The cobas pro integrated solutions is an IVD device used for the quantitation of clinical chemistry and Ion Selective Electrolyte parameters from various biological fluids.

Glucose HK Gen.3 is an in vitro test for the quantitative determination of glucose in human serum, plasma, urine and CSF on Roche/Hitachi cobas c systems. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia and pancreatic islet cell tumors.

The ISE indirect Na for Gen. 2 is intended for the quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. Sodium measurements are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance.

Elecsys TSH immunoassay is intended for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid and pituitary disorders. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

Device Description

The cobas pro integrated solutions (cobas pro) is a fully automated, random-access, software controlled system intended for in vitro quantitative analysis of analytes in body fluids. It will typically be used in clinical laboratories with large workload. The system consolidates clinical chemistry, homogenous and heterogeneous immunoassays as well as electrolyte testing within one workplace. It consists of a high throughput sample distribution unit (core unit) and different analytical units for ISE (cobas pro ISE analytical unit), clinical chemistry (c 503 analytical unit) and immunoassay (e 801 analytical) testing. The system hardware is comprised of new or previously cleared members of the Roche/Hitachi cobas c or Elecsys families of analyzers. The instrument software is unique to the cobas pro and was developed from previous generations of Roche/Hitachi instrument systems.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the cobas pro integrated solutions device, specifically focusing on the Glucose HK Gen.3, ISE indirect Na for Gen.2, and Elecsys TSH assays.

Preamble: This document describes a Traditional 510(k) Premarket Notification for the cobas pro integrated solutions. The core purpose is to show that previously cleared Glucose, Sodium, and TSH assays, when run on the new cobas pro integrated solutions system, are substantially equivalent to their predicate devices. Therefore, the acceptance criteria and studies presented are largely comparative or validation studies demonstrating consistent performance with previously cleared devices and established analytical standards.

1. Table of Acceptance Criteria and Reported Device Performance

Given that this is a 510(k) submission demonstrating substantial equivalence to pre-existing predicate devices for assays and a new integrated system, the acceptance criteria are generally focused on meeting established performance claims or showing equivalence within acceptable statistical limits. The summary provided focuses on the reported device performance which is then implicitly compared to internal acceptance criteria (often relative to the predicate device or CLSI guidelines).

Note on Acceptance Criteria: The document explicitly states "All samples met the predetermined acceptance criterion" for precision studies. For LoQ, it states "LoQ determined at maximum allowable %TE (total error) of no more than 20% (Glucose and TSH) and 30% (Sodium)." For endogenous interference, it was "recovery of 100±10%". For exogenous interference (common drugs for Elecsys TSH), it was "± 10% of the reference value". For method comparisons, the slope, intercept, and correlation coefficients approaching 1 or 0 respectively, indicate strong agreement, satisfying the intent of substantial equivalence. Specific numerical acceptance criteria are not always stated outright but are implied by the study design and conclusion of meeting criteria.

Category	Acceptance Criteria (Explicit or Implied)	Reported Device Performance (Worst Case/Summary)
Precision	Samples met predefined acceptance criteria (based on CLSI EP05-A3 guidelines).	Glucose HK Gen.3 (N=84 per application):- Serum Repeatability CV: 0.4%-9.2%- Serum Intermediate Precision CV: 0.5%-10.0%- Urine Repeatability CV: 0.4%-8.3%- Urine Intermediate Precision CV: 0.7%-8.5%- CSF Repeatability CV: 0.4%-3.0%- CSF Intermediate Precision CV: 0.5%-3.5%ISE indirect Na (N=84 per application):- Plasma Repeatability CV: 0.3%-0.6%- Plasma Intermediate Precision CV: 0.5%-1.5%- Serum Repeatability CV: 0.3%-0.5%- Serum Intermediate Precision CV: 0.5%-1.7%- Urine Repeatability CV: 0.3%-0.5%- Urine Intermediate Precision CV: 0.6%-4.8%Elecsys TSH (N=84):- Repeatability CV: 1.6%-6.3%- Intermediate Precision CV: 2.4%-11.7%
Analytical Sensitivity	LoQ: Total error not more than 20% (Glucose, TSH), 30% (Na).	Glucose HK Gen.3: LoB: 0.2 mg/dL, LoD: 0.4 mg/dL, LoQ: 1.4 mg/dL.Claimed: LoB: 2 mg/dL, LoD: 2 mg/dL, LoQ: 2 mg/dL.ISE indirect Na: LoB: 3.50 mmol/L, LoD: 4.42-4.51 mmol/L, LoQ: 11.8-12.2 mmol/L.Claimed: LoB: 3.5 mmol/L, LoD: 4.5 mmol/L, LoQ: 12.2 mmol/L.Elecsys TSH: LoB: 0.0013-0.0015 µIU/mL, LoD: 0.00282-0.00348 µIU/mL, LoQ: 0.00386-0.00495 µIU/mL.Claimed: LoB: 0.0025 µIU/mL, LoD: 0.005 µIU/mL, LoQ: 0.005 µIU/mL.
Linearity/Reportable Range	Deviations within predetermined acceptance criteria.	Glucose HK Gen.3: Serum (R2=0.9999), Urine (R2=0.9997), CSF (R2=0.9992) linear in claimed range (2.0-750 mg/dL).ISE indirect Na: Plasma (R2=0.9998), Serum (R2=0.9998), Urine (R2=0.9999) linear in claimed range (80-180 mmol/L for S/P, 20-250 mmol/L for U).Elecsys TSH: Serum (R2=0.9972) linear in range 0.004-118 uIU/mL.
High Dose Hook Effect	No hook effect observed up to a specified concentration.	Elecsys TSH: No hook effect up to 1466 uIU/mL TSH.
Endogenous Interference	Recovery of 100 ± 10%.	Glucose HK Gen.3: No interference from albumin, bilirubin, hemolysis, IgG, lipemia, etc. at specified high concentrations.ISE indirect Na: No interference from bilirubin, hemolysis, lipemia at specified high concentrations.Elecsys TSH: No interference from biotin, lipemia, hemoglobin, bilirubin, rheumatoid factor, immunoglobulins at specified high concentrations.
Exogenous Interference (Drugs)	± 10% of the reference value in comparison to unspiked samples.	ISE indirect Na: No interference from various common and special drugs at specified concentrations.Elecsys TSH: No interference from common and special drugs at specified concentrations.
Analytical Specificity/Cross-Reactivity	% cross-reactivity near zero.	Elecsys TSH: hGH, hCG, LH, FSH showed 0.000% cross-reactivity at high tested concentrations.
Method Comparison to Predicate	Strong correlation (slope ≈ 1, intercept ≈ 0, high R/tau values) indicating substantial equivalence to predicate device/reference method.	Glucose HK Gen.3: Slope close to 1.0, intercept close to 0, strong correlation (Pearson r/Kendall tau close to 1) comparing to cobas c 501.ISE indirect Na: Slope close to 1.0, intercept close to 0, strong correlation (Pearson r close to 1) comparing to cobas c 501 ISE and Flame Photometer.Elecsys TSH: Slope = 1.018 (LCL/UCL: 1.004/1.025), Intercept = -0.0018 µIU/mL (LCL/UCL: -0.0040/-0.0001), Pearson r = 0.999, Kendall tau = 0.977 when compared to predicate Elecsys TSH on cobas 8000.
Sample Matrix Comparison	Acceptable recovery of analyte values and strong correlation between different sample types (e.g., serum vs. various plasma anticoagulants).	Glucose HK Gen.3: Strong correlation (slope near 1, intercept near 0, r near 1) comparing serum to serum tube with separation gel, and various plasma anticoagulants (K2EDTA, Li-Heparin, NaF/K-Oxalate, NaF/Na2-EDTA, NaF/Citrate/Na2-EDTA, KF/Na2-EDTA).ISE indirect Na: Strong correlation (Slope = 1.015, Intercept = -2.69, r = 0.998) between Serum and Li-Heparin Plasma.Elecsys TSH: Strong correlation (slope near 1, intercept near 0, r near 1) comparing serum to Li-Heparin, K2-EDTA, and K3-EDTA plasma.
Stability	Stability data supports Roche Diagnostic's claims as reported in the package inserts. (Implied: device maintains performance over its claimed shelf life and in-use stability.)	Stability data for Glucose HK Gen.3, ISE indirect Na, and Elecsys TSH was provided in prior 510(k)s (K061048, K060373, and K190773 respectively) and supports the claims.

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

Glucose HK Gen.3 (Precision):
- Sample Size: 84 measurements for each control level (PreciControl ClinChem Multi 1 and 2) and 5 human serum samples per application (serum, urine, CSF). So, for repeatability and intermediate precision, 84 measurements for 2 controls + 5 samples, across serum, urine, and CSF applications.
- Data Provenance: Human serum, plasma, urine, and CSF samples. These were "native, single donors as well as pools." The study was conducted in-house by Roche Diagnostics (implied by the submission).
ISE indirect Na (Precision):
- Sample Size: 84 measurements for each control level (PreciControl ClinChem Multi 1 and 2, Liquichek 1 and 2) and 5 human plasma, serum, and urine samples per application. So, for repeatability and intermediate precision, 84 measurements for controls + 5 samples, across Li-Heparin Plasma, Serum, and Urine.
- Data Provenance: Human Li-Heparin plasma, serum, and urine samples. These were "native, single donors as well as pools." Conducted in-house by Roche Diagnostics.
Elecsys TSH (Precision):
- Sample Size: 84 measurements for each control level (PreciControl Universal, PC Thyro Sensitive) and 5 human serum samples.
- Data Provenance: Human serum samples. These were "native, single donors as well as pools." Conducted in-house by Roche Diagnostics.
Analytical Sensitivity (LoB, LoD, LoQ) for all assays:
- Sample Size:
  - LoB: ≥ 60 measurements of analyte-free samples.
  - LoD: 60 measurements (5 low-analyte concentration samples, measured in duplicate over 6 runs, 3 days).
  - LoQ: ≥ 60 measurements per sample type (samples with low analyte concentration measured over 3 to 5 days).
- Data Provenance: Not explicitly stated for specific blanks or low-concentration samples beyond "analyte-free" or "low-analyte concentration". Conducted in-house by Roche Diagnostics.
Linearity/Assay Reportable Range:
- Glucose HK Gen.3: Three high analyte human serum, urine, and CSF samples diluted to 12 levels.
- ISE indirect Na: Three high analyte human serum, urine, and CSF samples diluted to multiple aliquot concentrations.
- Elecsys TSH: Three high analyte human serum samples diluted to concentrations covering the measuring range.
- Data Provenance: Human serum, urine, CSF samples. Conducted in-house by Roche Diagnostics.
Endogenous Interference:
- Glucose HK Gen.3: Plasma and urine samples, glucose levels ~79.5 mg/dL and ~116.3 mg/dL.
- ISE indirect Na: Human plasma, serum, and urine samples. Low (~124 mmol/L) and high (~151 mmol/L) for S/P; low (26.3 mmol/L) and high (188 mmol/L) for urine.
- Elecsys TSH: Human serum samples with TSH concentrations ~0.462 uIU/mL, ~3.95 µIU/mL, and ~7.54 µIU/mL.
- Data Provenance: Human samples. Conducted in-house by Roche Diagnostics.
Exogenous Interference (Drugs):
- ISE indirect Na: Two sample pools (low and high concentration ISE indirect Na).
- Elecsys TSH: Two human serum samples (~0.5 uIU/mL and ~8 uIU/mL TSH).
- Data Provenance: Human samples. Conducted in-house by Roche Diagnostics.
Analytical Specificity/Cross-Reactivity (Elecsys TSH):
- Sample Size: Native human serum sample pool.
- Data Provenance: Human serum samples. Conducted in-house by Roche Diagnostics.
Method Comparison to Predicate:
- Glucose HK Gen.3: 74 native human serum samples, 67 native human urine samples, 75 native CSF samples.
- ISE indirect Na: 120 human Lithium heparin plasma samples (vs cobas c 501 ISE), 118 human Lithium heparin plasma (vs Flame Photometer), 120 human serum (vs cobas c 501 ISE), 120 human serum (vs Flame Photometer), 120 human urine (vs cobas c 501 ISE/Flame Photometer).
- Elecsys TSH: 138 samples (129 native human serum, 9 diluted human serum samples; single donors and pools).
- Data Provenance: Native human samples (serum, plasma, urine, CSF), some diluted. Conducted in-house by Roche Diagnostics.
Sample Matrix Comparison:
- Glucose HK Gen.3: At least 39 serum/plasma pairs for each anticoagulant type (K2-EDTA, Li-Heparin, NaF/K-Oxalate, NaF/Na2-EDTA, NaF/Citrate/Na2-EDTA, KF/Na2-EDTA plasma tubes) + serum vs. serum tube with separation gel.
- ISE indirect Na: 50 serum/Li-Heparin plasma pairs.
- Elecsys TSH: Minimum of 56 serum/plasma pairs for Li-Heparin, K2-EDTA, K3-EDTA plasma tubes. Serum separation tubes from 3 manufacturers, blood from five donors were used.
- Data Provenance: Native human samples. Conducted in-house by Roche Diagnostics.

3. Number of Experts and Qualifications for Ground Truth

This submission concerns in vitro diagnostic (IVD) devices for quantitative measurements of analytes. For such devices, "ground truth" is typically established by:

Reference methods (e.g., flame photometry for Sodium reference),
Previously cleared and validated predicate devices,
Known concentrations in control materials or spiked samples, or
The inherent chemical/physical measurement by the device itself (for analytical performance criteria like precision, linearity).
No human "experts" (like radiologists interpreting images) were used to establish ground truth in the context of these analytical performance studies. The "ground truth" is analytical, derived from established chemical/instrumental methods and reference standards.

4. Adjudication Method for the Test Set

Since this is an IVD device for quantitative measurements and the studies are analytical performance evaluations based on instrumental precision, accuracy, and comparison to established methods or predicate devices, there is no adjudication method (e.g., 2+1, 3+1) involving human experts as would be seen in diagnostic imaging studies. The data points are quantitative measurements from the instruments themselves or reference methods. Statistical analysis (e.g., regression, CVs, SDs) is used to assess performance against pre-defined criteria.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC comparative effectiveness study was done. This type of study, involving multiple human readers interpreting cases with and without AI assistance, is relevant for diagnostic imaging AI algorithms where human interpretation is part of the clinical pathway. This submission is for an in vitro diagnostic (IVD) measurement system, not an AI-powered diagnostic imaging tool that assists human readers. The comparative studies involved comparing the new system's analytical performance against predicate IVD systems or reference methods, not human readers.

6. Standalone Performance Study (Algorithm Only)

The entire non-clinical performance evaluation could be considered analogous to a "standalone" performance study, as it describes the analytical performance of the device itself (the integrated system with its assays) without human intervention in the measurement process. The device provides quantitative results, and these results are directly evaluated for precision, linearity, sensitivity, interference, and agreement with predicate devices or reference methods. There is no "human-in-the-loop" aspect to the core measurement and output of these IVD assays.

7. Type of Ground Truth Used

The ground truth used for these analytical studies consists of:

Known concentrations: For studies like linearity, analytical sensitivity (LoB, LoD, LoQ), and interference, samples prepared with known concentrations of analytes or interferents serve as the ground truth.
Reference methods: For method comparison studies, well-established and often independently validated reference methods (e.g., flame photometry for sodium measurement) serve as the ground truth or gold standard for comparison.
Predicate device results: For demonstrating substantial equivalence, the results obtained from a legally marketed predicate device (which itself has established ground truth capabilities) serve as the comparative ground truth.
Internal statistical controls: For precision studies, consistent and stable control materials are used, where the expected range or value is the "ground truth" against which repeatability and intermediate precision are measured.

8. Sample Size for the Training Set

This document describes the non-clinical performance evaluation for a 510(k) submission, primarily for demonstrating analytical performance and substantial equivalence. It does not describe the development or training of an AI algorithm based on machine learning, so there is no specific "training set" in the context of AI/ML models. The data presented here are validation data for the analytical performance of the assay and integrated system.

For a traditional IVD device, method development involves internal studies and optimization, but this is distinct from "training data" for a machine learning model. The various studies (precision, linearity, etc.) use samples/replicates as described in point 2.

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

As noted in point 8, there isn't a "training set" in the machine learning sense described in this document. If this were to refer to the developmental studies for the underlying assays (Glucose HK Gen.3, ISE indirect Na, Elecsys TSH, which are previously cleared), their ground truth would have been established during their initial development and validation process using:

Reference materials: Certified reference materials (CRMs) with known analyte concentrations.
Clinical samples: Patients samples characterized by confirmed diagnoses or clinical outcomes for intended use populations.
Comparison to established methods: Correlation with existing, approved methods, often considered the "gold standard."
Spiking and dilution experiments: Preparing samples with known added amounts of analyte.

These are standard practices in IVD assay development, ensuring the analytical and clinical performance of the individual assays before they are integrated into a new system like the cobas pro integrated solutions.

Summary

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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health & Human Services logo on the left and the FDA acronym along with the full name of the agency on the right. The FDA part of the logo is in blue, with the acronym in a square and the full name written out to the right of the square.

August 16, 2019

Roche Diagnostics Khoa Tran Regulatory Affairs Principal 9115 Hague Road Indianapolis, IN 46250

Re: K191899

Trade/Device Name: Glucose HK Gen.3 ISE indirect Na for Gen.2 Elecsys TSH, cobas pro integrated solutions Regulation Number: 21 CFR 862.1345 Regulation Name: Glucose test system Regulatory Class: Class II Product Code: CFR, JGS, JLW, JJE Dated: July 15, 2019 Received: July 16, 2019

Dear Khoa Tran:

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 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,

Kellie B. Kelm, Ph.D. Acting Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Ouality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K191899

Device Name cobas pro integrated solutions Glucose HK Gen.3; ISE indirect Na for Gen.2 Elecsys TSH

Indications for Use (Describe)

The cobas pro integrated solutions is an IVD device used for the quantitation of clinical chemistry and Ion Selective Electrolyte parameters from various biological fluids.

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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cobas pro integrated solutions K191899 510(k) Summary

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

In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).

The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the previously cleared Glucose, Sodium, and TSH assays on the cobas pro integrated solutions.

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Submitter Name	Roche Diagnostics
Address	9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250
Contact	Khoa TranPhone: (317) 521-3409Fax: (317) 521-2324Email: khoa.tran@roche.comSecondary Contact: Dave TribbettPhone: (317) 521-2964Fax: (317) 521-2324Email: david.tribbett@roche.com
Date Prepared	August 16, 2019
Proprietary Name	cobas pro integrated solutionsGlucose HK Gen.3ISE indirect Na for Gen.2Elecsys TSH
Common Name	cobas pro integrated solutions, ISE Na, GLUC3, TSH
Classification Name	Hexokinase, glucose Electrode, ion specific, sodium Radioimmunoassay, thyroid-stimulating hormone Analyzer, chemistry (photometric, discrete), for clinical use
Regulation Numbers,Regulation Name, RegulatoryClass and Product Codes	21 CFR 862.1345, Glucose test system, Class II, CFR, 21 CFR 862.1665, Sodium test system, Class II, JGS 21 CFR 862.1690, Thyroid stimulating hormone test system, Class II, JLW 21 CFR 862.2160, Discrete photometric chemistry analyzer for clinical use, Class I, JJE
Predicate Device(s)	cobas 6000 analyzer seriesGlucose HKISE IndirectElecsys TSH
Establishment Registration	For the cobas pro integrated solutions, Glucose HK, ISEindirect Na and Elecsys TSH, the establishment registrationnumber for Roche Diagnostics GmbH in Mannheim,Germany is 9610126, and for Penzberg, Germany, 9610529.The establishment registration number for RocheDiagnostics in the United States is 1823260.

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Device Description

1.1. System

Instrument Description Information

a. Instrument Name: cobas pro integrated solutions
b. Specimen Identification:

The specimen is in a tube with a barcode label. The system identifies specimen by scanning the barcode.

c. Specimen Sampling and Handling: The specimen is in a tube with the barcode label facing the side with the open slot of the rack. The rack is assigned with ID number and barcode.
d. Calibration:

The software of the cobas pro integrated solution automatically recommends calibration for all tests requiring calibration. Calibration may also be ordered manually at any time. The software recommends calibrations according to the application parameters for the

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assay. The system checks the validity of each calibration automatically. If the calibration was successful, the calibrated tests are valid and the system continues operation. Calibration is specific to each analytical unit, measuring channel, and reagent.

The calibrators are loaded onto a 5-position calibrator rack and loaded onto the system. The system automatically recognizes the specially designated (black) calibration rack. The calibrator solutions are specific to the assay and identified in the method sheet of each assay. Multi-calibrator solutions are available to calibrate multiple applications. The available calibration modes are linear and non-linear full calibration, 1- and 2-point recalibration, and automatic full calibration. The calibration type differs depending on the reagent assay and is coded into the application parameter file for each reagent application and is described in the method sheet for each reagent assay application. The recommended calibration frequency is described in the method sheet for each reagent assay application.

Quality Controls: e.

The system can be set up to recommend QC measurements based on test-specific timeout intervals. The method sheet for each assay used on the system contains QC recommendations for the specific application. The control intervals and limits should be adapted to each laboratory's individual requirements. Values obtained should fall within the defined limits. Each laboratory should establish corrective measures to be taken if values fall outside the defined limits. Follow the applicable government regulations and local guidelines for quality control.

1.2. Reagent

Glucose HK Gen.3

Glucose is phosphorylated by hexokinase (HK) in the presence of adenosine triphosphate (ATP) and magnesium ions to produce glucose-6-phosphate (G-6-P) and adenosine diphosphate (ADP). Glucose-6-phosphate dehydrogenase (G-6-PDH) specifically oxidizes G-6-P to 6-phosphogluconate with the concurrent reduction of nicotinamide adenine dinucleotide

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(NAD) to nicotinamide adenine dinucleotide reduced (NADH). One micromole of NADH is produced for each micromole of glucose consumed. The NADH produced absorbs light at 340 nm and can be detected spectrophotometrically as an increased absorbance.

The reagent working solutions include:

. R1 MES buffer: 5.0 mmol/L, pH 6.0; Mg2+, 24 mmol/L; ATP, ≥ 4.5 mmol/L; NADP, ≥ 7.0 mmol/L; preservative
R3 HEPES buffer: 200 mmol/L, pH 8.0; Mg2+, 4 mmol/L; HK (yeast), > 300 ukat/L; . G- 6- PDH (E. coli), ≥ 300 ukat/L; preservative

ISE indirect Na for Gen.2

The ISE module for Nat employs ion-selective membrane to develop an electrical potential (electromotive force, EMF) for the measurements of ions in solution. Selective membrane is in contact with both the test solution and an internal filling solution. Due to the selectivity of the membrane, only the ions to be measured contribute to the EMF. The membrane EMF is determined by the difference in concentration of the test ion in the test solution and the internal filling solution.

The ISE analytical unit of the Roche/Hitachi cobas c systems is intended for the quantitative determination of sodium in serum, plasma or urine using ion- selective electrodes. Sodium is the major extracellular cation and functions to maintain fluid distribution and osmotic pressure. Some causes of decreased levels of sodium include prolonged vomiting or diarrhea, diminished reabsorption in the kidney and excessive fluid retention. Common causes of increased sodium include excessive fluid loss, high salt intake and increased kidney reabsorption.

ISE Auxiliary Reagents include:

. ISE Reference Electrolyte: 1 mol/L potassium chloride
ISE Diluent: HEPES buffer, 10 mmol/L; Triethanolamine, 7 mmol/L; Preservative .
ISE Internal Standard: HEPES buffer, 10 mmol/L; Triethanolamine, 7 mmol/L; Sodium . chloride, 3.06 mmol/L; Sodium acetate, 1.45 mmol/L; Potassium chloride, 0.16 mmol/L; Preservative

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. ISE Cleaning Solution: Sodium hydroxide solution, 3 mol/L with sodium hypochlorite solution < 2 % active Cl
. ISE Deproteinizer: Sodium hydroxide solution, approximately 1.2 % active Cl
Electrodes: Sodium, Reference .

Elecsys TSH

The Elecsys TSH immunoasay makes use of a sandwich test principle using monoclonal antibodies specifically directed against human TSH. The antibodies labeled with ruthenium complex) consist of a chimeric construct from human and mouse specific components. The Elecsys TSH immunoassay is used for the in vitro quantitative determination of thyroid stimulating hormone in human serum and plasma. It is intended for use on the cobas e immunoassay analyzers.

The reagent working solutions include:

Rack Pack (kit placed on the analyzer)

M: Streptavidin-coated microparticles, 1 bottle, 14.1 mL: Streptavidin-coated . microparticles 0.72 mg/mL; preservative.
R1: Anti-TSH-Ab~biotin, 1 bottle, 15.8 mL: Biotinylated monoclonal anti TSH antibody . (mouse) 2.0 mg/L; phosphate buffer 100 mmol/L, pH 7.2; preservative.
. Anti-TSH-Ab~Ru(bpy), 1 bottle, 13.9 mL: Monoclonal anti TSH antibody R2: (mouse/human) labeled with ruthenium complex 1.5 mg/L; phosphate buffer 100 mmol/L, pH 7.2; preservative.

2. INDICATIONS FOR USE

2.1. Reagents

Glucose HK Gen.3

In vitro test for the quantitative determination of glucose in human serum, plasma, urine and CSF on Roche/Hitachi cobas c systems.

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Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, idiopathic hypoglycemia and pancreatic islet cell tumors.

ISE indirect Na for Gen.2

The ISE analytical unit of the Roche/Hitachi cobas c systems is intended for the quantitative determination of sodium in serum, plasma or urine using ion - selective electrodes.

Sodium measurements are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of large amounts of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance.

Elecsys TSH

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

2.2. System

The cobas pro integrated solutions is an IVD device used for the quantitation of clinical chemistry/ immunochemistry and Ion Selective Electrolyte parameters from various biological fluids.

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3. TECHNOLOGICAL CHARACTERISTICS

The following table lists the technical characteristics from the assays method sheets.

Assays Technical Characteristics Table 1:

Feature	Assays
Technology	ISE indirect Na
Application/test time	12 sec
Instrument platform	cobas pro ISE
Test type	Quantitative
Assay protocol	Sample + ISE Diluent
Handling of R1 and R2	Liquid, ready to use
Sample type/matrix	Serum, plasma, and urine
Measuring Range	80-180 mmol/L (Serum/Plasma); 20-250 mmoL (Urine)
Technology	Glucose HK Gen.3 (GLUC3)
Technology	Photometric
Application/test time	10 minutes
Instrument platform	cobas c 503 analytical unit
Test type	Quantitative
Assay protocol	R1+R3+sample+Diluent
Handling of R1 and R3	Liquid, ready to use
Sample type/matrix	Serum, plasma, urine and CSF
Measuring Range	2-750 mg/dL (0.11-41.6 mmol/L )
Technology	Elecsys TSH
Technology	ECLIA
Application/test time	18 minutes
Instrument platform	cobas e immunoassay analyzers
Test format	Sandwich
Test type	Quantitative
Assay protocol	R1+R2+sample, incubation, +beads, incubation
Handling of R1 and R2	Liquid, ready to use
Sample type/matrix	Serum and plasma
Measuring Range	0.005-100 μIU/mL

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Assay Principle of Operation

Glucose

The Glucose Hexokinase catalyzes the phosphorylation of glucose to glucose-6-phosphate by ATP.

HK Glucose + ATP G-6-P + ADP →→

Glucose-6-phosphate dehydrogenase oxidizes glucose-6-phosphate in the presence of NADP to gluconate-6-phosphate dehydrogenase. No other carbohydrate is oxidized. The rate of NADPH formation during the reaction is directly proportional to the glucose concentration and is measure photometrically.

G-6-PDH G-6-P + NADP+ gluconate-6-P + NADPH + H+ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Sodium

An Ion- Selective Electrode (ISE) makes use of the unique properties of ion - selective membrane to develop an electrical potential (electromotive force, EMF) for the measurements of ions in solution. Selective membrane is in contact with both the test solution and an internal filling solution. Due to the selectivity of the membrane, only the ions to be measured contribute to the EMF. The membrane EMF is determined by the difference in concentration of the test ion in the test solution and the internal filling solution. The EMF develops and ion concentration is determined according to the Nernst equation.

TSH

The TSH assay is based on the sandwich principle of competition. The total duration of the assay is 18 minutes.

. 1st incubation: 50 µL of sample, a biotinylated monoclonal TSH- specific antibody and a monoclonal TSH- specific antibody labeled with a ruthenium complex react to form a sandwich complex.

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2nd incubation: After addition of streptavidin-coated microparticles, the complex becomes . bound to the solid phase via interaction of biotin and streptavidin.
. The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell/ProCell M. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier.
. Results are determined via a calibration curve which is instrument specifically generated by 2- point calibration and a master curve provided via the reagent barcode or e- barcode.

Topic	cobas 6000 Analyzer Series(K060373)	cobas pro integratedsolutions(K191899)
Intended Use	Same	IVD device used for thequantitation of clinicalchemistry/ immunochemistryand Ion Selective Electrolyteparameters from variousbiological fluids
Software	cobas 6000 Analyzer Series SystemSoftware	cobas pro integratedsolutions system Software
Configuration	Several analytical units with one PC andone Core unit	Same as cobas 6000
Functionperformed	Data Input, Sample Processing, ResultCalculation, Result Reporting, QualityControl, Infrastructure (power, watersupply)	Same
PC (ControllerUnit) Functions	Data Input (Keyboard, Disc), DataOutput (Screen, printer)	Data Input (Touch screen,Disc), Data Output (Screen,printer)
Core UnitFunctions	Real time database, data input andoutput (via HOST communication),control of sample conveyer	Same
Analytical Unit(s)Functions	Control of analytic processes (pipetting,incubation, detection) Primary Signalprocessing	Same
Data Storage	Real time database in Core Unit (storageof System and Application parameters,Calibration Data, QC Data, SampleResults, Alarm history)	Same

Table 2: Substantial Equivalency System

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Topic	cobas 6000 Analyzer Series(K060373)	cobas pro integratedsolutions(K191899)
ResultCalculation	Automated measuring of signal usingvarious methods according to automatedcalculation of concentration viacalibration curve	Same
Flagging of errors	Available	Same
Units Controlled	cobas c 501 (with integrated ISE) andcobas e 601-analyzers	cobas c 503, cobas e 801,and cobas pro ISE analyzers
Initial cassettevolume check(ICVC) forreagent pipetting	Available	Same
Data concept(Applicationparameter,calibrator, controlvalue transfer)	Electronic transfer possible (user mustaccept transfer before parameter applied)	Same

Table 3: Substantial Equivalency Glucose HK Gen. 3

Item	Glucose HK Gen. 3( c 501 in cobas 6000 core)K060373	Glucose HK Gen. 3(c 503 in cobas pro core)K191899
Proprietary name	Glucose HK Gen. 3	Glucose HK Gen. 3
Catalog number	04404483190	08057800190
Intended use	In vitro test for thequantitative determinationof glucose in human serum,plasma, urine and CSF onRoche/Hitachi cobas csystems.	In vitro test for the quantitativedetermination of glucose inhuman serum, plasma, urine andCSF on Roche/Hitachi cobas csystems.
Technology	Photometric	Same
Test format	Enzymatic	Same
Test type	Quantitative	Same
Assay protocol	R1+R2+Diluent+Sample,incubation	Same
Pipetting volume sample	15 µL	Same
Pipetting volume R1	28 µL	Same
Pipetting volume R2	10 µL	Same
	Serum, plasma, urine andCSF	Same

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Item	Glucose HK Gen. 3(c 501 in cobas 6000 core)K060373	Glucose HK Gen. 3(c 503 in cobas pro core)K191899
Handling of R1 and R2	Liquid, ready to use	Same
Measuring Range	0.11-41.6 mmol/L	Same

Table 4: Substantial Equivalency ISE indirect Na for Gen.2

Item	cobas c 501 ISE(in cobas 6000 core)K060373	cobas pro ISE(in cobas pro core)K191899
Proprietary name	ISE indirect Na	ISE indirect Na
Intended use	The ISE analytical unit of theRoche/Hitachi cobas c systemsis intendedfor the quantitativedetermination of sodium inserum, plasma or urine using	The ISE analytical unit of theRoche/Hitachi cobas c systems isintendedfor the quantitative determinationof sodium in serum, plasma orurine using
	ion- selective electrodes.	ion- selective electrodes.
Technology	ISE Potentiometry	Same
Test type	Quantitative	Same
Typical samplevolumes	9.7 µL 15 µL	9.7 µL 15 µL
Default ISEDilution ratio1:31	1:31(9.7uL sample + 291uLDiluent)	Same(15 uL sample + 450uLDiluent)
Sample types	Serum, plasma, urine	Same
Sample handlingsystem	Input of samples via core inputbuffer using universal sampleracks	Same
Measuring Range	Serum/Plasma: 80-180mmol/LUrine: 20-250 mmol/L	Same

Table 5: Substantial Equivalency Elecsys TSH

Item	Elecsys TSH(e 801 in cobas 8000 core)K190773	Elecsys TSH(e 801 in cobas pro core)K191899
Proprietary name	Elecsys TSH	Elecsys TSH
Catalog number	08429324160	08429324160
Item	Elecsys TSH( e 801 in cobas 8000 core)K190773	Elecsys TSH(e 801 in cobas pro core)K191899
Intended use	Elecsys TSH immunoassay isintended for the in vitroquantitative determination ofthyrotropin in human serumand plasma. Measurements ofTSH are used in the diagnosisof thyroid and pituitarydisorders.The Elecsys TSHimmunoassay is anelectrochemiluminescenceimmunoassay “ECLIA”,which is intended for use onthe cobas e immunoassayanalyzers.	Immunoassay for the in vitroquantitative determination ofthyrotropin in human serumand plasma. Measurements ofTSH are used in the diagnosisof thyroid and pituitarydisorders.Theelectrochemiluminescenceimmunoassay "ECLIA" isintended for use on thecobas e immunoassayanalyzers.
Technology	ECLIA	Same
Test format	Sandwich	Same
Test type	Quantitative	Same
Assay protocol	R1+R2+sample, incubation,+beads, incubation	Same
Pipetting volumesample	50 μL	Same
Pipetting volumebeads	40 μL	Same
Pipetting volume R1	60 μL	Same
Pipetting volume R2	50 μL	Same
Handling of R1 andR2	Liquid, ready to use	Same
Buffer composition R1	phosphate buffer 100 mmol/L	Same
Biotinylated antibody	MAKM-TU1.20-F(ab')2-Bi(DDS*,mono)	MAKM-TU1.20-F(ab')2-Bi(PEG24**,mono)
Buffer composition R2	phosphate buffer 100 mmol/LAnti-Biotin Antibody; specificfor free, unconjugated biotin(

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4. NON-CLINICAL PERFORMANCE EVALUATION

The non-clinical performance studies for the Glucose HK, ISE indirect Na and Elecsys TSH are summarized below.

4.1. Precision

Precision was performed based on guidance from the Clinical and Laboratory Standards Institute (CLSI) document EP05-A3. A summary of results for each assay is presented below.

Glucose HK Gen.3: Repeatability and Intermediate Precision

The precision of the Glucose HK Gen.3 was evaluated on one cobas c 503 analytical unit with one reagent lot. The protocol consisted of testing 2 replicates of each control (PreciControl ClinChem Multi 1 and PreciControl ClinChem Multi 2) and human serum per run, 2 runs per day for 21 days. The samples were run in randomized order on the analyzer. Human serum samples used were all native, single donors as well as pools. The protocol was repeated for urine and CSF applications. The Repeatability and Intermediate precision were calculated according to EP05-A3. All samples met the predetermined acceptance criterion. The data presented in the tables below is the worst precision result of the 3 lots.

Repeatability and Intermediate Precision
Repeatability
Serum Application (N=84)	Mean Value		SD		CV %
Specimen	mmol/L	mg/dL	mmol/L	mg/dL	CV %
PreciControl ClinChem Multi 1(PCCC1)	5.61	101	0.0315	0.568	0.6
PreciControl ClinChem Multi 2(PCCC2)	12.6	227	0.0523	0.942	0.4
Serum 1	0.188	3.39	0.0174	0.313	9.2
Serum 2	3.57	64.3	0.0181	0.326	0.5
Serum 3	5.46	98.4	0.0233	0.420	0.4
Serum 4	19.6	353	0.121	2.18	0.6

Table 6: Glucose HK Gen.3 Summary of Repeatability and Intermediate Precision Results

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Serum 5	38.6	696	0.188	3.39	0.5
Urine Application (N=84)	Mean Value		SD		CV %
Specimen	mmol/L	mg/dL	mmol/L	mg/dL
LyQ_UR1	1.09	19.6	0.0215	0.387	2.0
LyQ_UR2	16.4	296	0.0655	1.18	0.4
Urine 1	0.227	4.09	0.0188	0.339	8.3
Urine 2	0.733	13.2	0.0143	0.258	1.9
Urine 3	4.10	73.9	0.0418	0.753	1.0
Urine 4	22.0	396	0.182	3.28	0.8
Urine 5	40.6	732	0.173	3.12	0.4
CSF Application (N=84)	Mean Value		SD		CV %
Specimen	mmol/L	mg/dL	mmol/L	mg/dL
LiQ_CSF1	3.31	59.6	0.0119	0.214	0.4
LiQ_CSF2	1.66	29.9	0.00970	0.175	0.6
CSF 1	0.273	4.92	0.00831	0.150	3.0
CSF 2	2.16	38.9	0.0180	0.324	0.8
CSF 3	3.81	68.7	0.0172	0.310	0.5
CSF 4	20.2	364	0.0824	1.48	0.4
CSF 5	39.9	719	0.193	3.48	0.5
Intermediate
Serum Application (N=84)	Mean Value		SD		CV %
Specimen	mmol/L	mg/dL	mmol/L	mg/dL
PreciControl ClinChem Multi 1(PCCC1)	5.61	101	0.0559	1.007	1.0
PreciControl ClinChem Multi 2(PCCC2)	12.8	231	0.106	1.910	0.8
Serum 1	0.188	3.39	0.0188	0.339	10.0
Serum 2	3.57	64.3	0.0212	0.382	0.6
Serum 3	5.46	98.4	0.0297	0.535	0.5
Serum 4	19.6	353	0.136	2.45	0.7
Serum 5	38.6	696	0.216	3.89	0.6
Urine Application (N=84)	Mean Value		SD		CV %
Specimen	mmol/L	mg/dL	mmol/L	mg/dL
LyQ_UR1	1.09	19.6	0.0278	0.501	2.5
LyQ_UR2	16.4	296	0.122	2.20	0.7
Urine 1	0.215	3.87	0.0183	0.330	8.5
Urine 2	0.744	13.4	0.0180	0.324	2.4
Urine 3	4.07	73.3	0.0478	0.861	1.2
Urine 4	22.0	396	0.452	8.15	2.1
Urine 5	40.4	728	0.344	6.20	0.8
CSF Application (N=84)	Mean Value		SD		CV %
Specimen	mmol/L	mg/dL	mmol/L	mg/dL	CV %
LiQ_CSF1	3.34	60.2	0.0163	0.294	0.5
LiQ_CSF2	1.66	29.9	0.0109	0.196	0.7
CSF 1	0.273	4.92	0.00966	0.174	3.5
CSF 2	2.16	38.9	0.0212	0.382	1.0
CSF 3	3.81	68.7	0.0240	0.432	0.6
CSF 4	20.2	364	0.0994	1.79	0.5
CSF 5	39.9	719	0.230	4.14	0.6

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ISE indirect Na: Repeatability and Intermediate Precision

Precision of the ISE indirect Na was evaluated on one cobas pro ISE analyzer with one reagent lot. The protocol consisted of testing 2 replicates of each control ClinChem Multi 1 and PreciControl ClinChem Multi 2) and Li-Heparin plasma, serum and urine per run, 2 runs per day for 21 days. The samples were run in randomized order on the analyzer. The plasma, serum and urine samples used were all native, single donors as well as pools. Repeatability and Intermediate precision were calculated according to EP05-A3. All samples met the predetermined acceptance criterion. The following table summarizes the precision data for the ISE indirect Na.

Precision of the ISE indirect Na for Gen.2 was evaluated on one cobas pro ISE with one reagent lot.

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Repeatability and Intermediate Precision
Repeatability
Specimen (Li Hep Plasma) (N=84)	Mean Concentration (mmol/L)	SD (mmol/L)	CV (%)
PreciControl ClinChem Multi 1	112	0.285	0.3
PreciControl ClinChem Multi 2	136	0.484	0.4
Sample 1	86.3	0.479	0.6
Sample 2	131	0.348	0.3
Sample 3	137	0.298	0.2
Sample 4	151	0.392	0.3
Sample 5	177	0.497	0.3
Specimen (Serum) (N=84)	Mean Concentration (mmol/L)	SD (mmol/L)	CV (%)
PreciControl ClinChem Multi 1	111	0.280	0.3
PreciControl ClinChem Multi 2	134	0.412	0.3
Sample 1	82.5	0.449	0.5
Sample 2	131	0.413	0.3
Sample 3	136	0.388	0.3
Sample 4	151	0.472	0.3
Sample 5	175	0.638	0.4
Specimen (Urine) (N=84)	Mean Concentration (mmol/L)	SD (mmol/L)	CV (%)
Liquichek 1	76.9	0.338	0.4
Liquichek 2	175	0.803	0.5
Sample 1	23.6	0.128	0.5
Sample 2	137	0.473	0.3
Sample 3	112	0.516	0.5
Sample 4	207	0.899	0.4
Sample 5	244	0.814	0.3

Table 7: ISE indirect Na Summary of Repeatability and Intermediate Precision Results

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Intermediate Precision
Specimen (Li Hep Plasma)(N=84)	Mean Concentration (mmol/L)	SD (mmol/L)	CV (%)
PreciControl ClinChem Multi 1	111	0.967	0.9
PreciControl ClinChem Multi 2	134	0.902	0.7
Sample 1	84.7	1.25	1.5
Sample 2	129	0.879	0.7
Sample 3	135	0.931	0.7
Sample 4	149	0.821	0.6
Sample 5	174	0.950	0.5
Specimen (Serum) (N=84)	Mean Concentration (mmol/L)	SD (mmol/L)	CV (%)
PreciControl ClinChem Multi 1	111	1.16	1.0
PreciControl ClinChem Multi 2	134	1.07	0.8
Sample 1	83.0	1.38	1.7
Sample 2	131	0.930	0.7
Sample 3	135	1.02	0.8
Sample 4	150	0.802	0.5
Sample 5	173	0.948	0.5
Specimen (Urine) (N=84)	Mean Concentration (mmol/L)	SD (mmol/L)	CV (%)
Liquichek 1	78.1	1.06	1.4
Liquichek 2	175	1.05	0.6
Sample 1	24.8	1.19	4.8
Sample 2	136	0.941	0.7
Sample 3	111	0.941	0.8
Sample 4	204	1.23	0.6
Sample 5	241	1.63	0.7

Elecsys TSH: Repeatability and Intermediate Precision

Precision of the Elecsys TSH assay was evaluated on one cobas e 801 immunoassay analyzer with one reagent lot. The protocol consisted of testing 2 replicates of each control (PreciControl Universal and PC Thyro Sensitive) and human sera (HS) per run, 2 runs per day for 21 days. The samples were run in randomized order on the analyzer. Human serum samples used were all native, single donors as well as pools. Repeatability and Intermediate imprecision were calculated according to EP05-A3. All samples met the predetermined acceptance criterion. The following table summarizes the precision data for the Elecsys TSH.

{21}------------------------------------------------

Precision of the Elecsys TSH assay was evaluated on one cobas e 801 immunoassay analyzer with one reagent lot.

		Repeatability		Intermediate precision
Sample (N=84)	Mean(µIU/mL)	SD(µIU/mL )	CV (%)	SD(µIU/mL )	CV (%)
Human serum 1	0.0133	0.000829	6.3	0.00155	11.7
Human serum 2	0.262	0.00447	1.7	0.00722	2.8
Human serum 3	3.95	0.0661	1.7	0.123	3.1
Human serum 4	57.3	1.50	2.6	2.24	3.9
Human serum 5	93.1	2.64	2.8	4.29	4.6
PC Universal 1	1.32	0.023	1.7	0.0319	2.4
PC Universal 2	8.00	0.142	1.8	0.234	2.9
PC Thyro Sensitive	0.168	0.00274	1.6	0.00488	2.9

Table 8: Summary of Repeatability and Intermediate Precision Results

4.2. Analytical Sensitivity

Limit of Blank (LoB), Limit of Detection (LoD) and Limit of Quantitation (LoQ)

The Limit of Blank, Limit of Detection and Limit of Quantitation were determined in accordance with the CLSI (Clinical and Laboratory Standards Institute) EP17 A2 requirements.

The Limit of Blank is the 95th percentile value from n ≥ 60 measurements of analyte- free samples over several independent series. The Limit of Blank corresponds to the concentration below which analyte- free samples are found with a probability of 95 %. The Limit of Blank was determined on the respective analytical unit, six runs on ≥ three days, with five blank samples with two replicates each per run. In total, 60 determinations for analyte free samples have been obtained.

The Limit of Detection was determined based on the Limit of Blank and the standard deviation of low concentration samples. The Limit of Detection corresponds to the lowest analyte concentration which can be detected (value above the Limit of Blank with a probability of 95%). The Limit of Detection was determined on the respective analytical unit, five samples

{22}------------------------------------------------

with low-analyte concentration was measured in two-fold determination in 6 runs, distributed over 3 days. In total 60 measurements were obtained per sample type.

LoQ determines the lowest amount of analyte that can be quantitatively determined with stated accuracy and stated experimental conditions. The LoO was determined as the lowest concentration of analyte which can be quantified with a total error of no more than 20% (Glucose and TSH) and 30% (Sodium).

Samples with low analyte concentration are measured over 3 to 5 days on the respective analyzer (n ≥ 60 per sample type). The mean value, SD, and %TE (total error) were calculated for each sample. The mean concentration is plotted versus the %TE, with LoQ determined at maximum allowable %TE.

A summary of empirical results for Glucose HK Gen. 3 is presented below in the following order: LoB, LoD and LoQ.

Serum	Reagent Lot	LoB [mg/dL]
	Lot 3	0.2
	Lot 1	0.1
Lot 2	0.2
Urine	Reagent Lot	LoB [mg/dL]
	Lot03	0.7
	Lot01	0.3
Lot02	0.3
CSF	Reagent Lot	LoB [mg/dL]
	Lot 3	0.2
	Lot 1	0.2
Lot 2	0.2

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Serum	Reagent Lot	LoD [mg/dL]
	Lot 3	0.4
	Lot 1	0.3
Lot 2	0.4
Urine	Reagent Lot	LoD [mg/dL]
	Lot03	1.0
	Lot01	0.6
Lot02	0.6
CSF	Reagent Lot	LoD [mg/dL]
	Lot 3	0.3
	Lot 1	0.3
Lot 2	0.3

Serum/Plasma	Reagent Lot	LoQ [mg/dL]
	Lot 3	1.3
	Lot 1	1.3
	Lot 2	1.4
Urine	Reagent Lot	LoQ [mg/dL]
	Lot03	1.4
	Lot01	1.3
	Lot02	1.5
CSF	Reagent Lot	LoQ [mg/dL]
	Lot 3	1.1
	Lot 1	1.1
	Lot 2	1.2

The results and labeling Claim for Glucose HK Gen.3

	Result	Claim
Limit of Blank (LoB)	0.2 mg/dL (0.011 mmol/L)	2 mg/dL (0.11 mmol/L)
Limit of Detection (LoD)	0.4 mg/dL (0.022 mmol/L)	2 mg/dL (0.11 mmol/L)
Limit of Quantitation (LoQ)	1.4 mg/dL (0.078 mmol/L)	2 mg/dL (0.11 mmol/L)

A summary of empirical results for ISE indirect Na for Gen.2 is presented below in the following order: LoB, LoD and LoQ.

{24}------------------------------------------------

Sample Type	Electrode Lot	LoB [mmol/L]
Plasma	E9012	3.50
Serum	E9012	3.50
Urine	E9012	3.50

Sample Type	Electrode Lot	LoD [mmol/L]
Plasma	E9012	4.44
Serum	E9012	4.42
Urine	E9012	4.51

Sample Type	Electrode Lot	LoQ [mmol/L]
Plasma	E9012	11.8
Serum	E9012	12.1
Urine	E9012	12.2

Labeling Claim for ISE indirect Na for Gen.2 as stated in the method sheet:

Limit of Blank = 3.5 mmol/L .
Limit of Detection = 4.5 mmol/L ●
Limit of Quantitation = 12.2 mmol/L .

A summary of empirical results for Elecsys TSH is presented below in the following order: LoB, LoD and LoQ.

Reagent Lot	LoB (µIU/mL)
344546	0.0013
344548	0.0015
344550	0.0014

Reagent Lot	LoD (μIU/mL)
-------------	--------------

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344546	0.00282
344548	0.00348
344550	0.00312

Reagent Lot	LoQ (µIU/mL)
344546	0.00410
344548	0.00386
344550	0.00495

Labeling Claim for Elecsys TSH as stated in the method sheet:

Limit of Blank = 0.0025 µIU/mL .
Limit of Detection = 0.005 µIU/mL .
. Limit of Quantitation = 0.005 μIU/mL

4.3. Linearity/Assay Reportable Range

Glucose HK Gen.3 (GLUC3)

Linearity was determined based on guidance from Clinical and Laboratory Standards Institute (CLSI) document EP06-A. Three high analyte human serum, urine and CSF samples were diluted to 12 levels covering the measuring range and were then measured. The aliquots were assayed in 3-fold determination within a single run. All deviations were within predetermined acceptance criteria. Linearity for serum, urine and CSF samples was confirmed in the claimed measuring range from 2.0 to 750 mg/dL (0.11 to 41.6 mmol/L).

Glucose HK Gen.3 (GLUC3)

Serum: The mean observed linear range concentrations ranged from 0.0 to 783.0 mg/dL ● for the sample set. The correlation with the expected concentrations according to the linear regression formulas: Serum: y = 0.999(x) + 0.00856; R2 = 0.9999.

{26}------------------------------------------------

. Urine: The mean observed linear range concentrations ranged from 0.0 to 788.4 mg/dL for the sample set. The correlation with the expected concentrations according to the linear regression formulas: Urine: y = 0.999(x) + 0.00435; R2 = 0.9997.
. CSF: The mean observed linear range concentrations ranged from 0.00 to 829.8 mg/dL for the sample set. The correlation with the expected concentrations according to the linear regression formulas: CSF: y = 0.998(x) + 0.0126; R2 = 0.9992

ISE indirect Na for Gen.2

Linearity was determined based on guidance from Clinical and Laboratory Standards Institute (CLSI) document EP06-A. Three high analyte human serum, urine and CSF samples were diluted to multiple aliquot concentrations covering the measuring range and were then measured. The aliquots were assayed in 3-fold determination within a single run. All deviations were within predetermined acceptance criteria. Linearity for Lithium heparin plasma and serum, and urine samples was confirmed in the claimed measuring range from 80-180 mmol/L and 20-250 mmol/L respectively.

. Plasma: The mean observed linear range concentrations ranged from 75.2 to 185 mmol/L for the sample set. The correlation with the expected concentrations according to the linear regression formulas: Plasma: y = 1.000(x) + 0.0; R2 = 0.9998.
. Serum: The mean observed linear range concentrations ranged from 75.7 to 186 mmol/L for the sample set. The correlation with the expected concentrations according to the linear regression formulas: Serum: y = 1.000(x) + 0.0; R2 = 0.9998.
. Urine: The mean observed linear range concentrations ranged from 13.7 to -265 mmol/L for the sample set. The correlation with the expected concentrations according to the linear regression formulas: Urine: y = 1.000(x) + 0.0; R2 = 0.9999.

Elecsys TSH

Linearity of the Elecsys TSH assay was assessed on the cobas e 801 analytical unit according to CLSI EP06-A. Three high analyte human serum samples were diluted and concentrations covering the measuring range were measured. Samples were assayed in 3-fold determination within a single run.

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. Serum: The linear range for the three human serum samples is 0.004 - 118 uIU/mL. Elecsys TSH correlated with expected concentrations according to the linear regression formulas: Serum: y = 1.082(x) -0.000156; R2 = 0.9972

4.4. High Dose Hook Effect

The high-dose hook effect of the Elecsys TSH assay was assessed on the cobas e 801 analytical unit in one-fold determination. Three human serum samples were spiked with analyte to achieve high TSH concentrations. For each sample, a dilution series was performed. No hook effect up to 1466 uIU/mL TSH.

4.5. Endogenous Interference

The purpose of this study was to evaluate endogenous substances for potential interference with the parameters measured with the Glucose HK on cobas c 503, ISE indirect Na on cobas pro ISE, and Elecsys TSH on the cobas e 801 analytical units. All the endogenous substances met the acceptance criteria of recovery of 100±10%.

Glucose HK

The effect on quantitation of analyte in the presence of endogenous interfering substances using the Glucose HK Gen.3 (GLUC3) assay was determined on the cobas pro c 503 analytical unit using plasma and urine samples and conducted according to CLSI EP07-A2. Glucose levels of approximately 79.5 mg/dL and 116.3 mg/dL were tested and the summary of results is presented in the two tables below.

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Potential Interferent	No Interference up to approximately
Plasma	Albumin	74.3 g/L
	Bilirubin	78 mg/dL
	Ditaurobilirubin	81 mg/dL
	Hemolysis	1081 mg/dL
	IgG	74.5g/L
	Lipemia	1668 mg/dL
Urine	Albumin	2.50 g/L
	Calcium	12.0 mg/dL
	Citrate	11.0 mg/dL
	Creatinine	88.4 mg/dL
	Hemolysis	1150 mg/dL
	IgG	1.10 g/L
	Magnesium	25.0 mg/dL
	Oxalate	1.50 mg/dL
	Phosphate	130 mg/dL
	Urea	1800 mg/dL
	Uric Acid	6.00 mg/dL
Urobilinogen	1.13 mg/dL

ISE indirect Na

Endogenous interference

The effect on quantitation of analyte in the presence of endogenous interfering substances using the Sodium electrode was determined on the cobas pro ISE analytical unit using human plasma, serum, and urine samples. A low (approximately 124 mmol/L) and high (approximately 151 mmol/L) samples were tested. A low concentration of 26.3 mmol/L and a high concentration of 188 mmol/L were tested for urine application. The summary of results is presented in the table below.

	Potential Interferent	No Interference up to approximately
Plasma	Bilirubin	63 mg/dL
	Ditaurobilirubin	69 mg/dL
	Hemolysis	1137 mg/dL
	Lipemia	2326 mg/dL
Serum	Bilirubin	68.0 mg/dL
	Ditaurobilirubin	71.0 mg/dL
	Hemolysis	1144 mg/dL
	Lipemia	2206 mg/dL
Urine	Hemolysis	1141 mg/dL

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Exogenous interference

The effect on quantitation of analyte in the presence of exogenous interfering substances was determined at 125 and 158 mmol/L for Serum and at 30 and 200 mmol/L for Urine applications.

Two sample pools, containing a low and high concentration of ISE indirect Na are used. These sample pools are divided into an appropriate number of aliquots. One aliquot is not spiked with the drugs and it is used as the reference sample for ISE indirect Na concentration. The ISE indirect Na concentration in the sample is determined with n=3 measurements on a cobas pro ISE analytical unit.

The other sample aliquots, with either the high or low ISE indirect Na concentrations, are spiked with the respective amount of drug. The ISE indirect Na concentration of the spiked aliquots are determined in triplicate and the mean of the triplicate determinations is compared to the ISE indirect Na concentration determined for the reference aliquot (mean of n=3).

Serum application
Interference	No Interference up to
Acetaminophen (paracetamol)	200 mg/L
Acetylcysteine	1660 mg/dL
Acetylsalicylic acid	1000 mg/L
Ampicillin- Na	1000 mg/L
Ascorbic acid	300 mg/L
Cefoxitin	2500 mg/L
Cyclosporin	5 mg/L
Doxycycline	50 mg/L
Heparin	5000 IU/L
Ibuprofen	500 mg/L
Intralipid	10000 mg/L
L- Dopa	20 mg/L
Methyldopa	20 mg/L
Metronidazol	200 mg/L
Phenylbutazone	400 mg/L
Rifampicin	60 mg/L

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CENTRAL CONSULT CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSl'heophylline	100 mg/L

Urine application
Interference	No Interference up to
Acetaminophen (paracetamol)	3000 mg/L
Acetylcysteine	10 mg/dL
Ascorbic acid	4000 mg/L
Gentamycin sulfate	400 mg/L
Ibuprofen	4000 mg/L
Levodopa	1000 mg/L
Methyldopa	2000 mg/L
Cefoxitin	12000 mg/L
Ofloxacine	900 mg/L
Phenazopyridine	300 mg/L
Salicyluric acid	6000 mg/L
Tetracycline	300 mg/L

Elecsys TSH

The serum samples may contain substances that could potentially interfere with the test. The following compounds were added to human serum samples with a low (approximately 0.462 uIU/mL), a mid (approximately 3.95 µIU/mL) and a high (approximately 7.54 µIU/mL) TSH concentration. One aliquot of each serum sample was spiked with the interfering substance, another aliquot was spiked with the same volume of isotonic NaCl solution (dilution pool). The interfering pool was then dilution pool in 10 % increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample. None of the serum samples showed any deviation from the expected results. No interference was observed for these compounds at the levels indicated below.

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Interference	Interference Substance
Biotin	1200 mg/dL
Lipemia (Intralipid)	2000 mg/dL
Hemoglobin	1000 mg/dL
Bilirubin	66 mg/dL
Rheumatoid Factor (RF)	1500 IU/mL
Immunoglobulin (IgG)	3.98 g/dL
Immunoglobulin (IgM)	0.730 g/dL

Analytical Specificity/Cross-Reactivity 4.6.

The effect on quantitation of analyte in the presence of potential cross-reacting compounds using the Elecsys TSH was determined on the cobas e 801 analytical unit using a native human serum sample pool. For each potential cross-reacting compound a human serum sample with a low concentration level of TSH was tested. Results from these spiked serum samples were matched against the unspiked references and the % cross-reactivity was calculated. No cross reactivity was observed at the concentration tested.

Table 9: Summary of Cross-Reactivity

Cross-reactant	Concentration tested (µIU/mL)	Cross-reactivity %
hGH	10000000	0.000
hCG	50000000	0.000
LH	10000000	0.000
FSH	10000000	0.000

4.7. Exogenous Interferences - Drugs

The effect on quantitation of TSH in the presence of drugs was determined by comparing values obtained from samples spiked with 17 commonly and 13 specially used pharmaceutical compounds with the reference sample (unspiked). Two human serum samples (native serum pools) with analyte concentration approximately 0.5 and 8 uIU/mL were used and tested on the cobas e

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801 analytical unit. The drug concentrations tested correspond at least to the three times maximum daily doses (or the one-time maximum daily dose, respectively). Drug interferences are measured based on recommendations given in CLSI guidelines EP07-ED3 and EP37-ED1 and other published literature. For all drugs tested, the specification of ± 10% of the reference value was met as each compound was found to be non-interfering at the drug concentration.

Table 10: Common Drugs

Potential interfering commonly useddrugs	Highest interferent concentration tested at which no significantinterference was observed (mg/L)
Acetylcysteine	150
Ampicillin - Na	75
Ascorbic acid	52.5
Cyclosporine	1.8
Cefoxitin	750
Heparin	3300 IU/mL
Levodopa	7.5
Methyldopa	22.5
Metronidazole	123
Phenylbutazone	321
Doxycycline	18
Acetylsalicylic acid	30
Rifampicin	48
Acetaminophen	156
Ibuprofen	219
Theophylline	60
Itraconazole	10

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Table 11: Special Drugs

Drug	Highest interferent concentration tested at which nosignificant interference was observed (mg/L)
Amiodarone	200
Carbimazole	30
Fluocortolone	100
Hydrocortisone	200
Iodide	0.2
Levothyroxine	0.25
Liothyronine	0.075
Methimazole	80
Octreotide	0.3
Prednisolone	100
Propranolol	240
Propylthiouracil	300
Perchlorate	2000

Method Comparison to Predicate 4.8.

Glucose HK

A method comparison was performed using the Glucose HK Gen.3 (GLUC3) assay (c 503, Y) and the predicate, Glucose HK Gen.3 (GLUC3) assay on the cobas c 501 analyzer(X) to assess the bias between the two analytical units in two different cores. A total of 74 native human serum samples, 67 native human urine samples and 75 native CSF samples were measured in singlicate on the cobas c 503 analyzer in one run covering the entire measuring range.

A summary of results is presented in the table below.

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Method	Sample Type(number ofsamples)	Passing/Bablok(Slope & Intercept)and correlation(Kendall tau ( t))	Linear Regression(Slope & Intercept)and correlation(Pearson ( r ))	Sampleconcentrationrange(mg/dL)
cobas c 503 vs. cobasc 501	Serum (74)	1.000x - 0.0200t = 0.987	0.997x - 0.00454r = 1.000	5.8 - 725.4
cobas c 503 vs cobasc 501	Urine (67)	0.995x - 0.0447t = 0.982	0.995x - 0.0402r = 1.000	3.1 - 736.2
cobas c 503 vs cobasc 501	CSF (75)	1.000x + 0.00400t = 0.957	1.001x + 0.0287r = 0.999	3.6 - 734.4

Table 12: Summary of Method Comparison

ISE indirect Na

A method comparison was performed using the ISE indirect Na assay (on cobas pro ISE in cobas pro core, Y) and the predicate device, cobas c 501 ISE, X) to assess the bias between the two test systems. Additionally, the results of the candidate test system were compared against flame photometry. A total of 120 human Lithium heparin plasma samples for cobas pro ISE versus cobas c 501 ISE, 118 human Lithium heparin plasma for cobas pro ISE vs Flame Photometer, 120 human serum for cobas pro ISE vs c 501 ISE, 120 human serum versus Flame Photometer and 120 human urine were measured in singleton on the cobas pro ISE analyzer in one run covering the entire measuring range.

Table 13: Summary of Method Comparison
----------------------------------------	--	--	--

cobas pro ISE vs	Sample Type(number ofsamples)	Passing/Bablok(Slope &Intercept) andcorrelation(Pearson ( r ))	Sampleconcentrationrange (mmol/L)
cobas c 501 ISE	Plasma (120)	$1.003x - 1.72$r = 1.000	84.2-177
Flame Photo.	Plasma (118)	$1.031x - 4.12$r = 0.997	80.4-175
cobas c 501 ISE	Serum (120)	$1.027x - 4.38$r = 1.000	84.4 -175
Flame Photo.	Serum (120)	$1.016x - 1.11$r = 0.996	81.3 -174
cobas c 501 ISE	Urine (120)	$1.019x - 2.90$r = 1.000	25.5-241
Flame Photo.	Urine (120)	$0.993x - 2.46$	22.5-249

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		r = 1.000
--	--	-----------	--

Elecsys TSH

A method comparison was performed using the Elecsys TSH assay (on cobas e 801 in cobas pro core, Y) and the Elecsys TSH assay (on cobas e 801 in cobas 8000 core, X) to assess the bias between the two test systems. A total of 138 samples (129 native human serum samples and 9 diluted human serum samples, single donors as well as pools diluted) were measured in singleton on each cobas e 801 analytical unit in one run covering the entire measuring range.

N	138
Range ( $\mu$ IU/mL)	0.006 – 97.8
Slope	1.018
(LCL / UCL)	(1.004 / 1.025)
Intercept ( $\mu$ IU/mL)	-0.0018
(LCL / UCL)	(-0.0040 /- 0.0001)
Correlation coefficient, Pearson (r)	0.999
Correlation coefficient, Kendall (tau)	0.977
Bias at 0.27 $\mu$ IU/mL	1.2%
(LCL / UCL)	(0.0%/ 1.8%)
Bias at 4.2 $\mu$ IU/mL	1.8%
(LCL / UCL)	(0.4% / 2.5%)

4.9. Sample Matrix Comparison

Glucose HK

The effect on quantitation of analyte in the presence of anticoagulants with the Glucose HK Gen. 3 assay was determined by comparing values obtained from samples (native human serum samples, single donors drawn into serum/gel separation tubes and K2-EDTA, Li-Heparin, NaF/K-Oxalate NaF/Na2-EDTA, NaF/Citrate/Na2-EDTA and KF/Na2-EDTA plasma tubes).

The recovery of analyte values in the presence of anticoagulants with the Glucose HK Gen.3 assay was determined on the cobas c 503 analytical unit by comparing values obtained from samples drawn into serum and plasma collection tubes. The recovery of each plasma sample to the matching

{36}------------------------------------------------

serum sample was calculated. At least 39 serum/plasma pairs were tested for each kind of anticoagulant in single determination.

	Table 15: Summary of Matrix Comparison

	Matrix Comparison (Passing/Bablok)
Serum vs Serum Tube withSeparation Gel	NRangeSlopeInterceptCorrelation coefficient r	393.6 - 694.8 mg/dL1.0000.005000.999
Serum tube vs K2EDTA PlasmaTube	NRangeSlopeInterceptCorrelation coefficient r	523.6 - 694.8 mg/dL1.005-0.01080.998
Serum tube vs Lithium HeparinPlasma Tube	NRangeSlopeInterceptCorrelation coefficient r	513.6 - 694.8 mg/dL1.007-0.02740.998
Serum tube vs NaF/K-OxalatePlasma Tube	NRangeSlopeInterceptCorrelation coefficient r	503.6 - 694.8 mg/dL1.006-0.01000.998
Serum tube vs NaF/ Na2-EDTAPlasma Tube	NRangeSlopeInterceptCorrelation coefficient r	503.6 - 694.8 mg/dL1.020-0.02410.998
Serum tube vs NaF/Citrate/ Na2-EDTA Plasma Tube	NRangeSlopeIntercept	503.6 - 694.8 mg/dL1.035-0.104

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Matrix Comparison (Passing/Bablok)
	Correlation coefficient r	0.998
	N	52
Serum tube vs KF/Na2-EDTAPlasma Tube	Range	3.6 – 694.8 mg/dL
	Slope	0.996
	Intercept	-0.0367
	Correlation coefficient r	1.000

ISE indirect Na

The effect on quantitation of analyte in the presence of anticoagulants with the ISE indirect Na was determined by comparing values obtained from samples drawn into serum and Li-Heparin plasma tubes. A total of 50 serum/ Li-Heparin plasma pairs per sample material were tested in singleton with one reagent lot on one cobas pro ISE analytical unit. Data were evaluated using a regression analysis according to Passing/Bablok.

Table 16: Summary of Matrix Comparison

Matrix Comparison (Passing/Bablok)
	N	50
	Range	83.1 – 174 mmol/L
Serum/Li-Heparin	Slope	1.015
	Intercept	-2.69
	Correlation coefficient r	0.998

Elecsys TSH

The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys TSH immunoassay was determined by comparing values obtained from samples (native human serum samples, single donors as well as pools) drawn into serum and Li-Heparin, K2-EDTA, K3-EDTA plasma tubes. A minimum of 56 serum/plasma pairs per sample material were tested in singleton with one reagent lot on one cobas e 801 analyzer. Data were evaluated using a regression analysis according to Passing/Bablok. Serum separation tubes from 3 separate manufacturers and blood from five donors were used. Measurements were performed in duplicate with one reagent lot and

{38}------------------------------------------------

evaluated on the basis of recovery relative to the serum / plasma tube without separating gel (reference).

Matrix Comparison (Passing/Bablok)
	N	50
Serum/Li-Heparin Plasma	Range	0.006 – 97.1 µIU/mL
	Slope	0.982
	Intercept	0.0002 µIU/mL
	Correlation coefficient r	0.999
	Bias at 0.2 µIU/mL	-1.7 %
	Bias at 2.5 µIU/mL	-1.8 %
	N	51
Serum/K2-EDTA Plasma	Range	0.006 – 97.1 µIU/mL
	Slope	0.977
	Intercept	-0.0015 µIU/mL
	Correlation coefficient r	1.000
	Bias at 0.2 µIU/mL	-2.8 %
	Bias at 2.5 µIU/mL	-2.3 %
	N	51
Serum/K3-EDTA Plasma	Range	0.006 – 97.1 µIU/mL
	Slope	0.971
	Intercept	-0.0123 µIU/mL
	Correlation coefficient r	1.000
	Bias at 0.2 µIU/mL	-7.5 %
	Bias at 2.5 µIU/mL	-3.2 %

Table 17: Summary of Matrix Comparison

4.10. Stability

The stability data for Glucose HK Gen.3, ISE indirect Na and Elecsys TSH was provided in K061048, K060373, and K190773 respectively. The stability data supports Roche Diagnostic's claims as reported in the package inserts.

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Conclusion 4.11.

Based on the analytical testing results and acceptance characteristics including sensitivity, precision, specificity, interference and method comparison of the device, it is concluded that Glucose, ISE indirect Na, TSH and the cobas pro integrated solutions are substantially equivalent to the predicate devices.

Regulation Number and Section

§ 862.1345 Glucose test system.

(a)
Identification. A glucose test system is a device intended to measure glucose quantitatively in blood and other body fluids. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma.(b)
Classification. Class II (special controls). The device, when it is solely intended for use as a drink to test glucose tolerance, is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9.