 2packs, 200 tests/pack(for candidateinstrument only) | One Configuration:200 determinations, 2packs, 100 tests/pack | | --- | --- | --- | | Device & Predicate Device(s): | K221225 | K121214 | | --- | --- | --- | | Device Trade Name | DxI 9000 Access Immunoassay Analyzer | Access 2 Immunoassay System | | General Device Characteristic Similarities | | | | Intended Use/Indications For Use | For the quantitative, semi-quantitative, or qualitative determination of various analyte concentrations found in human body fluids. | Same | | Signal Source | Photons generated by chemiluminescent substrate reacting with alkaline phosphatase. | Same | | Signal Detector | Photomultiplier tube (PMT) | Same | | Data Analysis | Internal data reduction methods via microcomputer | Same | | General Device Characteristic Differences | | | | Data Output | Digital display and PDF file creation | Digital display and printed alpha-numeric hard copy | | Temperature Control | The following modules are temperature controlled:• Reaction build and reaction incubation• Substrate reaction zone• Reagent storage | The following modules are temperature controlled:• Reaction incubation• Substrate reaction zone• Reagent storage | {6} | | • Sample aliquot storage • Reagent pipettors • Dispense probes | | | --- | --- | --- | | Sample Loading Capacity | 133 sample containers | 60 sample containers | | Sample Storage Capacity (on-board) | 268 sample vessels | None | | Reagent Capacity | 50 Access Reagent packs on board | 24 Access Reagent packs on board. | | Throughput (Maximum tests/hour) | Approximately 450 | Approximately 100 | | Number of Reagent Pipettors | Four | One | VI Standards/Guidance Documents Referenced: CLSI EP05-A3: Evaluation of Precision of Qualitative Measurement Methods Procedures; Approved Guideline – Third Edition CLSI EP06-Ed2: Evaluation of the Linearity of Quantitative Measurement Procedures – 2nd Edition CLSI EP25-A: Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline IEC 62304 Edition 1.1 2015-06 CONSOLIDATED VERSION IEC 62366-1 Edition 1.1 2020-06 CONSOLIDATED VERSION ISO 15223-1 Third Edition 2016-11-01 Medical devices - Symbols to be used with information to be supplied by the manufacturer - Part 1: General requirements VII Performance Characteristics (if/when applicable): A Analytical Performance: 1. Precision/Reproducibility: Precision studies were conducted to estimate repeatability and within-laboratory precision. The study was run on three DxI 9000 Immunoassay Analyzers and three reagent pack lots. Five serum samples with approximate TSH concentrations of 0.02, 0.4, 5.0, 12.0 and 50.0 $\mu$ IU/mL were used in the determination of imprecision. Each sample was assayed in duplicate, in two runs per day, over twenty days for a total of 40 runs and 80 replicates per instrument. Each instrument was evaluated with one reagent lot. The within-run, between-run, between-day, and total imprecision was calculated. Results from multiple lots were similar. Results from one representative lot are provided in the table below: {7} | Sample | n | Mean (μIU/mL) | Within-run | | Between-run | | Between-day | | Total | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | SD (μIU/mL) | CV (%) | SD (μIU/mL) | CV (%) | SD (μIU/ml) | CV (%) | SD (μIU/mL) | CV (%) | | 1 | 80 | 0.022 | 0.0012 | 5.5 | 0.0003 | 1.5 | 0.0006 | 2.8 | 0.0014 | 6.4 | | 2 | 80 | 0.36 | 0.009 | 2.6 | 0.007 | 2.0 | 0.008 | 2.3 | 0.014 | 4.0 | | 3 | 80 | 4.7 | 0.12 | 2.5 | 0.06 | 1.3 | 0.07 | 1.4 | 0.15 | 3.2 | | 4 | 80 | 12 | 0.4 | 3.8 | 0.0 | 0.1 | 0.2 | 2.1 | 0.5 | 4.3 | | 5 | 80 | 46 | 1.0 | 2.1 | 0.3 | 0.7 | 0.8 | 1.8 | 1.3 | 2.8 | A reproducibility study was conducted to assess instrument-to-instrument variability. Five serum samples with different TSH concentrations were run on three DxI 9000 Immunoassay Analyzers. The samples were tested across three reagent lots and one calibrator lot on each instrument with five replicates per run and one run per day over five days. The within-run, between-day, between-instrument, and reproducibility was calculated for each reagent lot. Results from multiple lots were similar. Results from one representative lot are provided below: | | n | Mean (μIU/mL) | Repeatability Within-run | | Between day | | Between instrument | | Reproducibility | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | SD (μIU/mL) | CV (%) | SD (μIU/mL) | CV (%) | SD (μIU/ml) | CV (%) | SD (μIU/mL) | CV (%) | | 1 | 75 | 0.024 | 0.0006 | 2.6 | 0.0004 | 1.8 | 0.0006 | 2.5 | 0.0010 | 4.0 | | 2 | 75 | 0.37 | 0.012 | 3.3 | 0.010 | 2.8 | 0.000 | 0.0 | 0.016 | 4.3 | | 3 | 75 | 4.8 | 0.11 | 2.3 | 0.14 | 2.8 | 0.04 | 0.7 | 0.18 | 3.7 | | 4 | 75 | 12 | 0.2 | 2.1 | 0.2 | 2.0 | 0.3 | 2.4 | 0.5 | 3.8 | | 5 | 75 | 46 | 1.1 | 2.4 | 0.5 | 1.1 | 1.0 | 2.1 | 1.6 | 3.4 | # 2. Linearity: Two studies were performed to determine the linearity of the Access TSH (3rd IS) assay on the DxI 9000 Access Immunoassay Analyzer. In Study One, serum samples covering the full analytical measuring range of the assay were used for the linearity determination. A native serum sample containing a low concentration of TSH and a high sample (prepared by spiking TSH antigen into a low serum sample) were mixed to make nine sample concentrations (0.002 - 58.545 $\mu$ IU/mL) evenly distributed across the analytical measuring range. The low sample was run in replicates of eight, and all other samples were run in replicates of four. This study was run on one DxI 9000 Immunoassay Analyzer, using three reagent lots and one calibrator lot. The deviation from linearity did not exceed 0.0000003 $\mu$ IU/mL for values $\leq 0.02$ $\mu$ IU/mL or $5\%$ for values $>0.02$ $\mu$ IU/mL. The results support the Access TSH (3rd IS) assay's claimed measuring range of 0.01 to $50.0~\mu \mathrm{IU / mL}$ . In Study Two, serum samples covering the low end of the assay measuring range were used for the linearity determination. A native serum sample containing a low concentration of TSH and the high sample (prepared at a concentration near $5\mu \mathrm{IU} / \mathrm{mL}$ by spiking TSH antigen into a low serum sample) were mixed to make nine sample concentrations (0.002 - 4.898 $\mu \mathrm{IU} / \mathrm{mL}$ ) to achieve concentrations that covered the low range of the assay. The low {8} sample was run in replicates of eight, and all other samples were run in replicates of four. This study was run on one DxI 9000 Immunoassay Analyzer, using three reagent pack lots and one calibrator lot. The deviation from linearity did not exceed $0.000001\ \mu\mathrm{IU/mL}$ for values $\leq 0.02\ \mu\mathrm{IU/mL}$ or $6\%$ for values $>0.02\ \mu\mathrm{IU/mL}$. The results support the Access TSH (3rd IS) assay's claimed measuring range of 0.01 to $50.0\ \mu\mathrm{IU/mL}$. 3. Analytical Specificity/Interference: The sponsor stated that the reagents for the Access TSH (3rd IS) reagent are unchanged in this submission. Therefore, specificity as reviewed in K153651 is adequate to describe the specificity of the candidate test system. 4. Assay Reportable Range: See section VII.A.2 Linearity. 5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods): Traceability: The measurand (TSH) in the Access TSH (3rd IS) Calibrator is traceable to WHO 3rd International Reference Preparation, (NIBSC Coded 81/565). 6. Detection Limit: i. Limit of Blank (LoB) The LoB study was run on three DxI 9000 Immunoassay Analyzers, using three reagent pack lots and one calibrator lot. Four S0 calibrator lots were used as sample for the LoB determination. Samples were tested over three days one run per day, five replicates per run, for each pack lot for a total of 180 replicates. The LoB was calculated for each lot and determined to be $0.002\ \mu\mathrm{IU/mL}$ using the $95\%$ non-parametric percentile of the replicates for each of three reagent lots. ii. Limit of Detection (LoD) The LoD study was run using eight serum samples with low TSH concentrations on three DxI 9000 Immunoassay Analyzers, using three reagent pack lots and one calibrator lot. In total, forty-five (45) replicates (nine replicates per day over five days) of each of the eight low serum samples were measured for the LoD determination. The LoD was calculated for each lot and determined to be $0.003\ \mu\mathrm{IU/mL}$ based on the precision model, multiplied by the $95^{\text{th}}$ percentile of the standard normal distribution and added to the LoB to calculate the LoD. iii. Limit of Quantitation (LoQ) The LoQ study was run using thirteen serum samples with low TSH concentrations. Samples were tested on three DxI 9000 Immunoassay Analyzers, using three reagent pack lots and one calibrator lot. Each of the samples were run in replicates of nine, in one run per {9} day, for five days on three reagent pack lots (45 replicates of each sample on each reagent lot). In total, one hundred thirty-five (135) replicates of each of the thirteen serum samples were measured for the LoQ determination. A variance components model was used to estimate the $\% \mathrm{CV}$ for each sample on each instrument and reagent lot combination. A log-log quadratic precision profile model was fitted to between-run $\% \mathrm{CV}$ versus observed sample mean. The fitted precision profile was used to calculate the $10\%$ CV LoQ for each combination of reagent lot and instrument. The claimed LoQ value is $0.003\mathrm{uIU / mL}$ . | Analyte | LoB | LoD | LoQ | | --- | --- | --- | --- | | Access TSH (3rd IS) | 0.002 μIU/mL | 0.003 μIU/mL | 0.003 μIU/mL | These studies support the Access TSH (3rd IS) assay's claimed measuring range of 0.01 to $50.0~\mu \mathrm{IU / mL}$ . # 7. Assay Cut-Off: Not applicable. # 8. Accuracy (Instrument): See Section VII B1. Method Comparison with Predicate Device. # 9. Carry-Over: The DxI 9000 analyzer utilizes disposable pipette tips when aspirating and dispensing samples to minimize carryover associated with samples containing high concentrations of analyte. Studies were conducted to measure and assess the risk of carryover on the DxI 9000 Access Immunoassay Analyzer. The results of the studies support that the risk of carryover based on the analyzer's design has been appropriately mitigated. # B Comparison Studies: # 1. Method Comparison with Predicate Device: A method comparison study was performed comparing the Access TSH (3rd IS) assay on the DxI 9000 analyzer to the comparator device, the Access TSH (3rd IS) assay on the Access 2 Immunoassay System. A total of one hundred eleven (111) native serum samples were evaluated. The study was run on three DxI 9000 instruments and three Access 2 instruments with three reagent pack lots and three calibrator lots. The Passing-Bablok regression analysis results between Access TSH (3rd IS) DxI 9000 analyzer values (dependent variable, y) and the Access TSH (3rd IS) assay on the Access 2 Immunoassay System values (x, comparator), are shown below: | N | Concentration Range (μIU/mL) | Intercept (95% CI) (μIU/mL) | Slope (95% CI) | Correlation Coefficient (r) | | --- | --- | --- | --- | --- | | 111 | 0.01 - 47 | -0.019 (-0.10 to -0.0037) | 1.06 (1.04 to 1.07) | 1.00 | {10} 2. **Matrix Comparison:** Matrix comparison studies for serum (no gel), serum (gel) and lithium heparin plasma were reviewed in K153651. **C Clinical Studies:** 1. **Clinical Sensitivity:** Not applicable 2. **Clinical Specificity:** Not applicable 3. **Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):** Not applicable **D Clinical Cut-Off:** Not applicable **E Expected Values/Reference Range:** Reference range information was reviewed in K153651. **F Other Supportive Instrument Performance Characteristics Data:** **VIII Proposed Labeling:** The labeling supports the finding of substantial equivalence for this device. **IX Conclusion:** The submitted information in this premarket notification is complete and supports a substantial equivalence decision.