ADVIA Centaur® TSH3-Ultra II (TSH3ULII)
Device Facts
| Record ID | K233050 |
|---|---|
| Device Name | ADVIA Centaur® TSH3-Ultra II (TSH3ULII) |
| Applicant | Siemens Healthcare Diagnostics, Inc. |
| Product Code | JLW · Clinical Chemistry |
| Decision Date | Apr 4, 2024 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1690 |
| Device Class | Class 2 |
| Attributes | Pediatric |
Indications for Use
The ADVIA Centaur® TSH3-Ultra II (TSH3ULII) assay is for in vitro diagnostic use in the quantitative determination of thyroid-stimulating hormone (TSH, thyrotropin) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP system. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.
Device Story
The ADVIA Centaur TSH3-Ultra II is an automated, third-generation in vitro diagnostic assay for quantitative TSH measurement. It utilizes an immunologic sandwich principle with direct chemiluminescent detection on the ADVIA Centaur XP system. Input samples consist of human serum or plasma (EDTA/lithium heparin). The assay employs paramagnetic particles coated with anti-fluorescein antibodies, an FITC-labeled anti-TSH capture antibody, and a tracer antibody conjugated to acridinium ester and BSA. The system processes these components to produce a chemiluminescent signal proportional to TSH concentration. Used in clinical laboratories, the device provides quantitative results to physicians to assist in diagnosing thyroid or pituitary dysfunction. The assay is standardized to the WHO 3rd IRP 81/565.
Clinical Evidence
Bench testing only. Precision studies (repeatability/within-lab) performed per CLSI EP05-A3; linearity per CLSI EP06; interference/cross-reactivity per CLSI EP07; detection limits (LoB/LoD/LoQ) per CLSI EP17-A2. Method comparison against predicate (N=404) showed slope 0.948, r=0.999. Matrix comparison (serum vs. EDTA/lithium heparin) showed high correlation (r≥0.990). No clinical studies were required.
Technological Characteristics
Direct chemiluminescent immunoassay; immunologic sandwich principle. Solid phase: paramagnetic particles with anti-fluorescein and FITC-labeled anti-TSH antibodies. Tracer: acridinium ester-labeled anti-TSH antibody. Automated system (ADVIA Centaur XP). Traceable to WHO 3rd IRP 81/565. Measuring range: 0.010–150.000 µIU/mL. Sample volume: 100 µL.
Indications for Use
Indicated for the quantitative determination of TSH in human serum and plasma (EDTA and lithium heparin) to aid in the diagnosis of thyroid or pituitary disorders in patients.
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
Related Devices
- K083844 — ADVIA CENTAUR TSH3-ULTRA METHOD · Siemens Healthcare Diagnostics · May 8, 2009
Submission Summary (Full Text)
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FDA
U.S. FOOD & DRUG
ADMINISTRATION
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
ASSAY ONLY
## I Background Information:
A 510(k) Number
K233050
B Applicant
Siemens Healthcare Diagnostics, Inc.
C Proprietary and Established Names
ADVIA Centaur TSH3-Ultra II (TSH3ULII)
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 |
## II Submission/Device Overview:
A Purpose for Submission:
Modification of existing device
B Measurand:
Thyroid Stimulating Hormone (TSH)
C Type of Test:
Quantitative, chemiluminescence immunoassay
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
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# III Intended Use/Indications for Use:
## A Intended Use(s):
See Indications for Use below.
## B Indication(s) for Use:
The ADVIA Centaur® TSH3-Ultra II (TSH3ULII) assay is for in vitro diagnostic use in the quantitative determination of thyroid-stimulating hormone (TSH, thyrotropin) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP system. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.
## C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
### Special Instrument Requirements:
ADVIA Centaur® XP System
# IV Device/System Characteristics:
## A Device Description:
ADVIA Centaur TSH3-Ultra (TSH3-UL) kit consists of the following reagents:
- Ultra-Lite Reagent- bovine serum albumin (BSA) conjugated to monoclonal anti- TSH (~0.3 µg/mL) labeled with acridinium ester in HEPES buffered saline, mouse IgG, BSA, goat serum, surfactant, and preservatives.
- Solid Phase Reagent - anti-fluorescein monoclonal mouse antibody covalently linked to paramagnetic particles (PMP) (~85 µg/mL) in HEPES buffered saline, BSA, goat serum, surfactant, and preservative.
- Ancillary Well Reagent – Fluorescein isothiocyanate conjugated to monoclonal anti-TSH (~3 µg/mL) in HEPES buffered saline, mouse IgG, BSA, goat serum, surfactant, and preservative.
### Product Materials/Contents:
The ADVIA Centaur TSH3ULII assay kit is comprised of the following components:
- 5 Ready Pack primary reagent packs containing TSH3ULII Lite Reagent, Solid Phase, and Ancillary Well Reagent (500 tests).
- Advia Centaur TSH3ULII master curve card.
- 2 vials CAL 3A low calibrator.
- 2 vials CAL 3A high calibrator.
- ADVIA Centaur CAL 3A calibrator assigned value cards and barcode labels.
### Materials Required but Not Provided
The ADVIA Centaur TSH3ULII assay requires ADVIA Centaur Wash 1 as it is utilized in the Assay Procedure (see section below).
## B Principle of Operation:
This assay is a third-generation assay that employs anti-FITC monoclonal antibody covalently bound to paramagnetic particles, an FITC-labeled anti-TSH capture mouse monoclonal antibody, and a tracer consisting of a proprietary acridinium ester and an anti-TSH mouse monoclonal antibody conjugated to bovine serum albumin (BSA) for chemiluminescent detection.
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A direct relationship exists between the amount of TSH present in the patient sample and the amount of relative light units (RLUs) detected by the system.
V Substantial Equivalence Information:
A Predicate Device Name(s):
ADVIA Centaur TSH3-Ultra (TSH3-UL)
B Predicate 510(k) Number(s):
K083844
C Comparison with Predicate(s):
| Device & Predicate Device(s): | K233050 | K083844 |
| --- | --- | --- |
| Device Trade Name | ADVIA Centaur TSH3-Ultra II (TSH3ULII) | ADVIA Centaur TSH3-Ultra (TSH3-UL) |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | Quantitative determination of thyroid-stimulating hormone (TSH, thyrotropin) in human serum and plasma. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders. | Same |
| General Device Characteristic Differences | | |
| Solid Phase Antibody | FITC-labeled mouse monoclonal anti-TSH antibody and mouse monoclonal anti-fluorescein antibody linked to paramagnetic particles. | Mouse monoclonal anti-fluorescein antibody linked to paramagnetic particles. |
VI Standards/Guidance Documents Referenced:
CLSI EP05-A3; 2019 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition
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CLSI EP17-A2; Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline – Second Edition
CLSI EP28-A3c (Formerly C28-A3c); Defining Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline -Third Edit
CLSI EP07 3rd Edition; Interference Testing in Clinical Chemistry.
CLSI EP06 2nd Edition; 7-306 Evaluation of the Linearity of Quantitative Measurement
CLSI EP25-A (Replaces EP25-P); Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline.
## VII Performance Characteristics (if/when applicable):
## A Analytical Performance:
1. Precision/Reproducibility:
Precision studies were conducted following the recommendations in CLSI EP05-A3 to estimate repeatability and within-laboratory precision.
**Repeatability**
The study was run on the candidate device, using 3 reagent lots and one instrument. Six human serum samples, 5 lithium heparin plasma samples, and controls (rhTSH in Multi-Diluent 15 (MDP 1-5)) were tested in duplicate over twenty days, 2 runs per day, 2 replicates per run with for a total of 40 runs and 80 replicates. Analysis was conducted using ANOVA (Analysis of Variance) and the results are summarized below.
| | | | Repeatability | | Within-Laboratory Precision | |
| --- | --- | --- | --- | --- | --- | --- |
| Sample | N | Mean μIU/ml (mlU/L) | SD μIU/ml (mlU/L) | CV (%) | SD μIU/ml (mlU/L) | CV (%) |
| Serum A | 80 | 0.088 | 0.0022 | 2.5 | 0.0032 | 3.6 |
| Serum B | 80 | 0.196 | 0.0035 | 1.8 | 0.0062 | 3.1 |
| Serum C | 80 | 0.507 | 0.0086 | 1.7 | 0.0134 | 2.6 |
| Serum D | 80 | 4.752 | 0.1083 | 2.3 | 0.1293 | 2.7 |
| Serum E | 80 | 46.749 | 1.1297 | 2.4 | 1.8749 | 4.0 |
| Serum F | 80 | 97.929 | 2.1282 | 2.2 | 3.4288 | 3.5 |
| Plasma, lithium heparin A | 80 | 0.099 | 0.0014 | 1.4 | 0.0029 | 2.9 |
| Plasma, lithium heparin B | 80 | 0.520 | 0.0089 | 1.7 | 0.0175 | 3.4 |
| Plasma, lithium heparin C | 80 | 4.908 | 0.0763 | 1.6 | 0.1139 | 2.3 |
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| | | | Repeatability | | Within-Laboratory Precision | |
| --- | --- | --- | --- | --- | --- | --- |
| Sample | N | Mean μIU/ml (mlU/L) | SD μIU/ml (mlU/L) | CV (%) | SD μIU/ml (mlU/L) | CV (%) |
| Plasma, lithium heparin D | 80 | 53.262 | 0.7579 | 1.4 | 1.5032 | 2.8 |
| Plasma, lithium heparin E | 80 | 91.993 | 3.2754 | 3.6 | 5.7348 | 6.2 |
| Control 1 | 80 | 0.104 | 0.0021 | 2.1 | 0.0035 | 3.4 |
| Control 2 | 80 | 0.516 | 0.0087 | 1.7 | 0.0203 | 3.9 |
| Control 3 | 80 | 4.778 | 0.0811 | 1.7 | 0.1316 | 2.8 |
| Control 4 | 80 | 47.494 | 0.6508 | 1.4 | 1.7552 | 3.7 |
| Control 5 | 80 | 99.366 | 1.5194 | 1.5 | 2.9443 | 3.0 |
## Reproducibility
Six human serum samples, five lithium heparin plasma samples, and controls (MDP 1-5) were tested in replicates of five with one run per day over five days for a total of 225 replicates per sample. Testing was performed using three instruments and three reagent lots. The analysis and results were similar to the repeatability study summarized above.
## 2. Linearity:
Linearity testing was performed in accordance with CLSI EP06 2nd Edition. The dilution series contained samples spanning 15 concentrations throughout the measuring range. The maximum % deviation from linearity observed was 7.2%. The results of the linearity study support the claimed measuring range of 0.010-150.000 mIU/L.
## 3. Analytical Specificity/Interference:
### Interference:
Interference testing was performed following the recommendations in CLSI EP07 3rd Edition. Human serum specimen pools with native analyte were supplemented with potentially interfering compounds at the levels listed in the table below. The sponsor provided information to support the following claims:
| Substances | Concentration tested that demonstrated no significant interference |
| --- | --- |
| Hemoglobin | 500 mg/dL |
| Triglycerides | 1000 mg/dL |
| Conjugated bilirubin | 40 mg/dL |
| Unconjugated bilirubin | 40 mg/dL |
| Biotin | 0.35 mg/dL |
| Acetaminophen | 15.60 mg/dL |
| Acetylcysteine | 15.00 mg/dL |
| Acetylsalicylic acid | 3.00 mg/dL |
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| Substances | Concentration tested that demonstrated no significant interference |
| --- | --- |
| Ampicillin Sodium | 7.50 mg/dL |
| Ascorbic Acid | 5.25 mg/dL |
| Carbimazole | 3.00 mg/dL |
| Cefoxitin | 495.00 mg/dL |
| Cyclosporine | 0.18 mg/dL |
| Doxycycline | 1.80 mg/dL |
| Heparin | 7500 units/dL |
| Ibuprofen | 21.90 mg/dL |
| Levodopa | 0.75 mg/dL |
| Levothyroxine | 0.0429 mg/dL |
| Liothyronine | 0.0075 mg/dL |
| Methimazole | 8.00 mg/dL |
| Methyldopa | 2.25 mg/dL |
| Metronidazole | 12.30 mg/dL |
| Octreotide | 0.03 mg/dL |
| Phenylbutazone | 32.10 mg/dL |
| Propranolol | 24.00 mg/dL |
| Propylthiouracil | 30.00 mg/dL |
| Rifampicin | 4.80 mg/dL |
| Theophylline | 6.00 mg/dL |
| Total Protein | 15 g/dL |
| Cholesterol | 400.00 mg/dL |
| Rheumatoid Factor | 00 IU/mL |
The sponsor includes the following limitations in their labeling: Patient samples may contain heterophilic antibodies that could react in immunoassays to give falsely elevated or depressed results. This assay is designed to minimize interference from heterophilic antibodies.
Do not use samples that contain fluorescein. Fluorescein levels > 0.24 µg/mL may decrease results in this assay. Evidence suggests that patients undergoing retinal fluorescein angiography can retain amounts of fluorescein in the body for up to 48–72 hours post-treatment. In the cases of patients with renal insufficiency, including many diabetics, retention could be much longer. Such samples can produce falsely depressed values when tested with this assay, and should not be tested. Testing of samples spiked with a theoretical maximum level of fluorescein (250 µg/mL) used in these patients have resulted in TSH levels < 0.06 µIU/mL instead of the true value of 27.99 µIU/mL.
As with any immuno-recognition measurement of a peptide, extremely rare genetic variants may exhibit varying degrees of detection.
## Cross-Reactivity Testing:
Cross-reactivity was determined using the candidate device in accordance with CLSI EP07 3rd Edition. Cross-reactivity of samples spiked with various substances did not exceed 5%
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at TSH concentrations of approximately 0.400 mIU/L, 5.00 mIU/L, 17.00 mIU/L, and 90.00 mIU/L.
| Substance | Concentration Tested (pg/mL) |
| --- | --- |
| hCG | 200000 mIU/mL |
| FSH | 1500 mIU/mL |
| LH | 600 mIU/mL |
**High-Dose Hook Effect:**
The high-dose hook effect of the candidate device was measured on one instrument using a dilution series. No hook effect was seen up to 3000 µIU/mL. Samples with TSH concentrations above the measuring interval and as high as 3000 µIU/mL will report > 150 mIU/L.
4. **Assay Reportable Range:**
See section VII.A.2 Linearity.
5. **Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):**
This assay is traceable to the World Health Organization (WHO) 3rd International Reference Preparation for human TSH (IRP 81/565).
6. **Detection Limit:**
Detection capability was determined in accordance with CLSI Document EP17-A2.
The limit of blank (LoB) was determined to be 0.005 µIU/mL (mIU/L), the limit of detection (LoD) was determined to be 0.008 µIU/mL (mIU/L) and the limit of Quantitation (LoQ) was determined to be 0.010 µIU/mL (mIU/L).
The LoB corresponds to the highest measurement result likely to be observed for a blank sample with a probability of 95%. The LoD corresponds to the lowest analyte concentration that can be detected with a probability of 95%. The LoQ corresponds to the lowest analyte concentration at which the within laboratory CV is ≤ 20%.
7. **Assay Cut-Off:**
Not applicable.
**B Comparison Studies:**
1. **Method Comparison with Predicate Device:**
A total of 404 native human serum samples were assayed using the candidate (y) and predicate (x) devices and the results were analyzed using Passing & Bablok regression. The results from one representative lot are presented below.
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| N | Sample range | | Slope | r | Regression Equation |
| --- | --- | --- | --- | --- | --- |
| | Low | High | | | |
| 404 | 0.028 | 147.337 | 0.948 | 0.999 | y = 0.95x - 0.016 μIU/mL |
2. Matrix Comparison:
A matrix comparison study was conducted using matched Serum and Lithium Heparin samples and matched Serum and K2-EDTA samples. The results were analyzed using Passing & Bablok regression. The results are presented below.
| Tube (y) vs Serum (x) | Regression Equation | Sample Interval | N | r |
| --- | --- | --- | --- | --- |
| Plasma, EDTA | Y=0.99x - 0.019 | 0.050-147.805 μIU/mL | 52 | 0.999 |
| Plasma, lithium heparin | Y = 1.01x - 0.034 | 0.115-135.881 μIU/mL | 57 | 0.990 |
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:
The sponsor provided information to support the following claimed expected values reported in the labeling.
| Group | N | Reference Interval μIU/mL (mIU/L) |
| --- | --- | --- |
| Euthyroid Adults | 229 | 0.55-4.78 |
| Infants (1-23 months) | 94 | 0.87-6.15 |
| Children (2-12 years) | 198 | 0.67-4.16 |
| Adolescents | 150 | 0.48-4.17 |
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.
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