The Urine/CSF Albumin reagent is intended to be used for the quantitation of albumin concentration in human urine and cerebrospinal fluid (CSF) on the Beckman Coulter AU clinical chemistry systems as an aid in the diagnosis of kidney diseases. For in vitro diagnostic use only.

Urine/CSF Albumin Calibrator:

The Urine/CSF Albumin calibrator is intended to be used to calibrate the Urine/CSF Albumin reagent on the Beckman Coulter AU clinical chemistry systems. For in vitro diagnostic use only.

Device Description

The Urine/CSF Albumin reagent kit is in a liquid, ready to use format. There are two kit concepts available. Each kit concept contains an R1 and an R2 reagent vial with different fill volumes. The Urine/CSF Albumin calibrator kit is in a liquid, ready to use format and contains 5 x 2 mL calibrator levels. It is packaged and sold separately to the reagent kit. Urine/CSF Albumin reagent is used to measure albumin concentration by a turbidimetric method. In the reaction, anti-human serum albumin antibodies combine with albumin from the sample to form immune complexes that scatter light in proportion to their size, shape and concentration. The absorbance of these aggregates is proportional to the albumin concentration in the sample. Change in absorbance is measured at 380nm with subtraction of a reference wavelength at 800nm. The Urine/CSF Albumin reagent and calibrator is designed for optimal performance on Beckman Coulter AU clinical chemistry analyzers.

AI/ML Overview

This looks like a 510(k) premarket notification for a medical device: "Urine/CSF Albumin and Urine/CSF Albumin Calibrator." The document describes various analytical performance studies to demonstrate substantial equivalence to predicate devices, rather than a clinical study establishing a new clinical claim. Therefore, some of the requested information (like MRMC study effect size, number of experts for ground truth, adjudication method, and training set details) is not directly applicable to this type of submission.

However, I can extract and organize the available "acceptance criteria" (implicitly, the performance targets demonstrated) and "device performance" (the results of the studies).

1. Table of Acceptance Criteria and Reported Device Performance

Since this is a submission demonstrating equivalence through analytical performance, the "acceptance criteria" are implied by the precision, linearity, sensitivity, and interference limits typically expected for such devices, and demonstrated by the successful results presented. The "reported device performance" is the direct result from the validation studies.

Acceptance Criterion (Implicit)	Reported Device Performance
Precision (Within-Run/Repeatability)	Urine: - Low: 0.02 SD (0.9% CV) - Mid: 0.02 SD (0.6% CV) - High: 0.3 SD (1.4% CV) CSF: - Low: 0.07 SD (1.0% CV) - Mid: 0.4 SD (1.6% CV) - High: 0.7 SD (1.9% CV)
Precision (Within Laboratory/Total Imprecision)	Urine: - Low: 0.07 SD (4.3% CV) - Mid: 0.08 SD (2.5% CV) - High: 0.4 SD (2.1% CV) CSF: - Low: 0.11 SD (1.8% CV) - Mid: 0.6 SD (2.4% CV) - High: 0.9 SD (2.5% CV)
Analytical Range (Linearity)	Urine: 0.7 - 45 mg/dL (acceptable linearity demonstrated) CSF: 1 - 45 mg/dL (acceptable linearity demonstrated)
Reagent Shelf-Life Stability	18 months at 2-8°C
Calibrator Shelf-Life Stability	18 months at 2-8°C
Reagent On-Board Stability	60 days
Calibration Frequency	60 days
Calibrator Open Vial Stability	30 days
Sensitivity (LoB)	Urine: 0.00 mg/dL CSF: 0.00 mg/dL
Sensitivity (LoD)	Urine: 0.07 mg/dL CSF: 0.13 mg/dL
Sensitivity (LoQ) (≤ 0.7 mg/dL for urine, ≤ 1.0 mg/dL for CSF)	Urine: 0.70 mg/dL CSF: 0.70 mg/dL (met acceptance criteria)
Interference (No Significant Interference: ≤ ± 10% or ± 0.2 mg/dL)	Urine: - Calcium: NSI up to 78 mg/dL - Creatinine: NSI up to 300 mg/dL - Glucose: NSI up to 3000 mg/dL - Urea: NSI up to 5000 mg/dL - Ascorbic Acid: NSI up to 500 mg/dL - Citrate: NSI up to 50 mg/dL - Magnesium: NSI up to 400 mg/dL - Oxalate: NSI up to 30 mg/dL - Conjugated Bilirubin: NSI up to 40 mg/dL - Hemoglobin: NSI up to 500 mg/dL - Acetone: NSI up to 350 mg/dL - Uric Acid: NSI up to 10 mg/dL - Urobilinogen: NSI up to 2.25 mg/dL - Acetaminophen: NSI up to 300 mg/dL - Ibuprofen: NSI up to 400 mg/dL - Metronidazole: NSI up to 600 mg/dL - 5-aminosalicylic acid: NSI up to 150 mg/dL CSF: - Hemoglobin: NSI up to 500 mg/dL - Conjugated Bilirubin: NSI up to 40 mg/dL
Prozone Tolerance	All samples from upper end of linear range up to claimed prozone tolerance generated a flagged result (indicating a result above the linear range), meaning no false low readings for high concentrations. Prozone high pool tested at ≥ 2000 mg/dL.
Method Comparison (Urine) (vs. commercially available assay)	Slope = 1.09, Intercept = 0.03 mg/dL, r = 1.0; Sample range = 0.81 - 40.7 mg/dL (n=131)
Method Comparison (CSF) (vs. commercially available assay)	Slope = 1.05, Intercept = -0.77 mg/dL, r = 0.99; Sample range = 1.72 - 41.2 mg/dL (n=131)

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

Precision (Repeatability and Total Imprecision): 3 sample levels (Low, Mid, High) for both Urine and CSF. Each level analyzed in duplicate, twice daily, over 20 working days (n=80 total measurements per level).
- Data Provenance: Pooled human urine samples (spiked with purified human serum albumin) and pooled human CSF samples (diluted or spiked with purified human serum albumin). Origin country not specified but implied to be from samples handled in a clinical laboratory setting within the context of a US FDA submission. Prospective for the purpose of the study.
Analytical Range (Linearity): 11 linearity concentration levels. Each dilution assayed in quadruplicate.
- Data Provenance: Urine and CSF pools prepared by spiking with HSA or dilution. Origin country not specified. Prospective for the purpose of the study.
Sensitivity (LoB, LoD, LoQ):
- LoB/LoD: Replicate measurements on blank and low-level samples using three reagent lots. 60 blank replicates per reagent lot and 60 low-level sample replicates per reagent lot (total of 180 blanks and 180 low-level samples across 3 lots). Comprised of 4 blank samples and 4 low-level samples for urine and CSF, run 5-fold for 3 days. Four separate saline pools were used as blanks.
- LoQ: Six pools (0.1, 0.2, 0.35, 0.5, 0.7, 1 mg/dL albumin in urine and CSF). Each pool measured in duplicate, twice daily, over 20 working days (n=80 total measurements per pool).
- Data Provenance: Saline for blanks, quantified urine and CSF pools (diluted with saline) for low-level samples, and spiked urine and CSF pools for LoQ. Origin country not specified. Prospective for the purpose of the study.
Interferences: Urine and CSF pools tested at two different albumin concentrations (1.5-3 mg/dL and 10-20 mg/dL for urine; 10-20 mg/dL and 25-35 mg/dL for CSF). Each interferent concentration tested in quadruplicate.
- Data Provenance: Pooled human urine and CSF samples, spiked with purified human serum albumin and various interfering substances. Origin country not specified. Prospective for the purpose of the study.
Prozone: Human urine and CSF spiked with human serum to create a prozone high pool (≥ 2000 mg/dL). Prozone panels run n=3.
- Data Provenance: Human urine and CSF, spiked. Origin country not specified. Prospective for the purpose of the study.
Method Comparison (Urine): n = 131 patient urine samples.
- Data Provenance: Patient urine samples. Origin country not specified. Retrospective/prospective (typically, such studies use archived or freshly collected patient samples).
Method Comparison (CSF): n = 131 patient CSF samples.
- Data Provenance: Patient CSF samples. Origin country not specified. Retrospective/prospective (typically, such studies use archived or freshly collected patient samples).
Reference Interval Validation (Urine): 20 urine samples.
- Data Provenance: Urine samples. Origin country not specified. Prospective for the purpose of validation.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

Not applicable. This is an in vitro diagnostic (IVD) device for quantitative measurement. The "ground truth" for the analytical performance studies is established by the known concentrations of calibrators, spiked samples, or comparison to a cleared reference method, not by expert interpretation.

4. Adjudication Method for the Test Set

Not applicable. As described above, "ground truth" is analytical, not based on expert review and adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This is an IVD device, not an AI-assisted diagnostic imaging or interpretation device that would involve human "readers." The device quantifies albumin concentration directly.

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

Yes, the device (Urine/CSF Albumin reagent and calibrator on Beckman Coulter AU clinical chemistry systems) is a standalone algorithm/instrument-based system that quantifies albumin concentration. Its performance is evaluated analytically, without a human-in-the-loop component for the direct measurement itself. Human oversight and interpretation of the numerical results are part of clinical practice, but the device's measurement function is autonomous.

7. The Type of Ground Truth Used

The "ground truth" or reference for the analytical performance studies relies on:

Known concentrations: For precision, linearity, and sensitivity studies, this is achieved by using prepared pools with known added amounts of human serum albumin (HSA) or specific dilutions.
Traceability to a Certified Reference Material: The Urine/CSF Albumin calibrator values are traceable to the International Federation of Clinical Chemistry Certified Reference Material ERM® - DA470k.
Comparison to a legally marketed predicate device/method: For method comparison studies, the results are compared against another commercially available and presumably FDA-cleared assay for Urine Albumin and CSF Albumin.
Literature-based reference intervals: Expected values/reference ranges are drawn from established medical literature.

8. The Sample Size for the Training Set

Not applicable. This device is not an AI/Machine Learning algorithm that requires a "training set" in the conventional sense for diagnostic image interpretation or similar tasks. It's an immunoassay for quantitative analysis. The development process would involve internal R&D tests and optimization, but a defined training set for an AI model is not relevant here.

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

Not applicable, as there is no "training set" in the context of an AI/ML algorithm.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

October 15, 2014

BECKMAN COULTER IRELAND, INC. ANNE-MARIE SHINE REGULATORY AFFAIRS SPECIALIST LISMEEHAN, O'CALLAGHANS MILLS CO. CLARE, IRELAND

Re: K142346

Trade/Device Name: Urine/CSF Albumin and Urine/CSF Albumin Calibrator Regulation Number: 21 CFR 866.5040 Regulation Name: Albumin immunological test system Regulatory Class: II Product Code: DCF, JIT Dated: August 20, 2014 Received: August 22, 2014

Dear Ms. Anne-Marie Shine:

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. 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 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. 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

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours.

Courtney

Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K142346

Device Name

Urine/CSF Albumin and Urine/CSF Albumin Calibrator

Indications for Use (Describe)

Urine/CSF Albumin:

Urine/CSF Albumin Calibrator:

The Urine/CSF Albumin calibrator is intended to be used to calibrate the Urine/CSF Albumin reagent on the Beckman Coulter AU clinical chemistry systems. For in vitro diagnostic use only.

Type of Use (Select one or both, as applicable)
-------------------------------------------------	--

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

Urine/CSF Albumin and Urine/CSF Albumin Calibrator

1.0 Submitted By:

Anne-Marie Shine Regulatory Affairs Specialist Beckman Coulter Ireland Inc., Lismeehan, O'Callaghan's Mills, Co. Clare, Ireland. Phone: +353-65-683-1138 FAX: +353-65-683-1122 email: amshine@beckman.com

2.0 Date Prepared:

20th August 2014

3.0 Device Identifications

Proprietary Name:	Urine/CSF Albumin and Urine/CSF Albumin Calibrator
Common Name:	Urine/CSF Albumin and Urine/CSF Albumin Calibrator
Classification:	Class II (Limitations tripped)/Class II
Product Codes:	DCF and JIS
Regulation Number:	21CFR 866.5040/862.1150

4.0 Predicate Devices

Urine Predicate

Proposed Device	Predicate Device	Manufacturer	Docket Number
Urine/CSF Albumin,Model Nos.B38858B46435	SYNCHRON® SystemsMicroalbumin (MA) Reagent,Model No. 475100	Beckman Coulter, Inc.	K082251

CSF Predicate

Proposed Device	Predicate Device	Manufacturer	Docket Number
Urine/CSF Albumin,Model Nos.B38858B46435	IMMAGE® ImmunochemistrySystem Albumin (ALB) Reagent,Model No. 447600	Beckman Coulter, Inc.(Previously BeckmanInstruments, Inc.)	K964695

Calibrator Predicate

Proposed Device	Predicate Device	Manufacturer	Docket Number
Urine/CSF AlbuminCalibrator,Model No.B38859	SYNCHRON® SystemsMicroalbumin (MA) Calibrator,Model No. 475089	Beckman Coulter, Inc.	K000331

Urine/CSF Albumin and Urine/CSF Albumin Calibrator are substantially equivalent to the Beckman Coulter, Inc. predicate products listed above currently in commercial distribution.

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5.0 Description

The calibrator is manufactured from human material; therefore it should be handled as though capable of transmitting infectious disease. Each serum or plasma donor unit used in the preparation of this material was tested by United States Food and Drug Administration (FDA) approved methods and found to be negative for the antibodies to HIV and HCV and nonreactive for HB Ag. Because no test method can offer complete assurance that HIV. hepatitis B virus, and hepatitis C virus or other infectious agents are absent, this material and all patient samples should be handled as though capable of transmitting infectious disease. This product may also contain other human source material for which there is no approved test. The FDA recommends such samples be handled as specified in the Centers for Disease Control's Biosafety Level 2 guidelines.

6.0 Intended Use

Urine/CSF Albumin

Urine/CSF Albumin Calibrator

The Urine/CSF Albumin calibrator is intended to be used to calibrate the Urine/CSF Albumin reagent on the Beckman Coulter AU clinical chemistry systems. For in vitro diagnostic use only.

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7.0 Comparison to the Predicate(s)

Urine/CSF Albumin claims to be substantially equivalent to the predicate identified in section 4. The following tables show similarities and differences between the reagent predicates and proposed device.

Test System	Urine Predicate	Proposed New System
Proprietary andEstablishedNames	SYNCHRON® Systems Microalbumin (MA)Reagent	Urine/CSF Albumin
	SIMILARITIES
Intended use	MA reagent, when used in conjunction withUniCel® DxC 600/800 System(s) andSYNCHRON® Systems MA Calibrator isintended for quantitative determination ofAlbumin concentration in human urine.	SameThe Urine/CSF Albumin reagent isintended to be used for thequantitation of albuminconcentration in human urine.
Technology	Photometric	Same
OperatingPrinciple	Turbidimetric Method	Same
Sample Types	Urine	Same
ReagentMaterial:Antibodies	Antibody specific for human albumin (goatpolyclonal)	Same
ReagentMaterial: Buffer	Phosphate buffer with PEG	Same
Reagent On-Board Stability	60 days	Same
ReagentStorage/ ClosedShelf Life	2-8°C until expiration date	Same
PrecisionWithin Run	≤ 5.4% CV or 0.125 mg/dL	Similar≤ 5% CV or 0.1 mg/dL
ReferenceInterval	Reference Interval Based on LiteratureReference:American Diabetes Association, "DiabeticNephropathy", Diabetes Care, 20 [Suppl 1]:524 7 (1997)	Same

Urine Application

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Test System	Urine Predicate	Proposed New System
ProprietaryandEstablishedNames	SYNCHRON® Systems Microalbumin (MA)Reagent	Urine/CSF Albumin
DIFFERENCES
TechnologyType	Instrumentation: SYNCHRON LX® Systems,UniCel® DxC 600/800 Systems	Instrumentation: Beckman CoulterAU clinical chemistry systems
Analyzers	SYNCHRON LX® Systems,UniCel® DxC 600/800 Systems	AU Clinical Chemistry Analyzers

CSF Application

Test System	CSF Predicate	Proposed New System
Proprietary andEstablishedNames	IMMAGE® Immunochemistry System Albumin(ALB) Reagent	Urine/CSF Albumin
SIMILARITIES
Intended use	ALB reagent, when used in conjunction withIMMAGE® Immunochemistry Systems andCalibrator 3, is intended for quantitativedetermination of Albumin (ALB) in humanserum or cerebrospinal fluid (CSF) by ratenephelometry.	SameThe Urine/CSF Albumin reagent isintended to be used for thequantitation of albuminconcentration in cerebrospinalfluid (CSF).
Technology	Photometric	Same
ReagentMaterial:Antibodies	Antibody specific for human albumin (goatpolyclonal)	Same
ReagentMaterial: Buffer	Phosphate buffer with PEG	Same
Sample Types	Serum and CSF	SimilarCSF
ReagentStorage/ ClosedShelf Life	2-8°C until expiration date	Same

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Test System	CSF Predicate	Proposed New System
ProprietaryandEstablishedNames	IMMAGE® Immunochemistry SystemAlbumin (ALB) Reagent	Urine/CSF Albumin
DIFFERENCES
TechnologyType	Instrumentation: Beckman IMMAGEImmunochemistry Systems	Instrumentation: Beckman Coulter AUclinical chemistry systems
OperatingPrinciple	Rate nephelometry	Turbidimetric
Analyzers	IMMAGE Immunochemistry System	AU Clinical Chemistry Analyzers
Sample Types	Serum and CSF	CSF

Urine/CSF Albumin Calibrator claims to be substantially equivalent to the predicate identified in section 4. The following table shows similarities and differences between the calibrator predicate and proposed device.

Test System	Calibrator Predicate	Proposed New System
Proprietary andEstablishedNames	SYNCHRON® SystemsMA Calibrator	Urine/CSF Albumin Calibrator
	SIMILARITIES
Intended use	MA Calibrator, when used in conjunctionwith SYNCHRON Systems MA Reagent (P/N475100), is intended for use on theSYNCHRON LX® and UniCel® DxC Systems forthe calibration of Microalbumin.	SimilarThe Urine/CSF Albumin calibratoris intended to be used to calibratethe Urine/CSF Albumin reagenton the Beckman Coulter AUclinical chemistry systems.For in vitro diagnostic use only.
SingleConstituentCalibratorComposition	pH buffered human serum albumin	Same
CalibratorMatrix Base	Aqueous pH buffer	Same
CalibratorTraceability	ERM® - DA470	Same
CalibratorStorage/ ClosedShelf Life	2-8°C until expiration date	Same

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Test System	Calibrator Predicate	Proposed New System
ProprietaryandEstablishedNames	SYNCHRON® SystemsMA Calibrator	Urine/CSF Albumin Calibrator
DIFFERENCES
Calibrator	SYNCHRON® SystemsMA Calibrator475089(1 Level)	Urine/CSF Albumin CalibratorB38859(5 levels)
CalibrationFrequency	Every 30 days	Every 60 days

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8.0 Performance Characteristics - Analytical Performance

Precision a.

Within run (repeatability) and total imprecision (within laboratory) studies were designed from CLSI quideline EP05-A2 "Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline - Second Edition". All testing was carried out using an AU5800 analyzer.

Pooled human urine samples were spiked using purified human serum albumin and used for the urine pools. Pooled human CSF samples were either diluted using 0.9% saline or spiked using purified human serum albumin and used for the CSF pools.

The experimental design utilized duplicate sample analysis, twice daily, over the course of 20 working days (n=80) for 3 sample levels. There was a minimum interval of 2 hours between the two runs on each day. The results are presented in the table below:

SampleType	Pool	Meanmg/dL	Repeatability/Within-Run		WithinLaboratory/Total
			SDmg/dL	CV %	SDmg/dL	CV %
CSF	Low	6.30	0.07	1.0	0.11	1.8
CSF	Mid	26.5	0.4	1.6	0.6	2.4
CSF	High	35.0	0.7	1.9	0.9	2.5
Urine	Low	1.68	0.02	0.9	0.07	4.3
Urine	Mid	3.28	0.02	0.6	0.08	2.5
Urine	High	20.0	0.3	1.4	0.4	2.1

b. Analytical Range (Linearity)

Analytical range (linearity) studies were designed to meet the requirements of CLSI guidelines EP06-A "Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach: Approved Guideline". All testing was carried out using an AU5800 analyzer.

High and low albumin pools were prepared to achieve albumin concentrations spanning the required linear range. The high pool was prepared by spiking pools with HSA. The high urine and CSF pools were diluted with urine and CSF respectively to generate the lower concentrations required for the 11 point linearity panel.

The studies were performed on 11 linearity concentration levels. Each dilution was assaved in quadruplicate and the mean analytical results were plotted versus the relative analyte concentration.

A polynomial regression analysis was performed on the data and the bias of the polynomial from the 1st order curve was evaluated.

This study demonstrates acceptable linearity for the claimed measuring ranges.

Sample Type	Measuring Range (mg/dL)
Urine	0.7 - 45
CSF	1 - 45

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C. Traceability and Value Assignment

The Urine/CSF Albumin calibrator values are traceable to the International Federation of Clinical Chemistry Certified Reference Material ERM® - DA470k.

The calibrator was standardized to the reference standard ERM®- DA470k. The assignment was carried out by determining multiple calibration curves using multiple dilutions of DA470k.

The assignment of the master calibrator from the international standard was carried out using an AU2700 analyzer and the values were confirmed and performance tested on an AU640 and AU2700 analyzer.

The assignment of other calibrator lots from the master calibrator was carried out using an AU680 analyzer and the values were confirmed and performance tested on an AU400 and AU680 analyzer.

Reagent and Calibrator Stability d.

Shelf-Life

Accelerated stability testing was carried out following CLSI quideline EP25-A "Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline"; with the aim to establish initial claims of 18 months for both reagent and calibrator. The testing followed the guidelines for a packaging design change to an existing product with established stability claims. All testing was carried out using an AU5800 analyzer. Testing was performed at multiple elevated temperatures using three reagent lots and three calibrator lots and demonstrated that the reagent and calibrator are stable for 18 months at 2 - 8°C.

Reagent On-Board, Calibration Frequency and Calibrator Open Vial Stability

On-Board (OB) stability, calibration frequency, and calibrator open vial stability testing was carried out following CLSI guideline EP25-A "Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline". All testing was carried out using an AU5800 analyzer.

Testing was performed using three reagent lots and three calibration was performed on the first day. At each time point Urine & CSF control material was run in duplicate. The maximum time point exceeded the claim. For the reagent. linearity was assessed after the final time point.

A 60 day reagent on-board claim, a 60-day calibration frequency claim, and a 30-day calibrator open vial stability claim was established.

Sensitivity (Detection Limits) e.

LoB (Limit of Blank), LoD (Limit of Detection) and LoQ (Limit of Quantitation) studies were designed from CLSI guideline EP17-A2 "Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures Approved Guideline - Second Edition". All testing was carried out using an AU5800 analyzer.

Correctly operating AU Systems should exhibit sensitivity less than or equal to 0.7 mg/dL for Urine and less than or equal to 1.0 mg/dL for CSF. LoB was calculated as the upper 95th percent confidence interval of a result from an analyte free sample. Where the calculated LoB is < 0, this was rounded to 0. LoD is defined as the lowest albumin concentration that can be detected with a probability of 95 %. LoQ is defined as the lowest concentration with an inter-assay precision of < 20% CV.

LoB and LoD

The experimental design consisted of replicate measurements on blank and low level samples using three lots of reagent across multiple days. A total of 60 blank replicates per reagent lot and 60 low level sample replicates per reagent lot were generated. This was comprised of 4 blank samples and 4 low levels samples for urine and CSF, run 5-fold for 3 days. Four separate saline pools were used as blanks

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to determine LoB. and four concentrations of 0.1. 0.2. 0.35 and 0.5 mg/dL prepared by dilution of a quantified urine and CSF pool with 0.9% saline were used for determining LoD.

LoQ

For LoQ, the experimental design utilized functional sensitivity to establish the claim. Six pools with concentrations of approximately 0.1, 0.2, 0.35, 0.5, 0.7 and 1 mg/dL albumin in urine and CSF were used. For each pool, samples were measured in duplicate, twice daily, over the course of 20 working days (n=80). A minimum of a 2 hour interval was left between the two runs.

The LoQ sensitivity claim met acceptance criteria of ≤ 0.7 mg/dL for urine and ≤ 1.0 mg/dL for CSF.

Sample Type	LoB (mg/dL)	LoD (mg/dL)	LoQ (mg/dL)
Urine	0.00	0.07	0.70
CSF	0.00	0.13	0.70

f. Interferences (Analytical Specificity)

Interference studies were designed based on CLSI Guideline EP07-A2: "Interference Testing in Clinical Chemistry: Approved Guideline - Second Edition" and used to assess common or known substances which could interfere with the Urine/CSF Albumin Assay. All testing was carried out using an AU5800 analyzer.

The interfering substances analyzed were tested at two Urine/CSF Albumin concentrations, approximately 1.5 - 3 mg/dL and 10 - 20 mg/dL for the Urine application, and 10 - 20 mg/dL and 25 - 35 mg/dL for the CSF application. Urine pools were prepared by spiking pooled human urine samples with purified human serum albumin to achieve the required concentrations. CSF pools were prepared by diluting pooled human CSF samples with 0.9% saline to achieve the required concentrations. The sample pools tested were at ≥ 5 different levels of interferent to determine the magnitude of the effect. Each interferent concentration was tested in quadruplicate. The data analysis involved calculating the difference in recovery of the samples with and without the potential interfering substances. A summary of the sample pools and results are detailed in the table below.

Potential InterferingSubstance	Interference Pool Details	Interferent Level(mg/dL)
URINE
Calcium	Urine pools spiked with stock calciumchloride solution	NSI up to 78 mg/dL
Creatinine	Urine pools spiked with stock creatininesolution	NSI up to 300mg/dL
Glucose	Urine pools spiked with stock glucosesolution	NSI up to 3000mg/dL
Urea	Urine pools spiked with stock ureasolution	NSI up to 5000mg/dL
Ascorbic Acid	Urine pools spiked with stock ascorbicacid solution	NSI up to 500mg/dL
Potential InterferingSubstance	Interference Pool Details	Interferent Level(mg/dL)
Citrate	Urine pools spiked with stock sodiumcitrate solution	NSI up to 50 mg/dL
Magnesium	Urine pools spiked with stockmagnesium chloride solution	NSI up to 400mg/dL
Oxalate	Urine pools spiked with stock sodiumoxalate Solution	NSI up to 30 mg/dL
Conjugated Bilirubin	Urine pools spiked with stockconjugated bilirubin solution	NSI up to 40 mg/dL
Hemoglobin	Urine pools spiked with stockhemoglobin solution	NSI up to 500 mg/dL
Acetone	Urine pools spiked with stock acetonesolution	NSI up to 350 mg/dL
Uric Acid	Urine pools spiked with stock uric acidsolution	NSI up to 10 mg/dL
Urobilinogen	Urine pools spiked with stockurobilinogen solution	NSI up to 2.25 mg/dL
Acetaminophen	Urine pools spiked with stockacetaminophen solution	NSI up to 300 mg/dL
Ibuprofen	Urine pools spiked with stock ibuprofensolution	NSI up to 400 mg/dL
Metronidazole	Urine pools spiked with stockmetronidazole solution	NSI up to 600 mg/dL
5-aminosalicylic acid	Urine pools spiked with stock 5-aminosalicylic acid solution	NSI up to 150 mg/dL
CSF
Hemoglobin	CSF pools spiked with stock hemoglobinsolution	NSI up to 500 mg/dL
Conjugated Bilirubin	CSF pools spiked with stock conjugatedbilirubin solution	NSI up to 40 mg/dL

Note: No significant interference (NSI) is defined as ≤ ± 10% or ± 0.2 mg/dL.

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Prozone g.

All testing was carried out using an AU5800 analyzer. Human urine and CSF were spiked with human serum to create a prozone high pool of ≥ 2000 mg/dL. The albumin concentration of the high prozone pools were determined using 3 replicates of at least 3 dilutions in the measuring range. Urine or 0.9% saline was used to prepare a series of dilutions of the high pool. Prozone panels were run n = 3. All samples from the upper end of the linear range up to the claimed prozone tolerance generated a flagged result that indicated a result above the linear range.

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Performance Characteristics - Comparison Studies

Method Comparison a.

Method comparison and bias estimation experiments were designed using CLSI Guideline EP09-A3 "Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved Guideline".

Urine Application

Patient urine samples were run to compare this Urine Albumin assay on the AU5800 analyzer against another commercially available assay. Results of Deming regression analysis were as follows:

Slope = 1.09	Intercept = 0.03 mg/dL	r = 1.0	n = 131	Sample range = (0.81 - 40.7 mg/dL)
--------------	------------------------	---------	---------	------------------------------------

CSF Application

Patient CSF samples were run to compare this CSF Albumin assay on the AU5800 analyzer against another commercially available assay. Results of Deming regression analysis were as follows:

Slope = 1.05	Intercept =	r =	n =	Sample range =
	-0.77 mg/dL	0.99	131	1.72 - 41.2 mg/dL

Expected Values/Reference Interval b.

Reference Intervals were taken from the literature.

Expected values/Reference range for Urine Albumin excretion:

Matrix		24-hr collection(mg/24 h)	Timed collection(µg/min)	Spot Collection(µg/mg creatinine)
Urine1	Normal	<30	<20	<30
	Moderately Increased	30-299	20-199	30-299
	Clinical Albuminuria	≥300	≥200	≥300

Expected values/Reference range for CSF Albumin:

CSF2:	3 mo - 4y	0 - 45 mg/dL
	> 4 y	10 - 30 mg/dL

1. American Diabetes Association. Diabetic Nephropathy. Diabetes Care 25:(Suppl. 1):S85-S89.
1. Painter PC, Cope JY, Smith JL. Reference information for the clinical laboratory. In: Burtis CA, Ashwood ER, eds. Tietz textbook of clinical chemistry, Philadelphia: WB Saunders Company, 1999; 1800pp.

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Urine Application:

CLSI guideline EP28-A3c "Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition" was used as a guideline to validate this reference interval using 20 urine samples.

Clinical Studies ﻥ

Not applicable

Clinical Cut-off d.

Not applicable

9.0 Conclusion

The conclusions drawn from the non-clinical testing (discussed above) demonstrate that the Urine/CSF Albumin and Urine/CSF Albumin Calibrator is as safe, as effective, and performs as well as the predicate devices. The submitted information in this pre-market notification is complete and supports a substantial equivalence decision.

Regulation Number and Section

§ 866.5040 Albumin immunological test system.

(a)
Identification. An albumin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the albumin (a plasma protein) in serum and other body fluids. Measurement of albumin aids in the diagnosis of kidney and intestinal diseases.(b)
Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.