The Urea Nitrogen2 assay is an automated clinical chemistry assay. The Urea Nitrogen2 assay is a modification of a totally enzymatic procedure. The test is performed as a kinetic assay in which the initial rate of the reaction is linear for a limited period of time. Urea in the sample is hydrolyzed by urease to ammonia and carbon dioxide. The second reaction, catalyzed by glutamate dehydrogenase (GLDH), converts ammonia and a-ketoglutarate to glutamate and water with the concurrent oxidation of reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD). Two moles of NADH are oxidized for each mole of urea present. The initial rate of decrease in absorbance at 340 nm is proportional to the urea concentration in the sample.

AI/ML Overview

The provided document is a 510(k) premarket notification for a new in vitro diagnostic device, the Urea Nitrogen2 assay. This type of submission focuses on demonstrating substantial equivalence to a legally marketed predicate device rather than comprehensive clinical effectiveness studies as might be seen for novel devices. Therefore, the information provided primarily concerns non-clinical performance characteristics of the assay itself, rather than human-in-the-loop performance or diagnostic accuracy evaluated in a clinical setting with patient outcomes.

Based on the provided document, here's an analysis of the acceptance criteria and the study that proves the device meets them:

Core Purpose of the Submission: To demonstrate that the Urea Nitrogen2 assay is substantially equivalent to the predicate device (Urea Nitrogen assay, K981918) for the quantitative measurement of urea nitrogen in human serum, plasma, and urine on the ARCHITECT c System. This means proving the new device performs similarly and is as safe and effective as the predicate.

Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly derived from established clinical laboratory standards (CLSI guidelines) and comparison to the predicate device's known performance. The performance metrics evaluated are standard for in vitro diagnostic assays.

1. Table of Acceptance Criteria and Reported Device Performance

Performance Characteristic	Acceptance Criteria (Implicit)	Reported Device Performance (Urea Nitrogen2)
Reportable Interval	Must cover clinically relevant range and be supported by analytical performance (LoD, LoQ, linearity, imprecision, bias). It should be comparable to or improve upon the predicate device. Predicate: Serum 2-125 mg/dL, Urine 2-1991 mg/dL.	Serum/Plasma: AMI: 2-125 mg/dL, EMI: 125-625 mg/dL, Reportable Interval: 2-625 mg/dL. Urine: AMI: 16-1991 mg/dL, Reportable Interval: 11-1991 mg/dL. (Meets/Exceeds predicate in serum/plasma upper limit, comparable in urine.)
Within-Laboratory Precision (Imprecision)	Based on CLSI EP05-A3 guidelines. Low %CV (Coefficient of Variation) and SD (Standard Deviation) demonstrating consistent results. Comparable to or better than predicate. Predicate: Serum %CV 1.8-2.0% (15.5-48.0 mg/dL), Urine %CV 3.1-3.8% (504.8-896.4 mg/dL).	Serum/Plasma: Samples (4-102 mg/dL) demonstrated SDs ≤ 0.4 mg/dL and %CV ≤ 2.7%. Urine: Samples (55-1605 mg/dL) demonstrated SDs ≤ 11.7 mg/dL and %CV ≤ 2.1%. (Meets/Exceeds predicate with broader range tested and generally lower %CV.)
Accuracy (Bias)	Low percentage bias relative to a recognized standard reference material (NIST SRM 912b). Bias should be within acceptable limits for clinical utility.	Serum: Bias ranged from 1.6% to 4.2%. Urine: Bias ranged from -1.3% to 3.0%. (Demonstrates acceptable accuracy.)
Lower Limits of Measurement (LoB, LoD, LoQ)	Determined by CLSI EP17-A2 guidelines. LoB, LoD, and LoQ should be low enough to be clinically useful and comparable to the predicate. Predicate Serum: LoD 0.7 mg/dL, LoQ 1.4 mg/dL. Predicate Urine: LoD 15.0 mg/dL, LoQ 40.0 mg/dL.	Serum: LoB 1 mg/dL, LoD 2 mg/dL, LoQ 2 mg/dL. Urine: LoB 6 mg/dL, LoD 11 mg/dL, LoQ 16 mg/dL. (Comparable to predicate's analytical sensitivity; slight differences but within typical ranges for this type of assay.)
Linearity	Device should show a linear response across its stated analytical measuring interval as per CLSI EP06-A.	Serum: Linear across 2 to 125 mg/dL. Urine: Linear across 16 to 1991 mg/dL. (Demonstrates linearity across its Analytical Measuring Interval.)
Interference	No significant interference (typically defined as ±10% bias) from common endogenous and exogenous substances at specified levels. The scope and levels tested should address potential clinical interferences.	Serum/Plasma (Endogenous): No significant interference (within ±10%) for Bilirubin (60 mg/dL), Hemoglobin (2000 mg/dL), Triglycerides (1500 mg/dL). Interference was observed for Total Protein (11 g/dL at 10 mg/dL analyte level: 11% (9%, 14%) CI). Serum/Plasma (Exogenous): No significant interference (within ±10%) for a broad list of drugs. Interference was observed for Cefoxitin (6600 mg/L at 10 mg/dL analyte level: 10% (6%, 14%) CI). Urine (Endogenous): No significant interference (within ±10%) for Ascorbate (200 mg/dL), Glucose (1000 mg/dL), Protein (50 mg/dL). Urine (Exogenous): No significant interference (within ±10%) for a broad list of drugs/substances. (Generally good performance, with identified interferences clearly reported.)
Method Comparison	High correlation and acceptable agreement (slope and intercept near 1 and 0, respectively) when compared to the predicate device on the same platform. Expected correlation coefficient near 1.00.	Serum: N=124, Correlation Coefficient=1.00, Intercept=0.74, Slope=1.02 (Concentration Range 4-123 mg/dL). Urine: N=121, Correlation Coefficient=1.00, Intercept=8.95, Slope=1.03 (Concentration Range 41-1754 mg/dL). (Excellent correlation and agreement with the predicate.)
Tube Type Suitability	Demonstration that the device performs acceptably with specified blood collection tube types.	Serum: Serum tubes, Serum separator tubes. Plasma: Lithium heparin tubes, Lithium heparin separator tubes, Sodium heparin tubes. (Acceptable for specified tube types.)
Dilution Verification	Demonstration that the automated dilution protocol yields results comparable to manual dilution. Accuracy of diluted results compared to undiluted or expected values.	% difference values for automated dilution vs. manual dilution ranged from -2.8% to -1.3%, demonstrating acceptable performance. (Acceptable performance for automated dilution.)

Study Details

The studies described are primarily analytical performance studies, characteristic of a 510(k) submission for an in vitro diagnostic device, especially a chemical analyzer assay. They demonstrate the device's technical specifications and how it performs compared to a reference method or the predicate device.

2. Sample Size Used for the Test Set and Data Provenance

Precision Studies (Within-Laboratory):
- Serum/Plasma: 3 human serum panels + 2 controls. Each tested in duplicate, twice per day, for 20 days on 3 reagent lot/calibrator lot/instrument combinations. For a representative combination, n=80 per sample/control.
- Urine: 3 human urine panels + 2 controls. Each tested in duplicate, twice per day, for 20 days on 3 reagent lot/calibrator lot/instrument combinations. For a representative combination, n=80 per sample/control.
- Data Provenance: Not explicitly stated but inferred to be laboratory-based analytical studies, likely from the manufacturer's R&D facilities. No country of origin is specified. The studies are retrospective analytical evaluations of manufactured samples and controls.
Accuracy (Bias): 3 concentrations of standard across 3 reagent lots, 2 calibrator lots, and 1 instrument. (NIST SRM 912b is the standard).
Lower Limits of Measurement (LoB, LoD, LoQ): n ≥ 60 replicates of zero-analyte samples for LoB, n ≥ 60 replicates of low-analyte level samples for LoD/LoQ. Conducted using 3 reagent lots on 2 instruments over a minimum of 3 days.
Linearity: Not explicitly stated sample count, but typically involves preparing a dilution series of samples across the range.
Interference: "Each substance was tested at 2 levels of the analyte (approximately 10 mg/dL and 30 mg/dL for serum/plasma; 700 mg/dL and 1500 mg/dL for urine)." No specific N for how many replicates or individual samples are run per interferent level, but implied to be sufficient for statistical analysis (e.g., 95% CI).
Method Comparison:
- Serum: n=124 samples.
- Urine: n=121 samples.
- Data Provenance: Not explicitly stated, but these would be clinical or proficiency samples analyzed side-by-side with the predicate.
Tube Type: Samples collected from a minimum of 40 donors.
Dilution Verification: 5 human serum samples (spiked with urea). Each sample tested with automated dilution and 3 manual dilutions (by 2 technicians). Tested in replicates of 5.

3. Number of Experts Used to Establish Ground Truth and Qualifications

For this type of in vitro diagnostic device (a quantitative chemical assay), "ground truth" is established by:
- Reference materials: e.g., NIST SRM 912b for accuracy. This is a primary standard, not established by human experts.
- Predicate device measurements: For method comparison, the predicate device provides the comparative 'truth' (or established method performance).
- Clinical laboratory professional consensus/guidelines: Standards like CLSI (Clinical and Laboratory Standards Institute) guidelines (EP05-A3, EP17-A2, EP06-A, EP07, EP09-A3, EP34) serve as the "expert consensus" on how to conduct and interpret these analytical studies. These are published by committees of experts in laboratory medicine, clinical chemistry, and statistics.
No "expert readers" in the traditional sense (e.g., radiologists interpreting images) are involved in establishing ground truth for this type of device. The validation is based on metrological traceability to standards and comparison to an established analytical method.

4. Adjudication Method for the Test Set

Not applicable as this is an analytical performance study of a chemical assay, not a diagnostic accuracy study relying on human interpretation of subjective data (like imaging or pathology). Results are quantitative measurements read by the instrument.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No. An MRMC study is relevant for diagnostic devices that involve human interpretation (e.g., AI-assisted image interpretation) and aim to show an improvement in human reader performance. This device is a quantitative chemical assay that provides a numerical result; there is no human "reader" to assist in the primary measurement. The comparison is between the new assay's performance and the predicate assay's performance, as well as against analytical standards.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done

Yes, effectively. The entire submission details the standalone analytical performance of the Urea Nitrogen2 assay system (reagents + ARCHITECT c System instrument). Its performance (precision, accuracy, linearity, etc.) is evaluated independently of human interpretation of the final numerical result, beyond the standard operation and quality control typically performed in a clinical lab.

7. The Type of Ground Truth Used

Analytical Standards and Reference Methods/Predicate Device:
- NIST SRM 912b: Used as the true value for accuracy determination.
- Predicate Device (Urea Nitrogen assay): Used as the comparative reference for method comparison studies, demonstrating substantial equivalence.
- CLSI Guidelines: Act as the "ground truth" for the methodologies and acceptance criteria applied to evaluate the analytical performance (e.g., how LoQ is defined and determined, how precision is calculated).

8. The Sample Size for the Training Set

For this type of in vitro diagnostic assay, there isn't a "training set" in the machine learning sense (where an algorithm learns from data). The "training" for such an assay primarily refers to:
- Reagent formulation and optimization: This involves extensive R&D to achieve desired chemical reactions and stability.
- Instrument calibration: The ARCHITECT c System is calibrated using specific calibrators (Consolidated Chemistry Calibrator mentioned, which is itself traceable to standards) to ensure accurate measurement across the range.
The "training" is inherent in the chemical and engineering development of the assay and the instrument, rather than an algorithmic learning process on a large dataset. Therefore, a specific "training set sample size" as one would discuss for an AI model is not applicable.

9. How the Ground Truth for the Training Set Was Established

As explained above, there isn't a "training set" with ground truth in the AI/ML context for this device. Instead, the assay's performance characteristics (calibration, linearity, reaction kinetics, etc.) are optimized and confirmed through:
- Chemical principles and R&D: The enzymatic reaction (urease, GLDH kinetics) is based on established biochemical mechanisms.
- Quality control materials and calibrators: These materials have assigned values, often traceable to international standards (like NIST SRM), and are used to "train" or calibrate the instrument system.
- Iterative laboratory testing and optimization: The assay's components and instrument parameters are refined through repeated experiments to meet performance specifications.

Summary

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May 31, 2022

Abbott Ireland Diagnostics Division Tiffini Jenkins Regulatory Affairs Manager Lisnamuch Longford, Ireland

Re: K203771

Trade/Device Name: Urea Nitrogen2 Regulation Number: 21 CFR 862.1770 Regulation Name: Urea nitrogen test system Regulatory Class: Class II Product Code: CDO Dated: February 28, 2022 Received: March 2, 2022

Dear Tiffini Jenkins:

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.

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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); 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 Office of Product Evaluation and Quality Center for Devices and Radiological Health Food and Drug Administration

Enclosure

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Indications for Use

510(k) Number (if known) K203771

Device Name Urea Nitrogen2

Indications for Use (Describe)

The Urea Nitrogen2 assay is used for the quantitation of Urea Nitrogen in human serum, plasma, or urine on the ARCHITECT c System.

The Urea Nitrogen2 assay is to used as an aid in the diagnosis and treatment of certain renal and metabolic diseases.

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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Section 5: 510(k) Summary (Summary of Safety and Effectiveness)

This summary of the 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

I. 510(k) Number

K203771

II. Applicant Name

Abbott Ireland Diagnostics Division Lisnamuck, Longford, Longford, IE

Primary contact person for all communications:

Tiffini Jenkins, Regulatory Affairs Associate Director Abbott Diagnostics Division Phone (224) 668-8864 Fax (224) 668-0194

Secondary contact person for all communications:

Magdalena Suszko, Regulatory Affairs Associate Director Abbott Diagnostics Division Phone (224) 667-9025 Fax (224) 668-0194

Date Summary Prepared: May 24, 2022

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III. Device Name

Urea Nitrogen2

Reagents

Trade Name: Urea Nitrogen2 Device Classification: Class II Classification Name: Urease and Glutamic Dehydrogenase, Urea Nitrogen Governing Regulation Number: 21 CFR 862.1770 Product Code: CDQ

IV. Predicate Device

Urea Nitrogen (K981918)

V. Description of Device

A. Principles of the Procedure

The Urea Nitrogen2 assay is an automated clinical chemistry assay. The Urea Nitrogen2 assay is a modification of a totally enzymatic procedure. * The test is performed as a kinetic assay in which the initial rate of the reaction is linear for a limited period of time. Urea in the sample is hydrolyzed by urease to ammonia and carbon dioxide. The second reaction, catalyzed by glutamate dehydrogenase (GLDH), converts ammonia and a-ketoglutarate to glutamate and water with the concurrent oxidation of reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD). Two moles of NADH are oxidized for each mole of urea present. The initial rate of decrease in absorbance at 340 nm is proportional to the urea concentration in the sample.

Methodology: Urease

* Talke H, Schubert GE. Klinische Wochenschrift 1965;43:174.

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B. Reagents

The various kit configurations of the Urea Nitrogen2 reagent kit are described below.

	List Number
	04T1220	04T1230
Tests per cartridge set	350	1450
Number of cartridge sets per kit	4	4
Tests per kit	1400	5800
Reagent 1 (R1)	24.8 mL	53.9 mL
Reagent 2 (R2)	10.0 mL	33.1 mL

Active ingredient: β-NADH (1.915 g/L). Preservative: sodium azide. R1
R2 Active ingredients: α-ketoglutaric acid (13.149 g/L), GLDH (60.000 KU/L), and urease (10.000 KU/L). Preservative: sodium azide.

VI. Intended Use of the Device

The Urea Nitrogen2 assay is used for the quantitation of urea nitrogen in human serum, plasma, or urine on the ARCHITECT c System.

The Urea Nitrogen2 assay is to be used as an aid in the diagnosis and treatment of certain renal and metabolic diseases.

VII. Comparison of Technological Characteristics

The Urea Nitrogen2 assay (subject device) is an automated clinical chemistry assay for the quantitation of urea nitrogen in human serum, plasma, or urine on the ARCHITECT c System.

The similarities and differences between the subject assay and the predicate device are presented in the following table.

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Characteristics	Subject DeviceUrea Nitrogen2 (List No. 04T12)	Predicate DeviceUrea Nitrogen (K981918;List No. 7D75)
Platform	ARCHITECT c System	Same†
Intended Useand Indicationsfor Use	The Urea Nitrogen2 assay is used forthe quantitation of urea nitrogen inhuman serum, plasma, or urine on theARCHITECT c System.The Urea Nitrogen2 assay is to be usedas an aid in the diagnosis andtreatment of certain renal andmetabolic diseases.	The Urea Nitrogen assay is used forthe quantitation of urea nitrogen inhuman serum, plasma, or urine.
Methodology	Urease	Same
Specimen Type	Human serum, plasma, urine	Same
Assay Principle/ Principle ofProcedure	The Urea Nitrogen2 assay is anautomated clinical chemistry assay.The Urea Nitrogen2 assay is amodification of a totally enzymaticprocedure.‡ The test is performed as akinetic assay in which the initial rateof the reaction is linear for a limitedperiod of time. Urea in the sample ishydrolyzed by urease to ammonia andcarbon dioxide. The second reaction,catalyzed by glutamate dehydrogenase(GLDH), converts ammonia and a-ketoglutarate to glutamate and waterwith the concurrent oxidation ofreduced nicotinamide adeninedinucleotide (NADH) to nicotinamideadenine dinucleotide (NAD). Twomoles of NADH are oxidized for eachmole of urea present. The initial rate ofdecrease in absorbance at 340 nm isproportional to the urea concentrationin the sample.	The Urea Nitrogen2 assay is amodification of a totally enzymaticprocedure first described by Talke andSchubert.‡ The test is performed as akinetic assay in which the initial rateof the reaction is linear for a limitedperiod of time. Urea in the sample ishydrolyzed by urease to ammonia andcarbon dioxide. The second reaction,catalyzed by glutamate dehydrogenase(GLD) converts ammonia andα-ketoglutarate to glutamate and waterwith the concurrent oxidation ofreduced nicotinamide adeninedinucleotide (NADH) to nicotinamideadenine dinucleotide (NAD). Twomoles of NADH are oxidized for eachmole of urea present. The initial rateof decrease in absorbance at 340 nm isproportional to the urea concentrationin the sample.

Characteristics	Subject DeviceUrea Nitrogen2 (List No. 04T12)	Predicate DeviceUrea Nitrogen (K981918; List No.7D75)
Standardization	NIST SRM 912b/Gravimetric	NIST SRM 912b/Differential ScanningCalorimetry
Use ofCalibrators	Yes	Same
Use of Controls	Yes	Same
Assay Range	Serum/Plasma:Analytical Measuring Interval:2 — 125 mg/dLExtended Measuring Interval:125 – 625 mg/dLReportable Interval:2 — 625 mg/dLUrine:	Urea Nitrogen serum is linear from2 to 125 mg/dL.Urea Nitrogen urine is linear from2 to 1991 mg/dL.
	Analytical Measuring Interval:16 – 1991 mg/dLReportable Interval: 11 - 1991 mg/dL
Precision	Serum/Plasma:Samples with urea nitrogenconcentrations between 4 and102 mg/dL were evaluated. Thesamples demonstrated standarddeviations (SDs) \u2264 0.4 mg/dL and% Coefficient of Variation (%CV)\u22642.7%.	Serum/Plasma:Samples with urea nitrogenconcentrations between 15.5 and48.0 mg/dL demonstrated %CV valuesranging from 1.8 to 2.0%.
	Urine:Samples with urea nitrogenconcentrations between 55 and1605 mg/dL were evaluated. Thesamples demonstrated SDs\u2264 11.7 mg/dL and %CV \u2264 2.1%.	Urine:Samples with urea nitrogenconcentrations between 504.8 and896.4 mg/dL demonstrated %CV valuesranging from 3.1 to 3.8%.

Characteristics	Subject DeviceUrea Nitrogen2 (List No. 04T12)	Predicate DeviceUrea Nitrogen (K981918; List No. 7D75)
Lower Limits ofMeasurement	Serum/Plasma:Limit of Blank: 1 mg/dLLimit of Detection: 2 mg/dLLimit of Quantitation: 2 mg/dLUrine:Limit of Blank: 6 mg/dLLimit of Detection: 11 mg/dLLimit of Quantitation: 16 mg/dL	Serum/Plasma:Limit of Detection: 0.7 mg/dLLimit of Quantitation: 1.4 mg/dLUrine:Limit of Detection: 15.0 mg/dLLimit of Quantitation: 40.0 mg/dL
Tube Types	Serum:- Serum tubes- Serum separator tubesPlasma:- Lithium heparin tubes- Lithium heparin separator tubes- Sodium heparin tubes	Same

Comparison of Subject Device (Urea Nitrogen2) to Predicate Device (Urea Nitrogen)

1 In accordance with FDA Guidance Document "Data for Commercialization of Original Equipment Manufacturer, Secondary and Generic Reagent for Automated Analyzers", issued June 10, 1996, the assay equivalency study on ARCHITECT c System vs. the original platform, AEROSET, was performed and submitted under K980367/A004 in May 2002.

‡ Talke H, Schubert GE. Klinische Wochenschrift 1965;43:174.

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Comparison of Subject Device (Urea Nitrogen2) to Predicate Device (Urea Nitrogen) (Continued)

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Comparison of Subject Device (Urea Nitrogen2) to Predicate Device (Urea Nitrogen) (Continued)

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VIII. Summary of Nonclinical Performance

A. Reportable Interval

Based on the limit of detection (LoD), limit of quantitation (LoQ), precision, and linearity, the ranges over which results can be reported are provided below according to the definitions from CLSI EP34, 1st ed. §

Serum/Plasma

	mg/dL
Analytical Measuring Interval (AMI)a	2 - 125
Extended Measuring Interval (EMI)b	125 - 625
Reportable Intervalc	2 - 625

a AMI: The AMI extends from the LoQ to the upper limit of quantitation (ULoQ). This is determined by the range of values in mg/dL that demonstrated acceptable performance for linearity, imprecision, and bias.

b EMI: The EMI extends from the ULoQ to the ULoQ × sample dilution.

° The reportable interval extends from the LoD to the upper limit of the EMI.

Urine

	mg/dL
Analytical Measuring Interval (AMI)a	16 - 1991
Reportable Intervalb	11 - 1991

b The reportable interval extends from the LoD to the upper limit of the AMI.

े Clinical and Laboratory Standards Institute(CLS). Establishing and Verifying an Extended Measuring Interval Through Specinen Dilution and Spiking. 1st ed. CLSI Document EP34. Wayne, PA: CLSI; 2018.

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B. Within-Laboratory Precision

Serum/Plasma

A study was performed based on guidance from CLSI EP05-A3. ** Testing was conducted using 3 lots of the Urea Nitrogen2 reagent, 3 lots of the Consolidated Chemistry Calibrator, and 1 lot of commercially available controls and 3 instruments. Two controls and 3 human serum panels were tested in duplicate, twice per day on 20 days on 3 reagent lot/calibrator lot/instrument combinations, where a unique reagent lot and a unique calibrator lot is paired with 1 instrument. The performance from a representative combination is shown in the following table.

			Within-Run(Repeatability)		Within-Laboratorya
Sample	n	Mean(mg/dL)	SD	%CV	SD(Rangeb)	%CV(Rangeb)
ControlLevel 1	80	15	0.3	2.1	0.4(0.2 - 0.4)	2.4(1.6 - 2.4)
Control Level 2	80	49	0.5	1.1	0.8(0.8 - 0.9)	1.7(1.6 - 1.7)
Panel A	80	4	0.2	4.7	0.2(0.0 - 0.2)	4.7(0.0 - 4.7)
Panel B	80	22	0.3	1.1	0.5(0.3 - 0.6)	2.1(1.4 - 2.7)
Panel C	80	102	0.8	0.8	1.9(1.2 - 2.5)	1.8(1.2 - 2.5)

a Includes within-run, between-run, and between-day variability.

b Minimum and maximum SD or %CV a cross all rea gent lot and instrument combinations.

** Clinical and Laboratory Standards Institute(CLSI). Evaluation of Quantitative Measurement Procedures; Approved Guideline-Third Edition. CLSI Document EP05-A3. Wayne, PA: CLSI; 2014.

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Urine

A study was performed based on guidance from CLSI EP05-A3.tt Testing was conducted using 3 lots of the Urea Nitrogen2 reagent, 3 lots of the Consolidated Chemistry Calibrator, and 1 lot of commercially available controls and 3 instruments. Two controls and 3 human urine panels were tested in duplicate, twice per day on 20 days on 3 reagent lot/calibrator lot/instrument combinations, where a unique reagent lot and a unique calibrator lot is paired with 1 instrument. The performance from a representative combination is shown in the following table.

			Within-Run(Repeatability)		Within-Laboratorya
Sample	n	Mean(mg/dL)	SD	%CV	SD(Rangeb)	%CV(Rangeb)
ControlLevel 1	80	447	3.7	0.8	7.1(7.1 - 11.7)	1.6(1.6 - 2.6)
ControlLevel2	80	729	5.2	0.7	11.4(11.2 - 15.4)	1.6(1.6 - 2.1)
Panel A	80	55	2.2	4.1	2.7(2.7 - 5.6)	5.0(5.0 - 10.3)
Panel B	80	715	6.2	0.9	10.2(10.2 - 15.1)	1.4(1.4 - 2.1)
Panel C	80	1605	12.6	0.8	22.6(22.6 - 27.8)	1.4(1.4 - 1.8)

ª Includes within-run, between-run, and between-day variability.

b Minimum and maximum SD or %CV a cross all rea gent lot and instrument combinations.

** Clinical and Laboratory Standards Institute (CLS). Evaluation of Quantitative Measurement Procedures; Approved Guideline-Third Edition. CLSI Document EP05-A3. Wayne, PA: CLSI; 2014.

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C. Accuracy

A study was performed to estimate the bias of the Urea Nitrogen2 assay relative to standard reference material (NIST SRM Standard 912b). Testing was conducted using 3 concentrations of standard across 3 lots of the Urea Nitrogen2 reagent, 2 lots of the Consolidated Chemistry Calibrator, and 1 instrument. The bias ranged from 1.6% to 4.2% for serum, and from -1.3% to 3.0% for urine.

D. Lower Limits of Measurement

A study was performed based on guidance from CLSI EP17-A2. # Testing was conducted using 3 lots of the Urea Nitrogen2 reagent on each of 2 instruments over a minimum of 3 days. The results of the study support limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) values as summarized below.

	mg/dL
LoBa	1
LoDb	2
LoQc	2

Serum

Urine

	mg/dL
LoBa	6
LoDb	11
LoQc	16

a The LoBrepresents the 95th percentile from n ≥ 60 replicates of zero-analyte samples.

b The LoD represents the lowest concentration at which the analyte can be detected with 95% probability based on n ≥ 60 replicates of low-analyte level samples.

6 The LoQ is defined as the lowest concentration at which a maximum allowable precision of 20% CV was met and was determined from n ≥ 60 replicates of low-analyte level samples.

# Clinical and Laboratory Standards Institute(CLS). Evaluation of Detection Capability for Clinical Laboratory Measurent Procedures; Approved Guideline-Second Edition. CLSI Document EP 17-A2. Wayne, PA: CLSI; 2012.

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E. Linearity

A study was performed based on guidance from CLSI EP06-A. § This assay is linear across the analytical measuring interval of 2 to 125 mg/dL for serum, and 16 to 1991 mg/dL for urine.

F. Potentially Interfering Endogenous and Exogenous Substances

Serum/Plasma - Potentially Interfering Endogenous Substances

A study was performed based on guidance from CLSI EP07, 3rd ed. *** Each substance was tested at 2 levels of the analyte (approximately 10 mg/dL and 30 mg/dL).

No significant interference (interference within±10%) was observed at the following concentrations.

Potentially Interfering Substance	Interferent Level
Bilirubin - conjugated	60 mg/dL
Bilirubin - unconjugated	60 mg/dL
Hemoglobin	2000 mg/dL
Total Protein	10 g/dL
Triglycerides	1500 mg/dL

Interference beyond ± 10% (based on 95% Confidence Intervals [CI]) was

observed at the concentrations and analyte levels shown below for the following substance.

Potentially Interfering Substance	Interferent Level	Analyte Level	% Interference(95% CI)
Total Protein	11 g/dL	10 mg/dL	11%(9%, 14%)

$$ Clinical and Laboratory Standards Institute(CLS). Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline. CLSI Document EP06-A. Wayne, PA: CLSI; 2003.

*** Clinical and Laboratory Standards Institute (CLSI). Interference Testing in Clinical Chemistry: 3rd ed. CLSI Guideline EP07. Wayne, PA: CLSI; 2018.

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Serum/Plasma - Potentially Interfering Exogenous Substances

A study was performed based on guidance from CLSI EP07, 3rd ed.t*f Each substance was tested at 2 levels of the analyte (approximately 10 mg/dL and 30 mg/dL).

No significant interference (interference within±10%) was observed at the following concentrations.

Potentially Interfering Substance	InterferentLevel	Potentially Interfering Substance	InterferentLevel
3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC)	0.6 mg/L	Doxycycline	20 mg/L
4-methylamino-antipyrine	3.3 mg/dL	Ibuprofen	220 mg/L
5-amino-4-imidazolecarboxamide(AIC)	3 mg/L	Levodopa	8 mg/L
Acetaminophen	160 mg/L	Methyldopa	25 mg/L
Acetylcysteine	150 mg/L	Metronidazole	130 mg/L
Acetylsalicylic acid	30 mg/L	Phenylbutazone	330 mg/L
Ampicillin-Na	80 mg/L	Rifampicin	50 mg/L
Ascorbic acid	60 mg/L	Sodium heparin	4 U/mL
Biotin	4250 ng/mL	Sulfapyridine	300 mg/L
Ca-dobesilate	60 mg/L	Sulfasalazine	300 mg/L
Cefoxitin	6287 mg/L	Temozolomide	20 mg/L
Cyclosporine	2 mg/L	Theophylline	60 mg/L
Dipyrone (metamizole)	45 mg/dL

Interference beyond ± 10% (based on 95% Confidence Intervals [CI]) was

observed at the concentrations and analyte levels shown below for the following substance.

Potentially Interfering Substance	Interferent Level	Analyte Level	% Interference(95% CI)
Cefoxitin	6600 mg/L	10 mg/dL	10%(6%, 14%)

"T" Clinical and Laboratory Standards Institute(CLS). Interference Testing in Clinical Chemistry. 3rd ed. CLSI Guideline EP07. Wayne, PA: CLSI; 2018.

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Urine - Potentially Interfering Endogenous Substances

A study was performed based on guidance from CLSI EP07, 3rd ed.## Each substance was tested at 2 levels of the analyte (approximately 700 mg/dL and 1500 mg/dL).

No significant interference (interference within±10%) was observed at the following concentrations.

Potentially Interfering Substance	Interferent Level
Ascorbate	200 mg/dL
Glucose	1000 mg/dL
Protein	50 mg/dL

Urine - Potentially Interfering Exogenous Substances

A study was performed based on guidance from CLSI EP07, 3rd ed. §§§ Each substance was tested at 2 levels of the analyte (approximately 700 mg/dL and 1500 mg/dL).

No significant interference (interference within±10%) was observed at the following concentrations.

Potentially Interfering Substance	Interferent Level
Acetaminophen	16 mg/dL
Acetic acid (8.5N)	6.25 mL/dL
Acetylcysteine	15 mg/dL
Biotin	4250 ng/mL
Boric acid	250 mg/dL
Hydrochloric acid (6N)	2.5 mL/dL
Ibuprofen	22 mg/dL
Nitric acid (6N)	5.0 mL/dL
Sodium carbonate	1.25 g/dL
Sodium fluoride	400 mg/dL
Sodium oxalate	60 mg/dL

## Clinical and Laboratory Standards Institute(CLS). Interference Testing in Clinical Chemisstry. 3rd ed. CLSI Guideline EP07. Wayne, PA: CLSI: 2018.

SSS Clinical and Laboratory Standards Institute(CLS). Interference Testing in Clinical Chemistry. 3rd ed. CLSI Guideline EP07. Wayne, PA: CLSI; 2018.

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G. Method Comparison

A study was performed based on guidance from CLSI EP09-A3 **** using the Passing-Bablok regression method.

Urea Nitrogen2 vs Urea Nitrogen on the ARCHITECT c System
	Units	n	CorrelationCoefficient	Intercept	Slope	ConcentrationRange
Serum	mg/dL	124	1.00	0.74	1.02	4 - 123
Urine	mg/dL	121	1.00	8.95	1.03	41 - 1754

H. Tube Type

A study was performed to evaluate the suitability of specific blood collection tube types for use with Urea Nitrogen2 assay. Samples were collected from a minimum of 40 donors and evaluated across tube types. The following blood collection tube types were determined to be acceptable for use with the Urea Nitrogen2 assay:

Serum

Serum tubes
. Serum separator tubes

Plasma

Lithium heparin tubes .
Lithium heparin separator tubes •
Sodium heparin tubes •

**** Samples; Approved Guideline-Third Edition. CLSI Document EP09-A3. Wayne, P A: CLSI; 2013.

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I. Dilution Verification

A study was performed to evaluate the performance of the Urea Nitrogen2 automated dilution protocol relative to the manual dilution procedure on the ARCHITECT c System. Five human serum samples were created by spiking urea stock solution into Serasub (a synthetic serum) to target concentration values of 150, 214, 278, 342, and 405 mg/dL. Each sample was divided into multiple aliquots. An aliquot of each sample was tested using the 1:5 automated dilution protocol on the ARCHITECT c System. The additional aliquots were divided such that 2 technicians each prepared 3 manual dilutions (1:5 dilution) of each sample using saline. Each sample preparation from a given technician was tested in a separate run.

The samples were tested in replicates of 5 using 1 lot each of reagents, calibrators, and controls on 2 instruments. The % difference values for the automated dilution protocol versus the manual dilution procedure ranged from -2.8% to -1.3% and therefore, demonstrated acceptable performance.

IX. Summary of Clinical Performance

This section does not apply.

X. Conclusion Drawn from Nonclinical Laboratory Studies

The similarities and differences between the subject device and predicate device are presented in Section 5-VII.

There is no known potential adverse effect to the operator when using this in vitro device according to the Urea Nitrogen2 reagent package insert instructions.

Regulation Number and Section

§ 862.1770 Urea nitrogen test system.

(a)
Identification. A urea nitrogen test system is a device intended to measure urea nitrogen (an end-product of nitrogen metabolism) in whole blood, serum, plasma, and urine. Measurements obtained by this device are used in the diagnosis and treatment of certain renal and metabolic diseases.(b)
Classification. Class II.