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

K191899 · Roche Diagnostics · CFR · Aug 16, 2019 · Clinical Chemistry

Device Facts

• Record ID: K191899
• Device Name: Glucose HK Gen.3, ISE indirect Na for Gen.2, Elecsys TSH, cobas pro integrated solutions
• Applicant: Roche Diagnostics
• Product Code: CFR · Clinical Chemistry
• Decision Date: Aug 16, 2019
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1345
• Device Class: Class 2
• Attributes: Pediatric

Intended Use

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 Story

Fully automated, random-access, software-controlled IVD system for clinical chemistry, electrolyte, and immunoassay testing. Inputs: biological fluid samples (serum, plasma, urine, CSF) in barcoded tubes. Operation: system scans barcodes; samples distributed to analytical units (c 503 for chemistry, ISE unit for sodium, e 801 for immunoassay). Glucose measured via hexokinase/G-6-PDH spectrophotometry; sodium via ion-selective electrodes (Nernst equation); TSH via sandwich ECLIA. System performs automated calibration, QC, and result calculation. Used in high-workload clinical labs by technicians. Output: quantitative analyte concentrations displayed on screen/printed. Results assist clinicians in diagnosing/treating metabolic, electrolyte, and endocrine disorders.

Clinical Evidence

Bench testing only. Precision (repeatability/intermediate) evaluated per CLSI EP05-A3 (N=84). Analytical sensitivity (LoB, LoD, LoQ) per CLSI EP17-A2. Linearity per CLSI EP06-A. Endogenous/exogenous interference and cross-reactivity tested per CLSI EP07-A2/EP37-ED1. Method comparison against predicates (N=67-138 samples) showed high correlation (r ≥ 0.997) and acceptable bias.

Technological Characteristics

System: fully automated, random-access, software-controlled. Glucose: Hexokinase/G-6-PDH photometric assay. Sodium: Ion-selective electrode (potentiometry). TSH: Sandwich ECLIA. Connectivity: Barcode-based sample ID, electronic data transfer. Software: System-specific, derived from previous Roche/Hitachi generations. Materials: Liquid, ready-to-use reagents.

Indications for Use

Indicated for quantitative determination of glucose (serum, plasma, urine, CSF), sodium (serum, plasma, urine), and thyrotropin (serum, plasma) in clinical laboratory settings for diagnosis/treatment of metabolic, electrolyte, thyroid, and pituitary disorders.

Regulatory Classification

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.

Special Controls

*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.

Submission Summary (Full Text)

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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 [phone] 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.

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.

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 Road<br>P.O. Box 50416<br>Indianapolis, IN 46250 |
| Contact | Khoa Tran<br>Phone: [phone]<br>Fax: [phone]<br>Email: [e-mail]<br><br>Secondary Contact: Dave Tribbett<br>Phone: [phone]<br>Fax: [phone]<br>Email: [e-mail] |
| Date Prepared | August 16, 2019 |
| Proprietary Name | cobas pro integrated solutions<br>Glucose HK Gen.3<br>ISE indirect Na for Gen.2<br>Elecsys 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,<br>Regulation Name, Regulatory<br>Class 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 series<br>Glucose HK<br>ISE Indirect<br>Elecsys TSH |
| Establishment Registration | For the cobas pro integrated solutions, Glucose HK, ISE<br>indirect Na and Elecsys TSH, the establishment registration<br>number for Roche Diagnostics GmbH in Mannheim,<br>Germany is 9610126, and for Penzberg, Germany, 9610529.<br>The establishment registration number for Roche<br>Diagnostics in the United States is 1823260. |

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### Device Description

#### 1.1. System

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.

### 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

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.

#### 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<br>(k060373) | cobas pro integrated<br>solutions<br>(k191899) |
|-----------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | Same | IVD device used for the<br>quantitation of clinical<br>chemistry/ immunochemistry<br>and Ion Selective Electrolyte<br>parameters from various<br>biological fluids |
| Software | cobas 6000 Analyzer Series System<br>Software | cobas pro integrated<br>solutions system Software |
| Configuration | Several analytical units with one PC and<br>one Core unit | Same as cobas 6000 |
| Function<br>performed | Data Input, Sample Processing, Result<br>Calculation, Result Reporting, Quality<br>Control, Infrastructure (power, water<br>supply) | Same |
| PC (Controller<br>Unit) Functions | Data Input (Keyboard, Disc), Data<br>Output (Screen, printer) | Data Input (Touch screen,<br>Disc), Data Output (Screen,<br>printer) |
| Core Unit<br>Functions | Real time database, data input and<br>output (via HOST communication),<br>control of sample conveyer | Same |
| Analytical Unit(s)<br>Functions | Control of analytic processes (pipetting,<br>incubation, detection) Primary Signal<br>processing | Same |
| Data Storage | Real time database in Core Unit (storage<br>of System and Application parameters,<br>Calibration Data, QC Data, Sample<br>Results, Alarm history) | Same |

Table 2: Substantial Equivalency System

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| Topic | cobas 6000 Analyzer Series<br>(k060373) | cobas pro integrated<br>solutions<br>(k191899) |
|--------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|
| Result<br>Calculation | Automated measuring of signal using<br>various methods according to automated<br>calculation of concentration via<br>calibration curve | Same |
| Flagging of errors | Available | Same |
| Units Controlled | cobas c 501 (with integrated ISE) and<br>cobas e 601-analyzers | cobas c 503, cobas e 801,<br>and cobas pro ISE analyzers |
| Initial cassette<br>volume check<br>(ICVC) for<br>reagent pipetting | Available | Same |
| Data concept<br>(Application<br>parameter,<br>calibrator, control<br>value transfer) | Electronic transfer possible (user must<br>accept transfer before parameter applied) | Same |

# Table 3: Substantial Equivalency Glucose HK Gen. 3

| Item | Glucose HK Gen. 3<br>( c 501 in cobas 6000 core)<br>k060373 | Glucose HK Gen. 3<br>(c 503 in cobas pro core)<br>k191899 |
|-------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|
| Proprietary name | Glucose HK Gen. 3 | Glucose HK Gen. 3 |
| Catalog number | 04404483190 | 08057800190 |
| Intended use | In vitro test for the<br>quantitative determination<br>of glucose in human serum,<br>plasma, urine and CSF on<br>Roche/Hitachi cobas c<br>systems. | In vitro test for the quantitative<br>determination of glucose in<br>human serum, plasma, urine and<br>CSF on Roche/Hitachi cobas c<br>systems. |
| Technology | Photometric | Same |
| Test format | Enzymatic | Same |
| Test type | Quantitative | Same |
| Assay protocol | R1+R2+Diluent+Sample,<br>incubation | Same |
| Pipetting volume sample | 15 µL | Same |
| Pipetting volume R1 | 28 µL | Same |
| Pipetting volume R2 | 10 µL | Same |
| | Serum, plasma, urine and<br>CSF | Same |

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| Item | Glucose HK Gen. 3<br>(c 501 in cobas 6000 core)<br>k060373 | Glucose HK Gen. 3<br>(c 503 in cobas pro core)<br>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<br>(in cobas 6000 core)<br>k060373 | cobas pro ISE<br>(in cobas pro core)<br>k191899 |
|---------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Proprietary name | ISE indirect Na | ISE indirect Na |
| Intended use | The ISE analytical unit of the<br>Roche/Hitachi cobas c systems<br>is intended<br>for the quantitative<br>determination of sodium in<br>serum, plasma or urine using | The ISE analytical unit of the<br>Roche/Hitachi cobas c systems is<br>intended<br>for the quantitative determination<br>of sodium in serum, plasma or<br>urine using |
| | ion- selective electrodes. | ion- selective electrodes. |
| Technology | ISE Potentiometry | Same |
| Test type | Quantitative | Same |
| Typical sample<br>volumes | 9.7 µL 15 µL | 9.7 µL 15 µL |
| Default ISE<br>Dilution ratio<br>1:31 | 1:31<br>(9.7uL sample + 291uL<br>Diluent) | Same<br>(15 uL sample + 450uLDiluent) |
| Sample types | Serum, plasma, urine | Same |
| Sample handling<br>system | Input of samples via core input<br>buffer using universal sample<br>racks | Same |
| Measuring Range | Serum/Plasma: 80-180<br>mmol/L<br>Urine: 20-250 mmol/L | Same |

# Table 5: Substantial Equivalency Elecsys TSH

| Item | Elecsys TSH<br>(e 801 in cobas 8000 core)<br>k190773 | Elecsys TSH<br>(e 801 in cobas pro core)<br>k191899 |
|----------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Proprietary name | Elecsys TSH | Elecsys TSH |
| Catalog number | 08429324160 | 08429324160 |
| Item | Elecsys TSH<br>( e 801 in cobas 8000 core)<br>k190773 | Elecsys TSH<br>(e 801 in cobas pro core)<br>k191899 |
| Intended use | Elecsys TSH immunoassay is<br>intended for the in vitro<br>quantitative determination of<br>thyrotropin in human serum<br>and plasma. Measurements of<br>TSH are used in the diagnosis<br>of thyroid and pituitary<br>disorders.<br>The Elecsys TSH<br>immunoassay is an<br>electrochemiluminescence<br>immunoassay “ECLIA”,<br>which is intended for use on<br>the cobas e immunoassay<br>analyzers. | Immunoassay for the in vitro<br>quantitative determination of<br>thyrotropin in human serum<br>and plasma. Measurements of<br>TSH are used in the diagnosis<br>of thyroid and pituitary<br>disorders.<br>The<br>electrochemiluminescence<br>immunoassay "ECLIA" is<br>intended for use on the<br>cobas e immunoassay<br>analyzers. |
| Technology | ECLIA | Same |
| Test format | Sandwich | Same |
| Test type | Quantitative | Same |
| Assay protocol | R1+R2+sample, incubation,<br>+beads, incubation | Same |
| Pipetting volume<br>sample | 50 μL | Same |
| Pipetting volume<br>beads | 40 μL | Same |
| Pipetting volume R1 | 60 μL | Same |
| Pipetting volume R2 | 50 μL | Same |
| Handling of R1 and<br>R2 | Liquid, ready to use | Same |
| Buffer composition R1 | phosphate buffer 100 mmol/L | Same |
| Biotinylated antibody | MAK<TSH>M-TU1.20-<br>F(ab')2-Bi(DDS*,mono) | MAK<TSH>M-TU1.20-<br>F(ab')2-Bi(PEG24**,mono) |
| Buffer composition R2 | phosphate buffer 100 mmol/L<br>Anti-Biotin Antibody; specific<br>for free, unconjugated biotin<br>( | |

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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<br>(PCCC1) | 5.61 | 101 | 0.0315 | 0.568 | 0.6 |
| PreciControl ClinChem Multi 2<br>(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<br>(PCCC1) | 5.61 | 101 | 0.0559 | 1.007 | 1.0 |
| PreciControl ClinChem Multi 2<br>(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)<br>(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.

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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<br>(µIU/mL) | SD<br>(µIU/mL ) | CV (%) | SD<br>(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

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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.

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| 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.

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- . 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 hum…