OLYMPUS TSH REAGENT, CALIBRATOR AND CONTROL AND AU3000I IMMUNOASSAY SYSTEM
Device Facts
| Record ID | K062581 |
|---|---|
| Device Name | OLYMPUS TSH REAGENT, CALIBRATOR AND CONTROL AND AU3000I IMMUNOASSAY SYSTEM |
| Applicant | Olympus America, Inc. |
| Product Code | JLW · Clinical Chemistry |
| Decision Date | Nov 29, 2006 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1690 |
| Device Class | Class 2 |
Indications for Use
The Olympus thyroid stimulating hormone (TSH) assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of TSH levels in human serum and plasma using the Olympus AU3000i™ Immunoassay System. Measurements of TSH produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders. The Olympus TSH Calibrator is used for calibrating the quantitative Olympus TSH Assay on the Olympus AU3000i Immunoassay System. The Olympus TSH Control is used for quality control of the Olympus TSH test system on the Olympus AU3000i Immunoassay System. The Olympus AU3000i Immunoassay System is a chemiluminescent discrete photometric chemistry analyzer for the quantitative determination of analytes in human serum and plasma.
Device Story
The Olympus TSH Test System is a two-step paramagnetic particle enzyme immunoassay performed on the Olympus AU3000i Immunoassay System. Input: human serum or plasma samples. Operation: samples incubate with monoclonal anti-TSH antibody-coated paramagnetic particles; a second alkaline phosphatase-conjugated anti-TSH antibody is added to form a sandwich complex; unbound material is washed away. A chemiluminescent substrate reacts with the bound alkaline phosphatase; the resulting light emission is measured by a luminometer. Output: TSH concentration in mIU/L or µIU/mL, calculated via a pre-defined calibration curve. Used in clinical laboratory settings by trained personnel. The system provides automated, high-throughput (240 results/hour) quantitative analysis to assist clinicians in diagnosing thyroid or pituitary disorders.
Clinical Evidence
Bench testing only. Precision evaluated per CLSI EP05-A2 (n=80, CVs 2.2-6.0%). Linearity/recovery assessed across 0.001-130 mIU/L range (mean recovery 93.68%). Analytical sensitivity (0.0002 mIU/L) and functional sensitivity (0.0013 mIU/L) established. Specificity testing showed no significant cross-reactivity with FSH, LH, or hCG. Interference testing confirmed robustness against bilirubin, hemoglobin, Intralipid, and rheumatoid factor. Method comparison (n=127) against predicate showed high correlation (r=0.9931). Matrix comparison validated serum, EDTA, and lithium heparin plasma.
Technological Characteristics
Two-step paramagnetic particle enzyme immunoassay. Reagents: murine monoclonal anti-TSH antibodies, alkaline phosphatase conjugate, Tris/MES buffers. Analyzer: Olympus AU3000i chemiluminescent discrete photometric chemistry analyzer. Energy: luminometer-based light detection. Connectivity: RS232C bidirectional host interface. Calibration: polygonal curve, max 16 master points. QC: Westgard multirule, Shewhart X-R. Software: automated calculation of TSH concentration.
Indications for Use
Indicated for the quantitative determination of TSH levels in human serum and plasma to aid in the diagnosis of thyroid or pituitary disorders. For use by clinical professionals on the Olympus AU3000i Immunoassay System.
Regulatory Classification
Identification
A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known as thyrotrophin and thyrotrophic hormone, in serum and plasma. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.
Predicate Devices
- Roche Elecsys® TSH Assay (k961491)
- Roche Elecsys® TSH CalSet (k060754)
- Roche Elecsys® PreciControl TSH (k962573)
- Roche Elecsys® 2010 analyzer (k961481)
Submission Summary (Full Text)
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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY AND INSTRUMENT COMBINATION TEMPLATE
A. 510(k) Number:
k062581
B. Purpose for Submission:
New device
C. Measurand:
Thyroid stimulating hormone (TSH)
D. Type of Test:
Quantitative, Chemiluminescent Immunoassay
E. Applicant:
Olympus America, Inc.
F. Proprietary and Established Names:
Olympus TSH Reagent, Calibrator and Control and AU3000i Immunoassay System
G. Regulatory Information:
1. Regulation section:
21 CFR §862.1690-Thyroid stimulating hormone test system.
21 CFR §862.1150-Calibrator.
21 CFR §862.1660-Quality control material (assayed and unassayed).
21 CFR §862.2160-Discrete Photometric Chemistry Analyzer for Clinical Use
2. Classification:
2, 2, 1 reserved, 1 respectively
3. Product code:
JLW Radioimmunoassay, Thyroid-Stimulating Hormone
JIS Calibrator, Primary
JJX Single (Specified) Analyte Controls (Assayed and Unassayed)
JJE Analyzer, Chemistry (Photometric, Discrete), For Clinical Use
4. Panel:
Chemistry (75)
H. Intended Use:
1. Intended use(s):
See indication for use below
2. Indication(s) for use:
The Olympus thyroid stimulating hormone (TSH) assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of TSH levels in human serum and plasma using the Olympus AU3000i™ Immunoassay System.
Measurements of TSH produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.
The Olympus TSH Calibrator is used for calibrating the quantitative Olympus TSH Assay on the Olympus AU3000i Immunoassay System.
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The Olympus TSH Control is used for quality control of the Olympus TSH test system on the Olympus AU3000i Immunoassay System.
The Olympus AU3000i Immunoassay System is a chemiluminescent discrete photometric chemistry analyzer for the quantitative determination of analytes in human serum and plasma.
3. Special conditions for use statement(s):
Prescription use only
4. Special instrument requirements:
Olympus AU3000i™ Immunoassay System.
# I. Device Description:
# Olympus TSH reagent kit
R1: Paramagnetic particles coated with murine monoclonal anti-TSH antibody, Tris buffer, pH 7.3 with protein stabilizers and preservative.
R2: Alkaline phosphatase labeled murine monoclonal anti-TSH antibody, MES buffer, pH 6.5 with protein stabilizers and preservative.
CALIBRATOR: TSH prepared in bovine matrix with preservative.
CONTROL: TSH prepared in human matrix with preservative.
The components used in this product contain materials of human or animal origin.
Components derived from human blood have been tested by an FDA approved method and found to be non-reactive for HBsAg, anti-HCV, and anti-HIV-1/HIV-2.
# J. Substantial Equivalence Information:
1. Predicate device name(s):
Reagent: Roche Elecsys® TSH Assay
Calibrator: Roche Elecsys® TSH CalSet
Control: Roche Elecsys® PreciControl TSH
Analyzer: Roche Elecsys® 2010 analyzer
2. Predicate 510(k) number(s):
k961491, k060754, k962573, k961481
3. Comparison with predicate:
| Item | Similarities | |
| --- | --- | --- |
| | AU3000i with TSH | Roche Elecsys® TSH |
| Intended Use | Quantitative determination of thyroid stimulating hormone (TSH) levels in human serum/plasma | Immunoassay for the in vitro quantitative determination of thyrotropin in human serum and plasma. |
| Traceability | WHO | WHO |
| Detection/Operating Principle | Chemiluminescence | Chemiluminescence |
| Assay Methodology | Sandwich immunoassay | Sandwich immunoassay |
| Solid Phase | Micro-particle | Micro-particle |
| Sample Type | Serum and plasma | Serum and plasma |
| Antibody | Monoclonal anti-TSH mouse antibody | Monoclonal anti-TSH mouse antibody |
| Analyzer Reagents | On-board StorageBar-coded (1-D & 2-D) reagent, calibrator & controlCap/septum for increased reagent | On-board StorageBar-coded (1-D & 2-D) reagent, calibrator & controlCap/septum for increased reagent |
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| Item | Similarities | |
| --- | --- | --- |
| | AU3000i with TSH | Roche Elecsys® TSH |
| | stability and evaporation control | stability and evaporation control |
| Reagent, Calibrator and Control storage form | Liquid | Liquid |
| Calibration and Control Stability | Unopened • At 2-8°C up to the stated expiration date Opened • 28 days / 4 weeks at 2-8°C | Unopened • At 2-8°C up to the stated expiration date Opened • 28 days / 4 weeks at 2-8°C |
| Control levels and target concentration range | One Euthyroid/Hyperthyroid threshold | One Euthyroid/Hyperthyroid threshold |
| Control constituents | Single | Single |
| Control Matrix | Human serum with added antigen | Human serum with added antigen |
| Analyzer System | Fully automated Random access Computer controlled Stat capability | Fully automated Random access Computer controlled Stat capability |
| Analyzer/User Interface | Keyboard/touch screen control Colored touch screen monitor Stationary barcode scanners Graphical user interface On line help | Keyboard/touch screen control Colored touch screen monitor Stationary barcode scanners Graphical user interface On line help |
| Analyzer Consumables | Disposable reaction vessels Disposable sample tips | Disposable reaction vessels Disposable sample tips |
| Analyzer Sample Detection | Liquid Level Detection Clot Detection | Liquid Level Detection Clot Detection |
| Analyzer Host Interface | RS232C bidirectional | RS232C bidirectional |
| Differences | | |
| Item | AU3000i with TSH | Roche Elecsys® TSH |
| Instrument Required | Olympus AU3000i™ Immunoassay System | Roche Elecsys and Modular analytics immunoassay analyzers. |
| Traceability | WHO 3rdIS 81/565 | WHO 2ndIRP 80/558 |
| Calibrator levels and target Concentration | One Cal: 13 mIU/L | Two Cal 1: 0 mIU/L Cal 2: 1.5 mIU/L |
| Solid phase binding principle | Direct coating | Biotin and streptavidin |
| Assay Range | 0.001 – 130 mIU/L | 0.005 – 100 mIU/L |
| Calibrator Matrix | Bovine serum human pituitary TSH | Horse serum with added recombinant TSH |
| Analyzer Sample Volume | 10 – 100 μl | 10 – 50 μl |
| Analyzer Reagent Positions | 24 reagent positions 2 diluent/pretreatment positions | 15 reagent positions 2 diluent/pretreatment positions |
| Analyzer Throughput | 240 results/hour | 88 results/hour |
# K. Standard/Guidance Document Referenced (if applicable):
CLSI - Evaluation of Precision Performance of Clinical Chemistry Devices - EP05-A2
CLSI - Interference Testing in Clinical Chemistry - EP07-A2
CLSI - Method Comparison and Bias Estimation Using Patient Samples - EP09-A2
CLSI - How to Define and Determine Reference Intervals in the Clinical Laboratory - EP28-A2
CLSI - Clinical Evaluation of Immunoassays - I/LA21-A
IEC - Medical Devices - Risk Analysis - EN 14971
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CEN - Stability Testing of In Vitro Diagnostic Reagents - EN 13640
L. Test Principle:
The Olympus TSH assay is a two-step paramagnetic particle enzyme immunoassay. It is based on the sandwich principle and used to quantitate TSH in serum/plasma.
The Olympus TSH assay reagent and sample are added to the assay cuvette in the following sequence:
1. Samples are incubated first with a monoclonal anti-TSH antibody bound to paramagnetic particles.
2. After a washing step, a second monoclonal anti-TSH antibody conjugated with alkaline phosphatase is added. The TSH reacts with the paramagnetic particles and the conjugated antibody to form a sandwich complex. Washing steps remove the unbound material.
3. The chemiluminescent substrate is added to the assay cuvette and reacts with the bound alkaline phosphatase (ALP). Light generated by the reaction is measured by the luminometer. The light emission is proportional to the quantity of TSH in the sample.
4. Results are calculated from a pre-defined calibration curve. The Olympus AU3000i system automatically calculates the TSH concentration of each sample in mIU/L or $\mu \mathrm{IU} / \mathrm{mL}$.
M. Performance Characteristics (if/when applicable):
1. Analytical performance:
a. Precision/Reproducibility:
Precision was determined using pooled human sera according to CLSI protocol EP5-A: 2 per day for 20 days (n=80).
| Sample | | Within run | | Total | |
| --- | --- | --- | --- | --- | --- |
| | Mean [mIU/L] | SD [mIU/L] | CV [%] | SD [mIU/L] | CV [%] |
| 1 | 0.119 | 0.003 | 2.7 | 0.003 | 2.9 |
| 2 | 2.145 | 0.047 | 2.2 | 0.128 | 6.0 |
| 3 | 46.255 | 1.070 | 2.3 | 1.696 | 3.7 |
b. Linearity/assay reportable range:
Assay measuring range is approximately $0.001 - 130\mathrm{mIU / L}$.
To assess performance of the device, four patient samples at various concentrations were serially diluted with a prepared standard solution built with an artificial matrix. The recovery of each sample was measured using the Olympus TSH Assay. Precent recovery was calculated as follows:
$$
\% \text{Recovery} = \frac{\text{Observed value}}{\text{Expected value}} \times 100
$$
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Results are summarized below:
| Sample | Dil. | Expected [mIU/L] | Observed [mIU/L] | Recovery [%] | Total Mean [%] |
| --- | --- | --- | --- | --- | --- |
| 1 | - | | 134.835 | 100.00 | |
| | 1:2 | 67.418 | 67.233 | 99.73 | |
| | 1:4 | 33.709 | 31.190 | 92.53 | |
| | 1:8 | 16.854 | 15.454 | 91.69 | |
| | 1:16 | 8.427 | 7.306 | 86.70 | |
| | Mean | | | 92.66 | |
| 2 | - | - | 29.404 | 100.00 | |
| | 1:2 | 14.702 | 15.373 | 104.57 | |
| | 1:4 | 7.351 | 6.878 | 93.56 | |
| | 1:8 | 3.6755 | 3.301 | 89.81 | |
| | 1:16 | 1.8378 | 1.581 | 86.01 | |
| | Mean | - | - | 93.49 | |
| 3 | - | - | 2.141 | 100.00 | |
| | 1:2 | 1.071 | 1.046 | 97.72 | |
| | 1:4 | 0.2676 | 0.465 | 86.86 | |
| | 1:8 | 0.5353 | 0.238 | 88.86 | |
| | 1:16 | 0.1338 | 0.120 | 90.03 | |
| | Mean | - | - | 90.87 | |
| 4 | - | - | 0.459 | 100.00 | |
| | 1:2 | 0.2295 | 0.229 | 99.66 | |
| | 1:4 | 0.1148 | 0.113 | 98.82 | |
| | 1:8 | 0.0574 | 0.056 | 97.49 | |
| | 1:16 | 0.0287 | 0.027 | 94.86 | |
| | Mean | - | - | 97.70 | |
Four human serum samples in the range of 0.459 to $134.835\ \mathrm{mIU/L}$ of TSH were diluted and assayed. The recoveries ranged from $86.01\%$ to $104.57\%$ with a mean of $93.68\%$. Therefore, the Olympus TSH assay can recover diluted analyte in serum within $\pm 10\%$ of the total mean.
c. Traceability, Stability, Expected values (controls, calibrators, or methods): The TSH calibrator is traceable to the WHO $3^{\text{rd}}$ International Standard 81/565. The calibration material is prepared by creating a master calibrator from the reference material and bovine serum matrix in which the value assignment is verified with 1 instrument, 3 runs, 6 replicates per run. Lot specific master curve and calibrator value assignment are determined on 1 instrument, 3 runs, 15 replicates per run. Once open, the calibrator is stable at $2-8^{\circ}\mathrm{C}$ for 28 days, and unopened until the stated expiration date which is validated with ongoing real time stability studies.
The TSH Control target concentration range is set at the euthroid/hyperthyroid threshold. Value assignments are determined on 3 instruments, 3 runs, 3 days, 5 replicates per run. Once open, the control is stable at $2-8^{\circ}\mathrm{C}$ for 28 days and unopened until the stated expiration date which is validated with ongoing real time stability studies.
d. Detection limit:
Analytical Sensitivity
The lowest detectable level on an Olympus AU3000i analyzer was calculated as $0.0002\ \mathrm{mIU/L}$. The lower end of the measuring range for this device was
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determined to be 0.001 mIU/L.
The lowest detectable level represents the lowest measurable level of TSH that can be distinguished from zero. It is calculated as the absolute mean plus two standard deviations of 20 replicates of an analyte free sample.
## Functional sensitivity
The functional sensitivity on an Olympus AU3000i analyzer was calculated as 0.0013 mIU/L.
The functional sensitivity is the lowest TSH concentration that can be measured reproducibly with an interassay CV of 20 %.
### e. Analytical specificity:
#### Analytical Specificity
The following cross-reactivities have been determined for the assay by adding a pre-defined amount of potential cross-reactants to a human sample.
The AU3000i TSH assay has no significant cross reactivity with the following substances, at the concentration levels listed.
- FSH - ≤ 1500 mIU/mL
- LH - ≤ 2500 mIU/mL
- hCG - ≤ 500,000 mIU/mL
#### Interfering Substances
Results of studies conducted to evaluate the susceptibility of the method to interference were as follows:
- Icterus: Interference less than 10% up to 40 mg/dL (or 684 µmol/L) bilirubin.
- Hemolysis: Interference less than 5% up to 5 g/L hemoglobin
- Lipemia: Interference less than 3% up to 10 g/L Intralipid®
- Rheumatoid factor: No significant interference up to 2010 IU/mL of rheumatoid factor.
### f. Assay cut-off:
Not Applicable
### 2. Comparison studies:
#### a. Method comparison with predicate device:
Patient serum/plasma samples were used to compare the Olympus TSH assay on the Olympus AU3000i analyzer against another commercially available TSH assay using CLSI protocol EP9-A. Results of regression by Passing-Bablok analysis were as follows:
| N | Range of concentrations [mIU/L] | Intercept [mIU/L] | Slope | Correlation Coefficient |
| --- | --- | --- | --- | --- |
| 127 | 0.005 - 136.630 | -0.0046 | 0.935 | 0.9931 |
#### b. Matrix comparison:
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Serum verses plasma study was carried out by collecting blood from at least 10 donors into various blood collection tubes and measuring the TSH concentration in each. The blood collection tubes tested were serum, EDTA plasma, and lithium heparin plasma.
The mean results from each tube were compared by using a paired t-test (95% confidence interval) and % bias.
| Collection Tubes | T-Test
Null
Hypothesis | Mean % Bias |
| --- | --- | --- |
| Serum vs. Li-H | Accepted | N/A |
| Serum vs. EDTA | Rejected | -3.7% |
The t-test showed no statistical difference between serum and lithium heparin plasma. In accordance with the procedures no further analysis was necessary and lithium heparin plasma was accepted as a suitable sample type.
The t-test showed a statistical difference between serum and EDTA plasma. The sponsor determined that the mean % bias between these matrices (-3.7%) was acceptable because it was lower that their predetermined total allowable error for the TSH assay (24.6%).
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:
Reference range defined by National Institutes of health:
0.40 - 4.00 mIU/L
N. Instrument Name:
Olympus AU3000i™ Immunoassay System.
O. System Descriptions:
1. Modes of Operation:
The Olympus AU3000i Immunoassay System is a chemiluminescent discrete random access photometric chemistry analyzer.
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:
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Sequential mode, Rack barcode scan mode, Sample barcode scan mode, download test order and patient identification
4. Specimen Sampling and Handling:
Serum or blood plasma, Urine, Others (RBC, CSF) in sample tubes or cups held in various sample racks
5. Calibration:
- Calibration types
- Polygonal curve
- Index by cut-off value
- Calibration parameters
- Maximum of 16 master calibration points per test
6. Quality Control:
- QC samples
- Maximum of 180 internal, Olympus-supplied controls
- Maximum of 99 external, non-Olympus controls
- Maximum of 6 levels per test can be used
- QC checks
- Shewhart X-R management (within day-to-day deviation)
- Multirule (Westgard method)
- Twin plot
P. Other Supportive Instrument Performance Characteristics Data Not Covered In The "Performance Characteristics" Section above:
Not applicable
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.
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