(131 days)
The Atellica® CH Enzymatic Creatinine 3 (ECre3) assay is for in vitro diagnostic use in the quantitative determination of creatinine in human serum, plasma (lithium heparin and dipotassium EDTA), and urine using the Atellica® CH Analyzer. Such measurements are used in the diagnosis and treatment of renal diseases and in monitoring renal dialysis.
The Atellica CH ECre3 assay measures the concentration of creatinine through a series of coupled enzymatic reactions and is based upon the method developed by Masaru and Mitsutaka. The Atellica CH ECre3 assay uses a series of coupled enzymatic reactions. In a "pretreatment" reaction, endogenous creatine and sarcosine are removed from a test sample by creatinase and sarcosine oxidase. The level of creatinine in a test sample is then determined through coupled enzymatic reactions. First, creatinine is enzymatically converted by creatininase into creatine. Creatine is then enzymatically converted to sarcosine by creatinase. This is followed by the oxidation of sarcosine by sarcosine oxidase to produce hydrogen peroxide. In the presence of peroxidase, the hydrogen peroxide allows for the oxidative condensation of 4-aminoantipyrine and N-ethyl-N-(3-methylphenyl)-N'-succinyl-ethylenediamine to produce a reddish purple quinone pigment. The absorbance of this quinone pigment is measured as an endpoint reaction at 545/694 nm.
This document describes the performance of the Atellica® CH Enzymatic Creatinine 3 (ECre3) assay, a new in vitro diagnostic device for quantitative determination of creatinine. The information provided is for a 510(k) Premarket Notification to the FDA, demonstrating substantial equivalence to a predicate device. Therefore, the "acceptance criteria" here refers to the performance thresholds that the new device must meet to show it functions as intended and is comparable to the predicate device. The "study" refers to the analytical performance validation studies conducted.
Here's the breakdown of the requested information:
1. Table of Acceptance Criteria and Reported Device Performance & 2. Sample Sizes and Data Provenance
Since this is an in vitro diagnostic (IVD) device, the "acceptance criteria" are typically defined as performance specifications that demonstrate the device's analytical accuracy, precision, linearity, and freedom from interferences. These are not clinical acceptance criteria in the sense of diagnostic accuracy to a specific disease state, but rather analytical performance metrics. The document compares the new device (candidate) to a predicate device and established standards.
| Acceptance Criteria Category | Specific Acceptance Criteria (Target/Goal) | Reported Device Performance (Achieved) | Sample Size for Test Set (and Provenance) |
|---|---|---|---|
| Detection Capability | LoQ: ≤ 0.15 mg/dL (serum/plasma), ≤ 2.00 mg/dL (urine) - (Lowest concentration at which total analytical error is ≤ 0.10 mg/dL for serum/plasma and ≤ 1.50 mg/dL for urine) | LoB: Serum/plasma: 0.05 mg/dL; Urine: 0.15 mg/dL LoD: Serum/plasma: 0.10 mg/dL; Urine: 0.50 mg/dL LoQ: Serum/plasma: 0.15 mg/dL; Urine: 2.00 mg/dL (Meets or exceeds design specifications for LoQ) | Not explicitly stated as a "sample size" for detection capability tests in terms of unique patient samples, but the methodology (CLSI Document EP17-A2) typically involves repeated measurements of blank, low-concentration, and spiked samples. Provenance is not specified for these control samples or blanks. |
| Precision | Not explicitly stated as a single numerical acceptance criterion (e.g., CV < X%), but expected to be within acceptable analytical variation for creatinine assays. Evaluated against CLSI EP05-A3. | Repeatability (Within-run SD/CV): Serum: CV 0.2-2.2% (SD 0.008-0.054 mg/dL) Urine: CV 0.1-0.2% (SD 0.064-0.320 mg/dL) Within-Lab (Total SD/CV from Precision Study): Serum: CV 0.5-3.2% (SD 0.013-0.121 mg/dL) Urine: CV 0.4-0.8% (SD 0.322-0.831 mg/dL) Total Reproducibility (from Reproducibility Study): Serum: CV 0.5-3.9% (SD 0.013-0.148 mg/dL) Urine: CV 0.5-0.7% (SD 0.225-1.267 mg/dL) | For Precision (EP05-A3): 80 results per sample (from 2 runs/day for 20 days) for various serum and urine concentrations. For Reproducibility (EP05-A3): 225 results per sample (from n=5 assays/day, 1 run/day for 5 days using 3 instruments and 3 reagent lots) for various serum and urine concentrations. Provenance of samples (e.g., control materials, spiked samples, patient samples if used) is not specified. Likely control materials and potentially pooled patient samples. |
| Assay Comparison / Method Comparison (vs. Predicate) | Correlation coefficient (r) ≥ 0.950 and a slope of 1.00 ± 0.05. | Serum vs. ADVIA Chemistry ECRE_2: y = 0.99x + 0.02 mg/dL; r = 1.000 Urine vs. ADVIA Chemistry ECRE_2: y = 0.98x + 0.05 mg/dL; r = 0.999 Serum/Plasma vs. IDMS: y = 1.01x + 0.01 mg/dL; r = 0.991 (Meets all pre-defined criteria) | Serum vs. Predicate: 105 samples Urine vs. Predicate: 102 samples Serum/Plasma vs. IDMS (Reference Method): 47 samples Provenance of these patient samples is not specified (e.g., country of origin, retrospective/prospective). It is implied these are human patient samples. |
| Specimen Equivalency | Not explicitly stated as a single numerical acceptance criterion (e.g., correlation > X), but expected to demonstrate strong correlation between plasma types and serum. Evaluated against CLSI EP09c. | Lithium heparin plasma vs. Serum: y = 0.99x + 0.00 mg/dL; r = 1.000 Dipotassium EDTA plasma vs. Serum: y = 0.97x + 0.02 mg/dL; r = 0.998 (Demonstrates strong equivalency) | For each comparison (Lithium heparin plasma vs. Serum, Dipotassium EDTA plasma vs. Serum): 55 samples. Provenance of these patient samples is not specified. Implied human patient samples. |
| Interferences (HIL) | ≤ 10% bias from hemoglobin, bilirubin, and lipemia. Bias > 10% is considered interference. | Hemoglobin: -3.2% to 6.0% (at tested concentrations) Bilirubin (conjugated & unconjugated): -1.6% to -6.2% (at tested concentrations) Lipemia (Intralipid®): -2.6% to -3.8% (at tested concentrations) (All tested HIL substances show ≤ 10% bias, meeting the criterion) | Not explicitly stated as "sample size" for this study. Interference testing typically involves preparing samples with known analyte concentrations and varying concentrations of interferents. Provenance of samples is not specified, likely control or pooled samples spiked with interferents. |
| Non-Interfering Substances | ≤ 10% bias at specific analyte concentrations (1.00 mg/dL and 8.00 mg/dL for serum; 40.00 mg/dL and 180.00 mg/dL for urine). | Various common substances (e.g., Acetaminophen, Cefoxitin, Glucose) tested showed biases generally well within the ±10% range. Phenindione is an exception, with a warning against its use due to reported falsely depressed results. (Generally meets criteria, with a clinically relevant exception noted) | Not explicitly stated as "sample size". Similar to HIL, involves preparation of spiked samples. Provenance of samples is not specified. |
| Linearity | Demonstrate linearity for the measuring interval from 0.15-30.00 mg/dL (serum/plasma) and 2.00–245.00 mg/dL (urine). | Achieved: Linear from 0.15-30.00 mg/dL for Serum/plasma and from 2.00–245.00 mg/dL for Urine. (Meets the specified measuring interval) | Not explicitly stated as "sample size". Linearity studies (CLSI EP06-A) typically involve preparing and testing several dilutions of high-concentration samples. Provenance is not specified. |
Data Provenance (General): The document does not explicitly state the country of origin for the patient samples used in method comparison or specimen equivalency studies. It also does not specify if the studies were retrospective or prospective, though for IVD analytical performance, they are typically prospective analytical studies using characterized samples (pooled, spiked, or real patient samples collected for the study).
Regarding items 3-9 for this IVD document:
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- For an IVD device like this, "ground truth" for analytical performance studies is established by reference methods (e.g., Isotope Dilution Mass Spectrometry - IDMS, as seen in the assay comparison) or against a legally marketed predicate device (ADVIA Chemistry ECRE_2 assay). It is not established by human experts (like radiologists reading images) for diagnostic accuracy or consensus in the typical sense for medical imaging or clinical decision support AI. The "experts" would be the metrologists or lab professionals validating the reference methods according to CLSI guidelines.
4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:
- Not applicable in the context of an IVD analytical performance study. Adjudication methods are relevant for subjective interpretations, like radiology image reads or pathological diagnoses, where human variability exists and a consensus "ground truth" needs to be established. Here, the "truth" is quantitative measurement by reference methods.
5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done:
- Not applicable. MRMC studies are used to assess the comparative effectiveness of different diagnostic methods (often involving human readers and AI) where subjectivity and reader variability are factors. This submission is for an in vitro diagnostic assay, which provides quantitative values, not an imaging-based AI or a system that aids human interpretation in a subjective setting.
6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done:
- This is inherently a "standalone" device in the sense that it is an automated laboratory assay. Its performance is measured directly (algorithm only) against reference methods or the predicate, as presented in the analytical performance section. There isn't a "human-in-the-loop" component in its operation or interpretation beyond the lab professional running the analyzer and reviewing results.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- The ground truth for this device's performance evaluation is established by:
- Reference Methods: Specifically, Isotope Dilution Mass Spectrometry (IDMS) for creatinine measurements, which is a highly accurate and precise chromatographic-mass spectrometric method. This is considered the "gold standard" for creatinine measurement.
- Comparison to a Legally Marketed Predicate Device: The ADVIA® Chemistry Enzymatic Creatinine_2 (ECRE_2) assay. The performance against the predicate is used to demonstrate "substantial equivalence."
- Internal analytical validation: Using controlled samples (e.g., spiked samples, control materials) for precision, linearity, interference studies, where the "ground truth" is the known concentration or expected behavior of the sample.
8. The sample size for the training set:
- This document describes the validation of the device's performance, not its development or "training." For an IVD assay (like a chemical reagent and analyzer system), there isn't a "training set" in the machine learning sense. The assay is based on established enzymatic reaction principles, not on learned patterns from a "training set" of data. Therefore, this concept is not applicable here.
9. How the ground truth for the training set was established:
- Not applicable, as there is no "training set" for this type of IVD device. The assay's chemical reactions and measurement principles are intrinsically defined, not learned from data.
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November 24, 2021
Siemens Healthcare Diagnostics Inc. Ian Thompson Regulatory Clinical Affairs Specialist 511 Benedict Avenue Tarrytown, New York 10591
Re: K212223
Trade/Device Name: Atellica® CH Enzymatic Creatinine 3 (ECre3) Regulation Number: 21 CFR 862.1225 Regulation Name: Creatinine Test System Regulatory Class: Class II Product Code: JFY Dated: July 15, 2021 Received: July 16, 2021
Dear Ian Thompson:
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/cdrl/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.
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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 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 medical devices and radiation -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.
Marianela Perez-Torres, Ph.D. Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K212223
Device Name Atellica® CH Enzymatic Creatinine 3 (ECre3)
Indications for Use (Describe)
The Atellica® CH Enzymatic Creatinine 3 (ECre3) assay is for in the quantitative determination of creatinine in human serum, plasma (lithium heparin and dipotassium EDTA), and urine using the Atellica® CH Analyzer. Such measurements are used in the diagnosis and treatment of renal diseases and in monitoring renal dialysis.
| 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) |
X Prescription Use (Part 21 CFR 801 Subpart D)
_ Over-The-Counter Use (21 CFR 801 Subpart C)
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510(k) Summary
This 510(k) Summary 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: K212223
-
- Date Prepared
July 15, 2021
- Date Prepared
2. Applicant Information
| Contact: | Ian ThompsonRegulatory Clinical Affairs Specialist |
|---|---|
| Address: | 511 Benedict AvenueTarrytown, NY 10591-5097 |
| Email: | ian_thompson@siemens-healthineers.com |
Regulatory Information 3.
Atellica® CH Enzymatic Creatinine_3 (ECre3) assay
| Trade Name: | Atellica® CH Enzymatic Creatinine_3 (ECre3) |
|---|---|
| Common Name: | Enzymatic Method, Creatinine |
| Classification Name: | Creatinine test system |
| FDA Classification: | Class II |
| Review Panel: | Clinical Chemistry |
| Product Code: | JFY |
| Regulation Number: | 21 CFR 862.1225 |
4. Predicate Device Information
Predicate Device Name: ADVIA® Chemistry Enzymatic Creatinine_2 (ECRE_2)
510(k) Number: K070727
5. Intended Use / Indications For Use
The Atellica® CH Enzymatic Creatinine_3 (ECre3) assay is for in vitro diagnostic use in the quantitative determination of creatinine in human serum, plasma (lithium heparin and dipotassium EDTA), and urine using the Atellica® CH Analyzer. Such measurements are used in the diagnosis and treatment of renal diseases and in monitoring renal dialysis.
Special Conditions for Use Statement(s): For Prescription Use Only.
6. Device Description
The Atellica CH ECre3 assay measures the concentration of creatinine through a series of coupled enzymatic reactions and is based upon the method developed by Masaru and Mitsutaka.
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The Atellica CH ECre3 assay uses a series of coupled enzymatic reactions. In a "pretreatment" reaction, endogenous creatine and sarcosine are removed from a test sample by creatinase and sarcosine oxidase. The level of creatinine in a test sample is then determined through coupled enzymatic reactions. First, creatinine is enzymatically converted by creatininase into creatine. Creatine is then enzymatically converted to sarcosine by creatinase. This is followed by the oxidation of sarcosine by sarcosine oxidase to produce hydrogen peroxide. In the presence of peroxidase, the hydrogen peroxide allows for the oxidative condensation of 4-aminoantipyrine and N-ethyl-N-(3-methylphenyl)-N'-succinyl-ethylenediamine to produce a reddish purple quinone pigment. The absorbance of this quinone pigment is measured as an endpoint reaction at 545/694 nm.545 / 694 nm.
Purpose of Submission 7.
The purpose of this submission is a premarket notification for a new device: Atellica CH Enzymatic Creatinine_3 (ECre3) assay.
8. Comparison of Candidate Device and Predicate Device
The table below describes the similarities and differences between the Atellica CH Enzymatic Creatinine_3 (ECre3) assay (Candidate Device), and the ADVIA® Chemistry Enzymatic Creatinine_2 (ECRE_2) (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. The performance studies gave acceptable results compared to the Predicate Device.
| Feature | Candidate Device | Predicate Device |
|---|---|---|
| Atellica® CH Enzymatic Creatinine_3(ECre3) | ADVIA Chemistry EnzymaticCreatinine_2 (ECRE_2) | |
| Intended Use | The Atellica CH EnzymaticCreatinine_3 (ECre3) assay is for invitro diagnostic use in the quantitativedetermination of creatinine in humanserum, plasma (lithium heparin anddipotassium EDTA), and urine usingthe Atellica CH Analyzer. | For in vitro diagnostic use in thequantitative determination ofcreatinine in human serum, plasma(lithium heparin and potassiumEDTA), and urine on ADVIAChemistry systems. |
| Indications for Use | Such measurements are used in thediagnosis and treatment of renaldiseases and in monitoring renaldialysis. | Same |
| Sample Type | Serum, plasma (lithium heparin anddipotassium EDTA), urine | serum, plasma (lithium heparin,potassium EDTA), urine |
| Units of Measure | mg/dL | Same |
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| Feature | Candidate Device | Predicate Device |
|---|---|---|
| Atellica® CH Enzymatic Creatinine_3(ECre3) | ADVIA Chemistry EnzymaticCreatinine_2 (ECRE_2) | |
| Assay Range /Measuring Interval | Serum/Plasma: 0.15–30.00 mg/dLUrine: 2.00–245.00 mg/dL | Serum/Plasma: 0.10–30.00 mg/dLUrine: 1.00-245.00 mg/dL |
| Expected ValuesSerum/Plasma | Males: 0.73-1.18 mg/dLFemales: 0.55-1.02 mg/dL | Males: 0.6-1.1 mg/dLFemales: 0.5-0.8 mg/dL |
| Expected ValuesUrine | Males: 800–2000 mg/dayFemales: 600-1800 mg/day | Same |
| Assay Principle | Enzymatic (Creatininase) | Same |
| Standardization | NIST SRM 967 | Same |
| Calibration | Single point | Same |
| Calibrators | Atellica CH Chemistry Calibrator(CHEM CAL) | ADVIA Chemistry Calibrator(K050374) |
Standard/Guidance Document References 9.
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-ED3).
- Measurement Procedure Comparison and Bias Estimation Using Patient Samples (CLSI EP09c-ED3).
- 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).
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Performance Characteristics for Atellica® CH Enzymatic Creatinine_3 10. (ECre3) Assay
Detection Capability 10.1
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 creatinine 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 creatinine in a sample at which the total analytical error is ≤ 0.10 mg/dL for serum and plasma and ≤ 1.50 mg/dL for urine. The assay is designed to have an LoQ ≤ 0.15 mg/dL (13 µmol/L) for serum and plasma and ≤ 2.00 mg/dL (177 umol/L) for urine.
Detection capability was determined in accordance with CLSI Document EP17-A2.
| Specimen Type | Detection Capability | mg/dL (µmol/L) |
|---|---|---|
| Serum/plasma | LoB | 0.05 (4) |
| LoD | 0.10 (9) | |
| LoQ | 0.15 (13) | |
| Urine | LoB | 0.15 (13) |
| LoD | 0.50 (44) | |
| LoQ | 2.00 (177) |
The study supports the following detection capability claims:
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:
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| Specimen Type | Na | Meanmg/dL (µmol/L) | Repeatability | Within-Lab | ||
|---|---|---|---|---|---|---|
| SDbmg/dL (µmol/L) | CVc(%) | SDmg/dL (µmol/L) | CV(%) | |||
| Serum 1 | 80 | 0.41 (36) | 0.009 (0.8) | 2.2 | 0.013 (1.1) | 3.2 |
| Serum 2 | 80 | 0.75 (66) | 0.008 (0.7) | 1.1 | 0.015 (1.3) | 2.0 |
| Serum 3 | 80 | 1.29 (114) | 0.010 (0.9) | 0.8 | 0.030 (2.7) | 2.3 |
| Serum QC 1 | 80 | 1.91 (169) | 0.012 (1.1) | 0.6 | 0.024 (2.1) | 1.3 |
| Serum QC 2 | 80 | 3.11 (275) | 0.009 (0.8) | 0.3 | 0.026 (2.3) | 0.8 |
| Serum 4 | 80 | 8.89 (786) | 0.021 (1.9) | 0.2 | 0.055 (4.9) | 0.6 |
| Serum 5 | 80 | 18.52 (1637) | 0.039 (3.4) | 0.2 | 0.093 (8.2) | 0.5 |
| Serum 6 | 80 | 26.49 (2342) | 0.054 (4.8) | 0.2 | 0.121 (10.7) | 0.5 |
| Urine 1 | 80 | 42.82 (3785) | 0.064 (5.7) | 0.1 | 0.322 (28.5) | 0.8 |
| Urine QC 1 | 80 | 86.41 (7639) | 0.156 (13.8) | 0.2 | 0.497 (43.9) | 0.6 |
| Urine 2 | 80 | 185.06 (16,359) | 0.320 (28.3) | 0.2 | 0.831 (73.5) | 0.4 |
a Number of results.
b Standard deviation. °Coefficient of variation.
10.3 Reproducibility
Reproducibility was determined in accordance with CLSI Document EP05-A3. Samples were assayed n=5 in 1 run for 5 days using 3 instruments and 3 reagent lots. The data were analyzed to calculate the following components of precision: repeatability, between-day, between-lot, between-instrument, and reproducibility (total). The following results were obtained:
| Repeatability | Between-Day | Between-Lot | Between-Instrument | TotalReproducibility | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SpecimenType | Na | Meanmg/dL(µmol/L) | SDbmg/dL(µmol/L) | CVc(%) | SDmg/dL(µmol/L) | CV(%) | SDmg/dL(µmol/L) | CV(%) | SDmg/dL(µmol/L) | CV(%) | SDmg/dL(µmol/L) | CV(%) |
| Serum 1 | 225 | 0.44(39) | 0.008(0.8) | 1.9 | 0.005(0.4) | 1.1 | 0.008(0.7) | 1.9 | 0.000(0.0) | 0.0 | 0.013(1.1) | 2.9 |
| Serum QC 1 | 225 | 0.79(70) | 0.011(0.9) | 1.3 | 0.004(0.3) | 0.5 | 0.008(0.7) | 1.0 | 0.000(0.0) | 0.0 | 0.014(1.2) | 1.7 |
| Serum 2 | 225 | 0.95(84) | 0.014(1.2) | 1.4 | 0.034(3.0) | 3.5 | 0.000(0.0) | 0.0 | 0.007(0.6) | 0.7 | 0.037(3.3) | 3.9 |
| Serum QC 2 | 225 | 1.88(166) | 0.011(1.0) | 0.6 | 0.008(0.7) | 0.4 | 0.009(0.8) | 0.5 | 0.000(0.0) | 0.0 | 0.016(1.4) | 0.8 |
| SerumQC 3 | 225 | 6.82(603) | 0.016(1.4) | 0.2 | 0.022(1.9) | 0.3 | 0.000(0.0) | 0.0 | 0.017(1.5) | 0.2 | 0.032(2.8) | 0.5 |
| Serum 3 | 225 | 7.96(703) | 0.021(1.8) | 0.3 | 0.034(3.0) | 0.4 | 0.000(0.0) | 0.0 | 0.019(1.7) | 0.2 | 0.045(3.9) | 0.6 |
| Serum 4 | 225 | 26.86(2374) | 0.051(4.5) | 0.2 | 0.105(9.3) | 0.4 | 0.039(3.5) | 0.1 | 0.082(7.2) | 0.3 | 0.148(13.1) | 0.6 |
| Urine 1 | 225 | 42.30(3739) | 0.106(9.3) | 0.2 | 0.102(9.0) | 0.2 | 0.000(0.0) | 0.0 | 0.171(15.1) | 0.4 | 0.225(19.9) | 0.5 |
| Urine 2 | 225 | 189.56(16,757) | 0.379(33.5) | 0.2 | 0.401(35.4) | 0.2 | 0.503(44.5) | 0.3 | 1.024(90.5) | 0.5 | 1.267(112.0) | 0.7 |
ª Number of results.
b Standard deviation.
°Coefficient of variation.
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Assay Comparison 10.4
The Atellica CH ECre3 assay (y) was designed to have a correlation coefficient of ≥ 0.950 and a slope of 1.00 ± 0.05 compared to the ADVIA Chemistry ECRE 2 assay. Assay comparison for serum was determined using the Deming regression model and for urine using the Weighted Deming regression model in accordance with CLSI Document EP09c. The following results were obtained:
| Specimen | Comparative Assay (x) | Regression Equation | Sample Interval | Na | rb |
|---|---|---|---|---|---|
| Serum | ADVIA Chemistry ECRE_2 | y = 0.99x + 0.02 mg/dL(y = 0.99x + 2 µmol/L) | 0.18–28.41 mg/dL(16–2511 µmol/L) | 105 | 1.000 |
| Urine | ADVIA Chemistry ECRE_2 | y = 0.98x + 0.05 mg/dL(y = 0.98x + 4 µmol/L) | 4.71–240.47 mg/dL(416–21,258 µmol/L) | 102 | 0.999 |
| Serum/Plasma | Isotope Dilution MassSpectrometry (IDMS) | y = 1.01x + 0.01 mg/dL(y = 1.01x + 1 µmol/L) | 0.35–26.70 mg/dL(31–2360 µmol/L) | 47 | 0.991 |
a Number of samples tested.
b Correlation coefficient.
10.5 Specimen Equivalency
The specimen equivalency was determined using the Deming regression model in accordance with CLSI Document EP09c. The following results were obtained:
| Specimen (y) | ReferenceSpecimen (x) | Regression Equation | Sample Interval | Na | rb |
|---|---|---|---|---|---|
| Lithium heparinplasma | Serum | y = 0.99x + 0.00 mg/dL(y = 0.99x + 0 μmol/L) | 0.50–26.91 mg/dL(44–2379 μmol/L) | 55 | 1.000 |
| DipotassiumEDTA plasma | Serum | y = 0.97x + 0.02 mg/dL(y = 0.97x + 2 μmol/L) | 0.50–26.91 mg/dL(44–2379 μmol/L) | 55 | 0.998 |
ª Number of samples tested.
b Correlation Coefficient.
10.6 Interferences
10.6.1 Hemolysis, Icterus, and Lipemia (HIL)
The Atellica CH ECre3 assay is designed to have ≤ 10% interference from hemoglobin, bilirubin, 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 percent. 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 for serum:
| Substance | Substance ConcentrationConventional Units (SI Units) | Analyte ConcentrationConventional Units (SI Units) | Bias% |
|---|---|---|---|
| Hemoglobin | 200 mg/dL (2.0 g/L) | 1.00 mg/dL (88 µmol/L) | 6.0 |
| 1000 mg/dL (10.0 g/L) | 8.25 mg/dL (729 µmol/L) | -3.2 |
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510(k) Summary
| 25 mg/dL (427.5 µmol/L) | 0.97 mg/dL (86 µmol/L) | -6.2 | |
|---|---|---|---|
| Bilirubin, conjugated | 25 mg/dL (427.5 µmol/L) | 8.76 mg/dL (774 µmol/L) | -3.1 |
| Bilirubin, unconjugated | 25 mg/dL (427.5 µmol/L) | 0.97 mg/dL (86 µmol/L) | -4.1 |
| 25 mg/dL (427.5 µmol/L) | 8.66 mg/dL (766 µmol/L) | -1.6 | |
| Lipemia (Intralipid®) | 2000 mg/dL (20.0 g/L) | 1.06 mg/dL (94 µmol/L) | -3.8 |
| 2000 mg/dL (20.0 g/L) | 8.06 mg/dL (713 µmol/L) | -2.6 |
Non-Interfering Substances 10.6.2
The following substances do not interfere with the Atellica CH ECre3 assay when present in serum, lithium heparin plasma, dipotassium EDTA plasma, and urine at the concentrations indicated in the tables below. Bias due to these substances is ≤ 10% at an analyte concentration of 1.00 mg/dL and 8.00 mg/dL for serum and 40.00 mg/dL and 180.00 mg/dL for urine.
Serum
| Substance | Highest Concentration Testedwith No InterferenceConventional Units (SI Units) | Analyte ConcentrationConventional Units (SI Units) | % |
|---|---|---|---|
| Acetaminophen | 200 µg/mL (1.3 mmol/L) | 0.94 mg/dL (83 µmol/L) | 1.1 |
| 200 µg/mL (1.3 mmol/L) | 8.32 mg/dL (735 µmol/L) | -0.2 | |
| Calcium dobesilate(Dexium) | 0.38 mg/dL (9.1 µmol/L) | 1.02 mg/dL (90 µmol/L) | -6.9 |
| 0.38 mg/dL (9.1 µmol/L) | 8.74 mg/dL (773 µmol/L) | -2.1 | |
| Cefoxitin | 6600 µg/mL (15.4 mmol/L) | 1.04 mg/dL (92 µmol/L) | -8.7 |
| 6600 µg/mL (15.4 mmol/L) | 7.44 mg/dL (658 µmol/L) | -1.1 | |
| Cephalexin | 200 µg/mL (575.7 µmol/L) | 0.92 mg/dL (81 µmol/L) | 1.1 |
| 200 µg/mL (575.7 µmol/L) | 7.90 mg/dL (698 µmol/L) | -0.4 | |
| Dicynone (Etamsylate) | 0.59 mg/dL (22.4 µmol/L) | 1.01 mg/dL (89 µmol/L) | -8.9 |
| 0.59 mg/dL (22.4 µmol/L) | 8.64 mg/dL (764 µmol/L) | -2.1 | |
| DL-proline | 11.5 mg/dL (998.9 µmol/L) | 0.98 mg/dL (87 µmol/L) | 3.1 |
| 11.5 mg/dL (998.9 µmol/L) | 8.49 mg/dL (751 µmol/L) | 0.2 | |
| Dobutamine | 5 µg/mL (16.6 µmol/L) | 0.98 mg/dL (87 µmol/L) | -5.1 |
| 5 µg/mL (16.6 µmol/L) | 8.62 mg/dL (762 µmol/L) | -2.3 | |
| Dopamine | 10 µg/mL (65.3 µmol/L) | 1.02 mg/dL (90 µmol/L) | -6.9 |
| 10 µg/mL (65.3 µmol/L) | 8.74 mg/dL (773 µmol/L) | -2.1 | |
| Ethylglycine (N-ethylglycine) | 6 µg/mL (58.2 µmol/L) | 1.01 mg/dL (89 µmol/L) | 0.0 |
| 6 µg/mL (58.2 µmol/L) | 8.66 mg/dL (766 µmol/L) | -0.2 | |
| Fluorocytosine | 200 µg/mL (1549 µmol/L) | 1.07 mg/dL (95 µmol/L) | -0.9 |
| 200 µg/mL (1549 µmol/L) | 7.94 mg/dL (702 µmol/L) | -0.1 | |
| Levodopa (L-dopa) | 15 µg/mL (76.1 µmol/L) | 1.03 mg/dL (91 µmol/L) | -4.9 |
| 15 µg/mL (76.1 µmol/L) | 8.63 mg/dL (763 µmol/L) | -2.3 | |
| Metamizole (Sulpyrine) | 25 mg/L (750 µmol/L) | 0.97 mg/dL (86 µmol/L) | -5.2 |
| 25 mg/L (750 µmol/L) | 8.37 mg/dL (740 µmol/L) | -4.2 |
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| Serum | |||
|---|---|---|---|
| Substance | Highest Concentration Testedwith No InterferenceConventional Units (SI Units) | Analyte ConcentrationConventional Units (SI Units) | % |
| Methyl dopa | 11.3 µg/mL (53.5 µmol/L) | 1.02 mg/dL (90 µmol/L) | -8.8 |
| 11.3 µg/mL (53.5 µmol/L) | 7.47 mg/dL (660 µmol/L) | -4.3 | |
| N-acetyl-p-benzoquinineimine (NAPQI) | 0.4 mg/L (26.8 µmol/L) | 1.02 mg/dL (90 µmol/L) | -2.9 |
| 0.4 mg/L (26.8 µmol/L) | 8.72 mg/dL (771 µmol/L) | -0.3 | |
| N-Acetyl Cysteine (NAC) | 37.5 mg/dL (2.3 mmol/L) | 0.98 mg/dL (87 µmol/L) | -7.1 |
| 37.5 mg/dL (2.3 mmol/L) | 8.36 mg/dL (739 µmol/L) | -0.7 | |
| Phenindionea | 5 mg/dL (225 µmol/L) | 0.97 mg/dL (86 µmol/L) | -5.2 |
| 5 mg/dL (225 µmol/L) | 7.76 mg/dL (686 µmol/L) | -4.3 | |
| Phenylbutazone | 321 µg/mL (1040.9 µmol/L) | 0.99 mg/dL (88 µmol/L) | -3.0 |
| 321 µg/mL (1040.9 µmol/L) | 8.43 mg/dL (745 µmol/L) | -1.5 | |
| Rifampicin | 2.4 mg/dL (29.2 µmol/L) | 1.02 mg/dL (90 µmol/L) | -2.0 |
| 2.4 mg/dL (29.2 µmol/L) | 8.57 mg/dL (758 µmol/L) | -0.6 | |
| Salicylate | 200 µg/mL (1448 µmol/L) | 0.99 mg/dL (88 µmol/L) | 1.0 |
| 200 µg/mL (1448 µmol/L) | 8.41 mg/dL (743 µmol/L) | -0.2 |
ª Use of this assay is not recommended for patients being treated with phenindione due to the reported falsely depressed results from phenindione metabolites. Sankaralingam A, Karim Y, Swaminathan R. Phenindione interferes with measurement of creatinine. Clin Biochem. 2013;46(18):1912–1913.
Urine
| Substance | Highest Concentration Testedwith No InterferenceConventional Units (SI Units) | Analyte ConcentrationConventional Units (SI Units) | % |
|---|---|---|---|
| 6N HCl | 0.01% | 41.72 mg/dL (3688 µmol/L) | 0.3 |
| 0.01% | 188.42 mg/dL (16,656 µmol/L) | -0.6 | |
| pH 4 | 4.0 pH | 42.73 mg/dL (3777 µmol/L) | -3.9 |
| 4.0 pH | 191.39 mg/dL (16,919 µmol/L) | -2.3 | |
| pH 9 | 9.0 pH | 42.73 mg/dL (3777 µmol/L) | -5.4 |
| 9.0 pH | 190.45 mg/dL (16,836 µmol/L) | -3.8 | |
| Acetaminophen | 200 mg/dL (13.2 mmol/L) | 40.36 mg/dL (3568 µmol/L) | 1.2 |
| 200 mg/dL (13.2 mmol/L) | 183.14 mg/dL (16,190 µmol/L) | 2.5 | |
| Acetic Acid | 25 mL/24 hr collection | 41.92 mg/dL (3706 µmol/L) | -0.6 |
| 25 mL/24 hr collection | 187.47 mg/dL (16,572 µmol/L) | -0.6 | |
| Albumin | 0.5 g/dL (5 g/L) | 42.50 mg/dL (3757 µmol/L) | -0.5 |
| 0.5 g/dL (5 g/L) | 192.04 mg/dL (16,976 µmol/L) | 0.4 | |
| Ascorbate | 3 mg/dL (199.9 µmol/L) | 41.94 mg/dL (3707 µmol/L) | 0.0 |
| 3 mg/dL (199.9 µmol/L) | 190.30 mg/dL (16,823 µmol/L) | -0.4 | |
| Boric acid | 1% w/v | 42.69 mg/dL (3774 µmol/L) | -0.4 |
| 1% w/v | 190.59 mg/dL (16,848 µmol/L) | -0.6 | |
| Conjugated bilirubin | 50 mg/dL (855 µmol/L) | 37.01 mg/dL (3272 µmol/L) | -0.9 |
| 50 mg/dL (855 µmol/L) | 168.09 mg/dL (14,859 µmol/L) | -0.5 | |
| Ethanol | 1 g/dL (216.9 mmol/L) | 41.43 mg/dL (3662 µmol/L) | 0.2 |
| 1 g/dL (216.9 mmol/L) | 187.49 mg/dL (16,574 µmol/L) | -0.3 | |
| Gamma Globulin | 0.5 g/dL (5 g/L) | 42.71 mg/dL (3776 µmol/L) | -0.5 |
| 0.5 g/dL (5 g/L) | 192.42 mg/dL (17,010 µmol/L) | -0.5 | |
| Glucose | 2000 mg/L (111.1 mmol/L) | 40.31 mg/dL (3563 µmol/L) | 0.6 |
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| 2000 mg/L (111.1 mmol/L) | 181.95 mg/dL (16,084 µmol/L) | 0.7 | |
|---|---|---|---|
| Hemoglobin | 100 mg/L (0.1 g/L) | 40.34 mg/dL (3566 µmol/L) | -0.3 |
| 100 mg/L (0.1 g/L) | 178.21 mg/dL (15,754 µmol/L) | 0.6 | |
| Ibuprofen | 500 mg/dL (24.3 mmol/L) | 40.34 mg/dL (3566 µmol/L) | 0.7 |
| 500 mg/dL (24.3 mmol/L) | 183.38 mg/dL (16,211 µmol/L) | 0.4 | |
| N-Acetylcysteine | 2 mg/dL (122.6 µmol/L) | 40.06 mg/dL (3541 µmol/L) | -0.1 |
| 2 mg/dL (122.6 µmol/L) | 180.00 mg/dL (15,912 µmol/L) | 0.1 | |
| Nitric Acid | 0.6% | 42.49 mg/dL (3756 µmol/L) | -0.2 |
| 0.6% | 187.60 mg/dL (16,584 µmol/L) | 0.3 | |
| Oxalic acid | 0.1 g/dL (11.1 mmol/L) | 40.31 mg/dL (3563 µmol/L) | -0.3 |
| 0.1 g/dL (11.1 mmol/L) | 182.59 mg/dL (16,141 µmol/L) | -0.3 | |
| Sodium carbonate | 5 g/24 hr collection | 40.15 mg/dL (3549 µmol/L) | -0.6 |
| 5 g/24 hr collection | 180.93 mg/dL (15,994 µmol/L) | -0.2 |
Clinical Study 11.
Not applicable.
11.1 Expected Values
Siemens Healthineers has verified the reference interval for serum, plasma and urine for the Atellica CH ECre3 assay, in accordance with CLSI Document EP28-A3c.
| Group Specimen Type | Reference Interval | Conventional Units (SI Units) |
|---|---|---|
| Malesa | Serum/plasma | 0.73–1.18 mg/dL(65–104 µmol/L) |
| Femalesa | Serum/plasma | 0.55–1.02 mg/dL(49–90 µmol/L) |
| Males | Urineb | 800–2000 mg/day |
| Females | Urineb | 600–1800 mg/day |
a These data were verified on the Atellica CH Analyzer.
6 Wu, AHB. Tietz Clinical Guide to Laboratory Tests. 4th ed. Philadelphia, PA: WB Saunders Company; 2006:316.
12. Linearity
Linearity testing was performed in accordance with CLSI Document EP06-A.
The assay is linear for the measuring interval from 0.15-30.00 mg/dL (13-2652 µmol/L) for Serum/plasma and from 2.00–245.00 mg/dL (177–21,658 µmol/L) for Urine.
13. Standardization
The assay is traceable to the National Institute of Standards and Technology (NIST) Standard Reference Material SRM967.
Assigned values for calibrators are traceable to this standardization.
Clinical Cut-off 14.
Not applicable.
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Conclusion 15.
The results from the performance studies support that the Candidate Device, Atellica CH Enzymatic Creatinine_3 (ECre3) assay, is substantially equivalent to the Predicate Device, ADVIA Chemistry Enzymatic Creatinine_2 (ECRE_2) assay (K070727).
§ 862.1225 Creatinine test system.
(a)
Identification. A creatinine test system is a device intended to measure creatinine levels in plasma and urine. Creatinine measurements are used in the diagnosis and treatment of renal diseases, in monitoring renal dialysis, and as a calculation basis for measuring other urine analytes.(b)
Classification. Class II.