(245 days)
The Atellica® CH Diazo Total Bilirubin (D TBil) assay is for in vitro diagnostic use in the quantitative determination of total bilirubin in adults and children (non-neonates) in human serum and plasma using the Atellica® CH Analyzer. Measurement of total bilirubin, an organic compound formed during the normal and abnormal destruction of red blood cells, is used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.
Atellica CH Diazo Total Bilirubin is a photometric test using 2,4-dichloroaniline (DCA). Direct bilirubin in presence of diazotized 2,4-dichloroaniline forms a red colored azocompound in acidic solution. A specific mixture of detergents enables the determination of the total bilirubin.
The provided document describes the Siemens Atellica® CH Diazo Total Bilirubin (D_TBil) assay, an in vitro diagnostic device, and its performance characteristics to demonstrate substantial equivalence to a predicate device (Dimension TBI Flex reagent cartridge).
Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria for this in-vitro diagnostic device are generally defined by demonstrating performance within established statistical limits or comparison to a predicate device, as per CLSI (Clinical and Laboratory Standards Institute) guidelines. The "acceptance criteria" themselves are not always explicitly stated as pass/fail thresholds for each performance characteristic in a simple numerical format, but rather as meeting the objectives of the study design (e.g., correlation coefficient of ≥ 0.950).
| Characteristic | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Detection Capability | LoQ < 0.10 mg/dL | LoB: 0.01 mg/dL, LoD: 0.02 mg/dL, LoQ: 0.10 mg/dL |
| Precision (Repeatability) | Not explicitly stated as a single value, but typically refers to a low %CV. | Serum 1 (1.02 mg/dL): SD 0.015 mg/dL (1.5%CV)Serum 2 (13.40 mg/dL): SD 0.053 mg/dL (0.4%CV)Serum 3 (22.39 mg/dL): SD 0.067 mg/dL (0.3%CV) |
| Precision (Within-Lab) | Not explicitly stated as a single value. | Serum 1 (1.02 mg/dL): SD 0.034 mg/dL (3.3%CV)Serum 2 (13.40 mg/dL): SD 0.140 mg/dL (1.0%CV)Serum 3 (22.39 mg/dL): SD 0.189 mg/dL (0.8%CV) |
| Reproducibility (Total) | Not explicitly stated as a single value. | Sample 1 (1.03 mg/dL): SD 0.023 mg/dL (2.2%CV)Sample 2 (13.24 mg/dL): SD 0.091 mg/dL (0.7%CV)Sample 3 (22.14 mg/dL): SD 0.146 mg/dL (0.7%CV) |
| Assay Comparison (Method) | Correlation coefficient (r) ≥ 0.950 and slope of 1.00 ± 0.10 compared to predicate. | r = 0.997 with predicate (Dimension TBI). Regression Equation: y = 1.02x + 0.08 mg/dL. The slope of 1.02 is within the 1.00 ± 0.10 range. |
| Specimen Equivalency | High correlation (r) and a close to 1.00 slope for different plasma types vs. serum. | Plasma (Lithium Heparin) vs. Serum: r = 0.997, y = 0.98x + 0.05 mg/dLPlasma (Sodium Heparin) vs. Serum: r = 0.998, y = 1.00x + 0.02 mg/dLPlasma (K2 EDTA) vs. Serum: r = 0.998, y = 0.99x + 0.03 mg/dL |
| Interferences (HIL) | ≤ 10% bias from hemoglobin and lipemia at specified concentrations. | Hemoglobin (1000 mg/dL): -9.3% bias (at 1.08 mg/dL Bilirubin), -7.1% bias (at 13.86 mg/dL Bilirubin)Lipemia (1000 mg/dL Triglyceride): -7.8% bias (at 0.90 mg/dL Bilirubin), 0.5% bias (at 12.94 mg/dL Bilirubin)All observed biases are ≤ 10%. |
| Non-Interfering Substances | Bias ≤ 10% for listed substances at specified concentrations (often with acceptance criteria of | All listed substances (e.g., Acetaminophen, Carbenicillin, Ascorbic acid, Ibuprofen, etc.) showed observed % bias ≤ 10% or within the specified acceptance criteria for the observed analyte concentration. |
| Expected Values | Verification of reference interval. | Verified reference interval: 0.3 - 1.2 mg/dL (5.13 - 20.52 µmol/L). |
2. Sample Size Used for the Test Set and Data Provenance
- Detection Capability: Not explicitly stated as a "test set" in the context of patient samples, but the determination was in accordance with CLSI Documents EP17-A2.
- Precision:
- Repeatability/Within-Lab Precision: 80 measurements for each of the three serum levels (Serum 1, 2, 3), assayed in duplicate over 20 days.
- Reproducibility: 225 measurements for each of the three serum levels (Sample ID 1, 2, 3), assayed with 5 replicates per run for 5 days using 3 instruments/sites and 3 reagent lots.
- Assay Comparison (Method Comparison): N = 103 patient samples (Serum)
- Specimen Equivalency: N = 57 patient samples for each plasma type (Lithium Heparin, Sodium Heparin, K2 EDTA) compared to serum.
- Interferences (HIL and Non-interfering Substances): The studies were performed with specific interferent concentrations and two bilirubin levels. The sample size refers to the number of spiked samples tested, but not explicitly the number of unique patient samples that may have been used to create these spiked materials.
- Data Provenance: The document does not specify the country of origin for the samples or whether the studies were retrospective or prospective. Given the nature of in-vitro diagnostic development, these are typically prospective studies using a mix of spiked and potentially remnant clinical samples.
3. Number of Experts Used to Establish Ground Truth and Qualifications
This information is not applicable and therefore not provided in the document. For an in-vitro diagnostic assay that quantitatively measures an analyte (total bilirubin), the "ground truth" is established by the reference method or comparison method (the predicate device in this case) and the inherent accuracy and traceability of the calibrators, rather than by human expert review of images or clinical cases. The ground truth for quantitative assays typically relies on metrological traceability to certified reference materials (NIST Standard Reference Material 916 in this case) and established laboratory protocols.
4. Adjudication Method for the Test Set
This is not applicable. Adjudication methods (like 2+1, 3+1) are common in studies involving human interpretation of medical images or clinical data, especially for AI applications where consensus among experts establishes the ground truth. For quantitative in-vitro diagnostics, the "ground truth" is determined by established analytical methods and reference standards, not by human adjudication of qualitative results.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
This is not applicable. An MRMC study is designed to assess the performance of a diagnostic system that involves human readers (e.g., radiologists interpreting images) and typically compares the effectiveness of human readers with and without AI assistance. The Atellica CH Diazo Total Bilirubin assay is an automated in-vitro diagnostic test, meaning it does not involve human readers for interpretation beyond the initial sample collection and analysis setup. It is a standalone analytical device.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
This is essentially what the entire submission describes. The performance characteristics presented (Detection Capability, Precision, Reproducibility, Assay Comparison, Specimen Equivalency, Interference) are all standalone performance studies of the medical device itself. There is no human-in-the-loop component for the interpretation or output of the assay. The device directly measures and reports total bilirubin levels.
7. Type of Ground Truth Used
The ground truth for this quantitative in-vitro diagnostic assay is established through:
- Metrological Traceability: The assay is traceable to the NIST Standard Reference Material 916. This provides a fundamental basis for accuracy.
- Comparison to a Predicate Device: The performance of the new device is compared against a legally marketed predicate device (Dimension TBI assay), which serves as the "truth" or reference in method comparison studies.
- Controlled Samples: Precision, reproducibility, and interference studies use manufactured control materials, internal validations, and spiked samples with known concentrations or interferent levels, whose 'truth' values are established through rigorous analytical methods and often validated against reference methods.
8. The Sample Size for the Training Set
This information is not provided in the document, and it's generally not applicable in the typical sense of "training set" for traditional in-vitro diagnostic devices. These devices are developed, validated, and optimized through a series of analytical studies using various types of samples (e.g., precision materials, linearity samples, spiked samples, patient samples). The "training" isn't a machine learning training phase, but rather the process of optimizing the reagent formulation, reaction kinetics, and instrument parameters. The data used for these optimizations would be proprietary and extensive, but not typically referred to as a "training set" in regulatory submissions for IVDs. The analytical performance studies (like those detailed above) serve as the validation and verification of the final, optimized product.
9. How the Ground Truth for the Training Set Was Established
As explained in point 8, the concept of a "training set" with a defined "ground truth" for a traditional IVD like this is generally not applicable in the same way as for AI/ML devices. The "ground truth" for the development and optimization of such an assay would be established through:
- Reference Methods: Using established, highly accurate reference methods to determine the true concentration of bilirubin in control materials and patient samples used during development.
- Certified Reference Materials: Calibrating and verifying the assay against NIST or other internationally recognized certified reference materials.
- Known Spiking: Creating samples with precisely known additions of bilirubin or interferents to test linearity, recovery, and interference effects.
In summary, the provided document details a comprehensive set of analytical studies to demonstrate the performance and substantial equivalence of the Atellica® CH Diazo Total Bilirubin assay as a standalone in-vitro diagnostic device. The evaluation follows a different paradigm than AI/ML algorithms, thus many questions related to expert review, adjudication, and MRMC studies are not relevant.
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March 20, 2023
Siemens Healthcare Diagnostics Inc. Anthony Calabro Regulatory Affairs Specialist 500 GBC Drive M/S 514, P.O. Box 6101 Newark, DE 19714
Re: K222104
Trade/Device Name: Atellica® CH Diazo Total Bilirubin (D_TBil) Regulation Number: 21 CFR 862.1110 Regulation Name: Bilirubin (Total Or Direct) Test System Regulatory Class: Class II Product Code: CIG Dated: December 22, 2022 Received: December 22, 2022
Dear Anthony Calabro:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal
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statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
| Paula | Digitally signed byPaula Caposino -S |
|---|---|
| Caposino -S Date: 2023.03.2016:51:17 -04'00' |
Paula Caposino, Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
Submission Number (if known)
K222104 Device Name
Atellica® CH Diazo Total Bilirubin (D TBil)
Indications for Use (Describe)
The Atellica® CH Diazo Total Bilirubin (D TBil) assay is for in vitro diagnostic use in the quantitative determination of total bilirubin in adults and children (non-neonates) in human serum and plasma using the Atellica® CH Analyzer. Measurement of total bilirubin, an organic compound formed during the normal and abnormal destruction of red blood cells, is used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.
Type of Use (Select one or both, as applicable)
< | Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
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This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92 and the Safe Medical Device Act of 1990.
The assigned 510(k) Number is: K222104
1. Date Prepared
December 14, 2022
2. Applicant Information
| Contact: | Anthony CalabroRegulatory Affairs Specialist |
|---|---|
| Address: | Siemens Healthcare Diagnostics Inc.P.O. Box 6101, M/S 514Newark, DE 19714-1601 |
| Email: | anthony.calabro@siemens-healthineers.com |
3. Regulatory Information
Atellica® CH Diazo Total Bilirubin (D_TBil) assay
Trade Name: Atellica® CH Diazo Total Bilirubin (D TBil) Common Name: Bilirubin (total or direct) test system Classification Name: Diazo Colorimetry, Bilirubin FDA Classification: Class II Review Panel: Chemistry Product Code: CIG Regulation Number: 21 CFR 862.1110
4. Predicate Device Information
Predicate Device Name: Dimension TBI Flex reagent cartridge 510(k) Number: K060628
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5. Intended Use / Indications For Use
The Atellica® CH Diazo Total Bilirubin (D_TBil) assay is for in vitro diagnostic use in the quantitative determination of total bilirubin in adults and children (non-neonates) in human serum and plasma using the Atellica® CHAnalyzer. Measurement of total bilirubin, an organic compound formed during the normal and abnormal destruction of red blood cells, is used in the diagnosis and treatment of liver,hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.
Special Conditions for Use Statement: For Prescription Use Only
6. Device Description
Atellica CH Diazo Total Bilirubin is a photometric test using 2,4-dichloroaniline (DCA). Direct bilirubin in presence of diazotized 2,4-dichloroaniline forms a red colored azocompound in acidic solution. A specific mixture of detergents enables the determination of the total bilirubin.
7. Purpose of Submission
The purpose of this submission is a premarket notification for a new device: Atellica CH Diazo Total Bilirubin (D TBil) assay
8. Comparison of Candidate Device and Predicate Device
The table below describes the similarities and differences between the Atellica CH Diazo Total Bilirubin assay (Candidate Device) and the Dimension TBI Flex reagent cartridge (Predicate Device).
Substantial equivalence was demonstrated by testing several performance characteristics including measuring interval, expected values, reference interval, precision, method comparison, interference, and specimen equivalence by method comparison.
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| Feature | Candidate Device | Predicate Device |
|---|---|---|
| Atellica® CH Diazo Total Bilirubin(D_TBil) | Dimension TBI Flex reagentcartridge(K060628) | |
| Intended Use | The Atellica® CH Diazo Total Bilirubin(D_TBil) assay is for in vitrodiagnostic use in thequantitative determination of totalbilirubin in adults and children (non-neonates) in human serum andplasma using the Atellica® CHAnalyzer. Measurement of totalbilirubin, an organic compoundformed during the normal andabnormal destruction of red bloodcells, is used in the diagnosis andtreatment of liver,hemolytic hematological, andmetabolic disorders, includinghepatitis and gall bladder block. | The TBI method for the Dimension®clinical chemistry system is an in vitrodiagnostic test intended toquantitatively measure total bilirubinin human serum and plasma.Measurements of total bilirubin areused in the diagnosis and treatment ofliver, hemolytic, hematological, andmetabolic disorders, includinghepatitis and gallbladder disease. |
| Sample Type | Human serum and plasma (lithium heparin,sodium heparin, dipotassium EDTA) | Human Serum and plasma (Lithiumheparin, EDTA) |
| Units of Measure | mg/dL | mg/dL |
| Assay Range / MeasuringInterval | 0.10 mg/dL - 25.0 mg/dL | 0.10 mg/dL - 25.0 mg/dL |
| Expected Values | 0.3mg/dL - 1.2 mg/dL | 0.2 mg/dL - 1.0mg/dL |
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| Feature | Candidate Device | Predicate Device |
|---|---|---|
| Atellica® CH Diazo Total Bilirubin (D_TBil) | Dimension TBI Flex reagent cartridge(K060628) | |
| Assay Principle | Photometric test using 2,4-dichloroaniline (DCA).Direct bilirubin in presence of diazotized 2,4-dichloroaniline forms a red coloredazocompound in acidic solution. A specificmixture of detergents enables the determinationof the total bilirubin. | Diazotized sulfanilic acid is formed bycombining sodium nitrite and sulfanilicacid at low pH. Bilirubin(unconjugated) in the sample issolubilized by dilution in a mixture ofcaffeine/benzoate/acetate/EDTA.Upon addition of the diazotizedsulfanilic acid, the solubilized bilirubinincluding conjugated bilirubins (monoand diglucoronides) and the deltaform4 (biliprotein-bilirubin covalentlybound to albumin) is converted todiazo-bilirubin, a red chromophorerepresenting the total bilirubin whichabsorbs at 540 nm and is measuredusing a bichromatic (540, 700 nm)endpoint technique. A sample blankcorrection is used. |
| Traceability | NIST Standard Reference Material 916 | Same |
| Calibration | Single level calibration | Multi-Level Calibration |
| Calibrators | Atellica CH Bilirubin Calibrator (BILI CAL) | Dimension TBI/DBI Calibrator |
| Reagents | Two liquid reagents, ready to use | Ready-for-use liquid reagents |
| Feature | Candidate Device | Predicate Device |
| Atellica® CH Diazo Total Bilirubin (D_TBil) | Dimension TBI Flex reagent cartridge (K060628) | |
| Composition | Pack 1:Well 1 Reagent 1:23.5mLPhosphate buffer (50mmol/L) ; NaCl (150mmol/L)Well 2 Reagent 1:23.5mLPhosphate buffer (50mmol/L) ; NaCl (150mmol/L)Pack 2:Well 1 Reagent 2:8.8mL2,4-Dichloroaniline (5 mmol/L); HCl (130 mmol/L); Na-Nitrite (0.5 mmol/L)Well 2 Reagent 2:8.8mL2,4-Dichloroaniline (5 mmol/L); HCl (130 mmol/L); Na-Nitrite (0.5 mmol/L) | Multi-Well liquid reagent cartridge that contains:Wells 1, 4-6: Acetate Buffer, Caffeine (168 mM), Sodium Benzoate (338 mM), Disodium EDTA (2.57mM)Well 2: Sulfanilic acid (25.89 mM), Hydrochloric acid (132 mM),Well 3: Sodium Nitrite (72.5 mM) |
| Interferences | Hemoglobin:No Interference ≤ 1000 mg/dLLipemia:No Interference ≤ 1000 mg/dL | Hemoglobin:No Interference ≤ 1000 mg/dLLipemia:No Interference ≤ 600mg/dL |
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9. Standard/Guidance Document References
The following recognized standards from Clinical Laboratory Standards Institute (CLSI) were used as a basis of the study procedures described in this submission:
• Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline—Third Edition. (CLSI EP05-A3).
- · Interference Testing in Clinical Chemistry (CLSI EP07).
· Measurement Procedure Comparison and Bias Estimation Using Patient Samples (CLS) EPO9-A3).
• Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline-Second Edition (EP17-A2).
- · Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline (CLSI EP25-A).
- Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory;
- Approved Guideline Third Edition (CLSI EP28-A3c).
• Establishing and Verifying an Extended Measuring Interval Through Specimen Dilution and Spiking (CLSI EP34-ED1)
• Metrological Traceability and Its Implementation; A Report (CLSI EP32-R)
- Supplemental tables for Interference Testing in Clinical Chemistry (CLSI EP37-ED1)
• Evaluation of the Linearity of Quantitative Measurement Procedures -200 Edition (CLSI EP06 ED2)
Performance Characteristics for Atellica® CH Diazo Total Bilirubin (D_TBil) 10.
10.1 Detection Capability
The Limit of Blank (LoB) corresponds to the highest measurement result that is likely to be observed for a blank sample. The assay is designed to have an LoB ≤ Limit of Detection (LoD).
The Limit of Detection (LoD) corresponds to the lowest concentration of total bilirubin that can be detected with a probability of 95%. The assay is designed to have an LoD ≤ Limit of Quantitation(LoQ).
The Limit of Quantitation (LoQ) corresponds to the lowest concentration of total bilirubin that met the required analyte level but did not reach 20% deviation The assay is designed to have an LoQ of < 0.10mg/dL.
Detection capability was determined in accordance with CLSI Documents EP17-A2.
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The following results were obtained:
| Specimen Type | Detection Capability | Result mg/dL |
|---|---|---|
| Serum/Plasma | LoB | 0.01 |
| LoD | 0.02 | |
| LoQ | 0.10 |
10.2 Precision
Precision was determined in accordance with CLSI Document EP05-A3. Samples were assayed on the Atellica CH Analyzer in duplicate in 2 runs per day for 20 days. The following results were obtained.
| SpecimenType | N | Mean | Repeatability | Within-Lab | |||||
|---|---|---|---|---|---|---|---|---|---|
| Meanmg/dL | Meanμmol/L | SDmg/dL | SDμmol/L | %CV | SDmg/dL | SDμmol/L | %CV | ||
| Serum 1 | 80 | 1.02 | 17.44 | 0.015 | 0.257 | 1.5 | 0.034 | 0.581 | 3.3 |
| Serum 2 | 80 | 13.40 | 229.14 | 0.053 | 0.906 | 0.4 | 0.140 | 2.394 | 1.0 |
| Serum 3 | 80 | 22.39 | 382.87 | 0.067 | 1.146 | 0.3 | 0.189 | 3.232 | 0.8 |
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10.3 Reproducibility
Reproducibility was determined in accordance with CLSI Document EP05-A3. Samples were assayed with 5 replicates per run for 5 days using 3 instruments/sites and 3 reagent lots. The data was analyzed to calculate the following components of precision: repeatability, between-day, between-lot, between-instrument, and reproducibility (total). The following results were obtained.
| Sample ID | Specimen Type | N | Mean mg/dL | Mean μmol/L | Repeatability | Between-Day | Between-LOT | Between SYSTEM | Reproducibility | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD mg/dL | SD μmol/L | % CV | SD mg/dL | SD μmol/L | % CV | SD mg/dL | SD μmol/L | % CV | SD mg/dL | SD μmol/L | % CV | SD mg/dL | SD μmol/L | % CV | |||||
| 1 | Serum | 225 | 1.03 | 17.61 | 0.012 | 0.205 | 1.2 | 0.009 | 0.154 | 0.9 | 0.013 | 0.222 | 1.3 | 0.011 | 0.188 | 1.1 | 0.023 | 0.393 | 2.2 |
| 2 | Serum | 225 | 13.24 | 226.40 | 0.037 | 0.633 | 0.3 | 0.062 | 1.060 | 0.5 | 0.028 | 0.479 | 0.2 | 0.047 | 0.804 | 0.4 | 0.091 | 1.556 | 0.7 |
| 3 | Serum | 225 | 22.14 | 378.59 | 0.057 | 0.975 | 0.3 | 0.106 | 1.813 | 0.5 | 0.053 | 0.906 | 0.2 | 0.063 | 1.077 | 0.3 | 0.146 | 2.497 | 0.7 |
10.4 Assay Comparison
The Atellica CH Diazo Total Bilirubin (D_TBil) assay was designed to have correlation coefficient of ≥ 0.950 and a slope of 1.00 ± 0.10 compared to the Dimension TBI assay. The following results were obtained.
| SpecimenType | ComparisonAssay (x) | Regression Equation | Sample Rangemg/dL(μmol/L) | N | r |
|---|---|---|---|---|---|
| Serum | DimensionTBI | y=1.02x+0.08mg/dL(y=1.02x+1.37μmol/L) | 0.14-22.55(2.39-385.61) | 103 | 0.997 |
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10.5 Specimen Equivalency
The specimen equivalency was determined using the Demming regression model in accordance with CLSI Document EP90c. The following results were obtained:
| SpecimenType | ComparisonAssay (x) | Regression Equation(μmol/L) | Sample Range mg/dL(µmol/L) | N | r |
|---|---|---|---|---|---|
| Plasma(Lithiumheparin) | Serum | y=0.98x + 0.05 mg/dL(y=0.98X + 0.86 µmol/L) | 0.24-22.61 mg/dL(4.10 – 386.63 µmol/L) | 57 | 0.997 |
| Plasma(SodiumHeparin) | Serum | y=1.00x + 0.02 mg/dL(y=1.00X + 0.34 µmol/L) | 0.24-22.61 mg/dL(4.10 – 386.63 µmol/L) | 57 | 0.998 |
| Plasma(K2 EDTA) | Serum | y=0.99x + 0.03 mg/dL(y=0.99X + 0.51 µmol/L) | 0.24-22.61 mg/dL(4.10 – 386.63 µmol/L) | 57 | 0.998 |
10.6 Interferences
10.6.1 Hemolysis, Icterus, and Lipemia (HIL)
The Atellica CH Diazo Total Bilirubin (D_TBil) assay is designed to have ≤ 10% interference from hemoglobin, and lipemia. Bias is the difference in the results between the control sample (does not contain the interferent) and the test sample (contains the interferent) expressed in a percentage. Bias > 10% is considered interference. Analyte results should not be corrected based on this bias.
Interference testing was performed in accordance with CLSI Document EP07. The following results were obtained:
| Interferent | InterferentConcentration (SI) | ObservedAnalytemg/dL(µmol/L) | Observed %Bias fromControl |
|---|---|---|---|
| Hemoglobin | 1000 mg/dL(10.0 g/L) | 1.08(18.47) | -9.3 |
| Hemoglobin | 1000 mg/dL(10.0 g/L) | 13.86(237.00) | -7.1 |
| Lipemia (from HighFractionTriglyceride) | 1000 mg/dL(10.0 g/L) | 0.90(15.39) | -7.8 |
| Lipemia (from HighFractionTriglyceride) | 1000 mg/dL(10.0 g/L) | 12.94(221.27) | 0.5 |
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10.6.2 Non-interfering Substances
The following substances do not interfere with Atellica CH Diazo Total Bilirubin (D_TBil) assay when present in serum and plasma at the concentrations indicated in the table below. Bias due to these substances is ≤ 10%.
Interference testing was performed in accordance with CLSI Document EP07. The following results were obtained:
| Interferent | InterferentConcentration(SI) | ObservedAnalytemg/dL(µmol/L) | AcceptanceCriteria | Observed% Bias | AcceptanceCriteria |
|---|---|---|---|---|---|
| Acetaminophen | 20 mg/dL1323.1 µmol/L | 1.04(17.78) | 1.00 mg/dL± 15.0% | -1.9 | ≤10.0% |
| Acetaminophen | 20 mg/dL1323.1 µmol/L | 13.85(236.84) | 14.00 mg/dL± 15.0% | -0.4 | ≤10.0% |
| Carbenicillin | 3 mg/dL79.3 µmol/L | 1.01(17.27) | 1.00 mg/dL± 15.0% | 2.0 | ≤10.0% |
| Carbenicillin | 3 mg/dL79.3 µmol/L | 13.82(236.32) | 14.00 mg/dL± 15.0% | 0.1 | ≤10.0% |
| Ascorbic acid | 5 mg/dL284.1 µmol/L | 1.01(17.27) | 1.00 mg/dL± 15.0% | -2.0 | ≤10.0% |
| Ascorbic acid | 5 mg/dL284.1 µmol/L | 13.51(231.02) | 14.00 mg/dL± 15.0% | -0.4 | ≤10.0% |
| Acetylsalicylic acid | 100 mg/dL5555.6 µmol/L | 1.01(17.27) | 1.00 mg/dL± 15.0% | 0.0 | ≤10.0% |
| Acetylsalicylic acid | 100 mg/dL5555.6 µmol/L | 13.62(232.90) | 14.00 mg/dL± 15.0% | 0.1 | ≤10.0% |
| Ibuprofen | 50 mg/dL | 1.01 | 1.00 mg/dL | -5.0 | ≤10.0% |
| Interferent | InterferentConcentration(SI) | ObservedAnalytemg/dL(µmol/L) | AcceptanceCriteria | Observed% Bias | AcceptanceCriteria |
| Ibuprofen | 2427.2 µmol/L | (17.27) | ± 15.0% | ||
| 50 mg/dL | 13.50 | 14.00 mg/dL | |||
| Ibuprofen | 2427.2 µmol/L | (230.85) | ± 15.0% | ||
| Rifampicin | 6 mg/dL | 1.02 | |||
| 72.9 µmol/L | (17.44) | ± 15.0% | |||
| Rifampicin | 6 mg/dL | 13.66 | 14.00 mg/dL | -3.5 | ≤10.0% |
| 72.9 µmol/L | (233.59) | ± 15.0% | |||
| Diazepam | 20 µg/mL | 1.03 | 1.00 mg/dL | -1.9 | ≤10.0% |
| 70.2 µmol/L | (17.61) | ± 15.0% | |||
| Diazepam | 20 µg/mL | 13.81 | 14.00 mg/dL | 0.2 | ≤10.0% |
| 70.2 µmol/L | (236.15) | ± 15.0% | |||
| Ethanol | 800 mg/dL | 1.04 | 1.00 mg/dL | -1.9 | ≤10.0% |
| 173.5 mmol/L | (17.78) | ± 15.0% | |||
| Ethanol | 800 mg/dL | 13.78 | 14.00 mg/dL | -0.7 | ≤10.0% |
| 173.5 mmol/L | (235.64) | ± 15.0% | |||
| Eltrombopag | 25 µg/mL | 0.99 | 1.00 mg/dL | 0.0 | ≤10.0% |
| 56.6 µmol/L | (16.93) | ± 15.0% | |||
| Eltrombopag | 25 µg/mL | 13.67 | 14.00 mg/dL | 0.3 | ≤10.0% |
| 56.6 µmol/L | (233.76) | ± 15.0% | |||
| Cholesterol | 500 mg/dL | 1.03 | 1.00 mg/dL | -1.0 | ≤10.0% |
| 12.9 mmol/L | (17.61) | ± 15.0% | |||
| Cholesterol | 500 mg/dL | 13.69 | 14.00 mg/dL | -0.7 | ≤10.0% |
| 12.9 mmol/L | (234.10) | ± 15.0% | |||
| Interferent | InterferentConcentration(SI) | ObservedAnalytemg/dL(µmol/L) | AcceptanceCriteria | Observed% Bias | AcceptanceCriteria |
| Phenazopyridine HCl | 80 µg/mL | 0.98 | 1.00 mg/dL | 0.0 | ≤10.0% |
| 32.04 µmol/L | (16.76) | ± 15.0% | |||
| Phenazopyridine HCl | 80 µg/mL | 12.99 | 14.00 mg/dL | 0.5 | ≤10.0% |
| 32.04 µmol/L | (222.13) | ± 15.0% | |||
| Phloroglucinol | 250 ng/mL | 1.01 | 1.00 mg/dL | 0.0 | ≤10.0% |
| 2 µmol/L | (17.27) | ± 15.0% | |||
| Phloroglucinol | 250 ng/mL | 13.77 | 14.00 mg/dL | -0.9 | ≤10.0% |
| 2 µmol/L | (235.47) | ± 15.0% | |||
| Cyanokit(Hydroxocobalamin) | 40 µg/mL | 1.01 | 1.00 mg/dL | -4.0 | ≤10.0% |
| 29.7 µmol/L | (17.27) | ± 15% | |||
| Cyanokit(Hydroxocobalamin) | 40 µg/mL | 13.58 | 14.00 mg/dL | -2.0 | ≤10.0% |
| 29.7 µmol/L | (232.22) | ± 15.0% | |||
| Levodopa | 225 µg/mL | 0.93 | 1.00 mg/dL | 8.6 | ≤10.0% |
| 1142.1 µmol/L | (15.90) | ± 15.0% | |||
| Levodopa | 300 µg/mL | 12.82 | 14.00 mg/dL | 0.5 | ≤10.0% |
| 1522.8 µmol/L | (219.22) | ± 15% | |||
| IgG | 5 g/dL | 0.96 | 1.00 mg/dL | -1.0 | ≤10.0% |
| 333.3 µmol/L | (16.42) | ± 15.0% | |||
| IgG | 5 g/dL | 12.90 | 14.00 mg/dL | -0.2 | ≤10.0% |
| 333.3 µmol/L | (220.59) | ± 15.0% | |||
| Indican | 1.5 mg/dL | 0.94 | 1.00 mg/dL | 7.9 | ≤10.0% |
| 59.7 µmol/L | (16.07) | ± 15.0% | |||
| Indican | 31.3 mg/dL | 13.59 | 14.00 mg/dL | 8.6 | ≤10.0% |
| Interferent | InterferentConcentration(SI) | ObservedAnalytemg/dL(µmol/L) | AcceptanceCriteria | Observed% Bias | AcceptanceCriteria |
| 1245.5 µmol/L | (232.39) | ± 15.0% |
{13}------------------------------------------------
{14}------------------------------------------------
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Clinical Study 11.
Not applicable.
11.1 Expected Values
Siemens Healthineers has verified the reference interval for serum and plasma for the Atellica CH Diazo Total Bilirubin assay, in accordance with CLSI Document EP28-A3c is 0.3 - 1.2mg/dL (5.13 - 20.52 µmol/L)
Traceability 12.
The assay is traceable to the NIST Standard Reference Material 916.
Clinical Cut-off 13.
Not applicable
Conclusion 14.
The results from the performance studies support that the Candidate Device, Atellica CH Diazo Total Bilirubin (D_TBil) assay is substantially equivalent to the Predicate Device, Dimension TBI assay (K060628)
§ 862.1110 Bilirubin (total or direct) test system.
(a)
Identification. A bilirubin (total or direct) test system is a device intended to measure the levels of bilirubin (total or direct) in plasma or serum. Measurements of the levels of bilirubin, an organic compound formed during the normal and abnormal distruction of red blood cells, if used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.(b)
Classification. Class II.