cobas pure integrated solutions is an automated analyzer, intended for running qualitative, semiguantitative and quantitative clinical chemistry and immunochemistry assays as well as ion selective measurements.

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 hypoqlycemia, idiopathic hypoglycemia and pancreatic islet cell tumors.

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.

Methadone II (MDN2) is an in vitro diagnostic test for the qualitative and semiquantitative detection of methadone in human urine on Roche/Hitachi cobas c systems at a cutoff concentration of 300 ng/mL. Semiquantitative test results may be obtained that permit laboratories to assess assay performance as part of a quality control program. Semiquantitative assays are intended to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as gas chromatography/mass spectrometry (GC-MS).

Elecsys TSH is an immunoassay 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 pure integrated solutions is a fully automated, random-access, software controlled system intended for in vitro quantitative and qualitative analysis of analytes in body fluids. It will typically be used in low to mid throughput clinical laboratories. The system consolidates clinical chemistry, homogenous immunoassays as well as electrolyte testing within one workplace. The cobas pure integrated solutions consists of a clinical chemistry analytical unit (cobas c 303) with an integrated ISE analytical unit, an immunoassay analytical unit (cobas e 402) and a core unit.

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 (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 ISE analytical unit for Na+ 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 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 diarrhed reabsorption in the kidney and excessive fluid retention. Common causes of include excessive fluid loss, high salt intake and increased kidney reabsorption.

The Methadone assay is based on the kinetic interaction of microparticles in a solution (KIMS) as measured by changes in light transmission. In the absence of sample drug conjugates bind to antibody-bound microparticles, causing the formation of particle aggregates. As the aggregation reaction proceeds in the absence of sample drug, the absorbance increases.

When a urine sample contains the drug in question, this drug derivative conjugate for microparticle-bound antibody. Antibody bound to sample drug is no longer available to promote particle aggregation, and subsequent particle lattice formation is inhibited. The presence of sample drug diminishes the increasing absorbance in proportion to the concentration of drug in the sample. Sample drug content is determined relative to the value obtained for a known cutoff concentration of drug.

The Elecsys TSH immunoassay makes use of a sandwich test principle using monoclonal antibodies specifically directed against human TSH. The antibodies labeled with ruthenium complex) construct from human and mouse specific components. 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. It is intended for use on the cobas e immunoassay analyzers.

AI/ML Overview

The provided text describes several in vitro diagnostic (IVD) devices and their performance characteristics. It outlines how Roche Diagnostics established the substantial equivalence of these devices (Glucose HK Gen.3, ISE indirect Na for Gen.2, ONLINE DAT Methadone II, Elecsys TSH, and the cobas pure integrated solutions analyzer) to their predicate devices through various non-clinical tests.

However, the document does not provide a table of acceptance criteria and reported device performance in a format that easily allows for direct comparison against specific numeric targets. Instead, it describes general study types and states that the "analytical performance data for all representative assays meet specifications and support the substantial equivalence."

Furthermore, it does not explicitly detail the following requested information:

Sample sizes used for the test set and data provenance: The document mentions "human serum, plasma, urine and CSF" as sample types but not explicit test set sample numbers or their country of origin for most tests. It generally refers to "human samples" or "pooled human plasma and serum samples."
Number of experts used to establish the ground truth for the test set and their qualifications: This information is not present for any of the described tests. The ground truth for these IVDs is typically established through reference methods or established control materials, not expert consensus on individual cases.
Adjudication method: Not applicable/provided as the tests are analytical and do not involve human interpretation requiring adjudication.
Multi Reader Multi Case (MRMC) comparative effectiveness study: Not applicable, as these are IVD assays, not AI-assisted reader studies.
Standalone performance: The entire document describes the standalone performance of the algorithms/assays.
Type of ground truth used: For quantitative assays (Glucose, Sodium, TSH), the ground truth is implicitly based on established reference methods or known concentrations in control materials. For qualitative/semi-quantitative assays like Methadone, it's based on known concentrations relative to a cutoff or confirmed by methods like GC-MS.
Sample size for the training set: Not explicitly stated, as these are typically not machine learning models in the sense of needing a distinct "training set" for classification, but rather reagents and analytical systems whose performance is validated. The mentioned "study" refers to validation studies, not AI model training.
How the ground truth for the training set was established: Not applicable, as explained above.

Given the nature of the document, which focuses on device-specific analytical performance claims rather than AI model validation, several of the requested categories are not directly addressed or are not relevant.

Below is an attempt to structure the available information, noting the limitations.

1. Table of Acceptance Criteria and Reported Device Performance

As specific numerical acceptance criteria (e.g., "sensitivity ≥ 95%") are not explicitly provided in the text, this table will summarize what types of performance were evaluated and that they met specifications as stated in the document.

Device/Assay	Performance Metric Evaluated	Reported Device Performance
Glucose HK Gen.3	Precision (Repeatability, Intermediate Precision)	Met specifications (according to CLSI EP05-A3)
	Linearity	Met specifications (according to CLSI EP06-A)
	Limit of Blank (LoB)	Determined; highest observed measurement value for analyte-free samples.
	Limit of Detection (LoD)	Determined; lowest amount of analyte detectable with 95% probability.
	Limit of Quantitation (LoQ)	Determined; lowest concentration quantifiable with ≤ 20% total error.
	Endogenous Interference	Effects determined for hemoglobin, lipemia, albumin, IgG, bilirubin.
	Drug Interference	Evaluated for potential interference.
	Method Comparison	Performed vs. Glucose HK Gen.3 on cobas c 503.
	Matrix Comparison	Supported use of different anticoagulant tube types.
	On-board Reagent Stability	Verified for 26 weeks.
	Post Dilution Check	Verified automatic rerun function.
	Recovery in Controls	Tested.
ISE indirect Na for Gen.2	Precision (Repeatability, Intermediate Precision)	Met specifications (according to CLSI EP05-A3)
	Linearity	Demonstrated across claimed measuring range (according to CLSI EP06-A).
	Limit of Blank (LoB)	Determined; highest observed measurement value for analyte-free samples.
	Limit of Detection (LoD)	Determined; lowest amount of analyte detectable with 95% probability.
	Limit of Quantitation (LoQ)	Determined; lowest concentration quantifiable with ≤ 30% total error.
	Endogenous Interference	Effects determined for bilirubin, hemolysis, lipemia.
	Drug Interference	Evaluated for potential interference.
	Method Comparison	Performed vs. ISE indirect Na for Gen2. on cobas pro ISE and flame photometry.
	Matrix Comparison	Determined effect of anticoagulants (Li-Heparin Plasma and Serum).
	Calibration Frequency	Study verifying performed.
	Post Dilution Check	Verified automatic rerun function.
	Recovery in Controls	Measured.
ONLINE DAT Methadone II	Precision (Repeatability, Intermediate Precision)	Met specifications (according to CLSI EP05-A3)
	Endogenous Interference	Tested effects of interfering substances on urine samples with methadone at -25% of cutoff.
	Drug Interference	Evaluated effects of various drugs/compounds on results relative to 300 ng/mL cutoff.
	Cross Reactivity	Inhibition curves generated; approximate quantity for equivalent reactivity to 300 ng/mL cutoff determined.
	Method Comparison	Performed vs. GC-MS and cobas c 503.
	Recovery in Controls	Tested.
Elecsys TSH	Precision (Repeatability, Intermediate Precision)	Met specifications (according to CLSI EP05-A3)
	Linearity	Assessed on cobas e 402 (according to CLSI EP06-A).
	Limit of Blank (LoB)	Determined; highest observed measurement values for samples.
	Limit of Detection (LoD)	Determined; lowest amount of analyte detectable with 95% probability.
	Limit of Quantitation (LoQ)	Determined; lowest concentration quantifiable with ≤ 20% total error.
	Endogenous Interfering Substances	Determined effect on quantitation in human serum samples.
	Drug Interference	Determined effect on quantitation by comparing spiked vs. unspiked samples.
	Cross-reacting Compounds	Determined effect on quantitation in human serum sample pool.
	On-board Reagent Stability	Tested on cobas e 402.
	Method Comparison	Performed vs. predicate Elecsys TSH on cobas e 801 to assess bias.
	Anticoagulants Effect	Determined effect on quantitation in various plasma tubes.
	High-dose Hook Effect	Assessed on cobas e 402.

Overall Conclusion for all devices: "The analytical performance data for all representative assays meet specifications and support the substantial equivalence...to the predicate devices."

2. Sample sizes used for the test set and the data provenance

Glucose HK Gen.3:
- Precision studies: "Two aliquots per run, two runs per day for ≥ 21 days". Types of samples (e.g., patient, control) not specified, but typically human-derived.
- Linearity, LoB, LoD, LoQ, Interference, Matrix Comparison, Post Dilution Check, Recovery in Controls: Sample numbers or types of samples for these specific studies are not detailed.
- Method Comparison: "all sample types" (e.g., human serum, plasma, urine, CSF) tested between cobas c 303 and cobas c 503.
- Data Provenance: Not specified (e.g., country of origin, retrospective/prospective).
ISE indirect Na for Gen.2:
- Precision studies: "One run per day for ≥ 21 days with two parts, two aliquots per part". Typically human-derived samples.
- Endogenous Interference: "pooled human plasma and serum samples spiked with varying levels of interferent."
- Linearity, LoB, LoD, LoQ, Drug Interference, Calibration Frequency, Post Dilution Check, Recovery in Controls: Sample numbers or specific types of samples not detailed.
- Method Comparison: "all sample types" (e.g., human serum, plasma, urine) tested.
- Data Provenance: Not specified.
ONLINE DAT Methadone II:
- Precision: "human samples and controls" (n=84 for repeatability, with 2 aliquots per run, 2 runs per day, 21 days for intermediate precision).
- Endogenous Interference: "urine containing methadone" and "pooled human urine".
- Drug Interference: "human urine containing methadone".
- Cross Reactivity: Details not given, but likely spiked drug solutions into human urine.
- Method Comparison: Urine samples compared against GC-MS and cobas c 503.
- Data Provenance: Not specified.
Elecsys TSH:
- Precision: Likely control materials and potentially patient samples.
- Endogenous Interfering Substances: "human serum samples (native serum pools)".
- Cross-reacting Compounds: "native human serum sample pool".
- Anticoagulants Effect: "native human serum samples, single donors as well as pools" drawn into various tubes.
- Linearity, LoB, LoD, LoQ, Drug Interference, On-board Reagent Stability, High-dose Hook Effect: Sample numbers or types not specified.
- Method Comparison: Human serum and plasma samples compared between cobas e 402 and cobas e 801.
- Data Provenance: Not specified.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

Not applicable. For in vitro diagnostic assays, "ground truth" is established through analytical reference methods, defined concentrations of calibrators/standards, or confirmed by other laboratory methods (e.g., GC-MS for Methadone) rather than expert human interpretation of results.

4. Adjudication method

Not applicable. These are analytical tests performed by automated systems; there is no human interpretation or adjudication involved in generating the primary test result.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This is for in vitro diagnostic assays on automated analyzers, not AI-assisted human reader studies. The "AI" would refer to the algorithms within the analytical unit, not a system designed to assist human readers.

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

Yes, the entire document focuses on the standalone performance of the analytical systems and assays. The results are generated directly by the device/analyzer without human intervention for interpretation beyond loading samples and performing quality control.

7. The type of ground truth used

For Glucose, Sodium, TSH (Quantitative assays): The ground truth for these quantitative measurements is based on reference methods, known concentrations in calibrators and controls, or comparative methods (e.g., flame photometry for sodium, or existing cleared assays on predicate devices).
For Methadone (Qualitative/Semi-quantitative assay): Ground truth is established by known concentrations relative to a cutoff (e.g., 225 ng/mL for negative control, 375 ng/mL for positive control) and confirmed by a "confirmatory method such as gas chromatography/mass spectrometry (GC-MS)".

8. The sample size for the training set

Not explicitly specified. These are not AI/ML models in the typical sense that require a distinct "training set." The development of reagents and analytical platforms involves extensive R&D and optimization, but the validation studies described here are for demonstrating performance and equivalence, not for "training" an algorithm in a machine learning context.

9. How the ground truth for the training set was established

Not applicable, as a distinct "training set" with established ground truth in the context of machine learning model development is not typically associated with the development and validation of these types of in vitro diagnostic reagents and analyzers. The principles are generally based on established biochemical reactions, electrochemical measurements, or immunoassays.

Summary

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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.

September 16, 2022

Roche Diagnostics Noel Mencias Program Manager, Regulatory Affairs 9115 Hague Road Indianapolis, IN 46250

Re: K220134

Trade/Device Name: Glucose HK Gen.3, ISE indirect Na for Gen.2, Elecsys TSH, ONLINE DAT Methadone II, cobas pure integrated solutions Regulation Number: 21 CFR 862.1345 Regulation Name: Glucose test system Regulatory Class: Class II Product Code: CFR, JGS, JLW, DJR, JJE Dated: July 1, 2022 Received: July 5, 2022

Dear Noel Mencias:

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.

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

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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 (OS) 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 mediation-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,

Paula V. Caposino, Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Ouality Center for Devices and Radiological Health

Enclosure

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Indications for Use

Submission Number (if known)

K220134 Device Name

cobas pure integrated solutions; Glucose HK Gen.3; ISE indirect Na for Gen.2; ONLINE DAT Methadone II; Elecsys TSH ndications for Use (Describe)

Indications for Use (Describe)

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

Prescription Use (Part 21 CFR 801 Subpart D)

e-Counter Use (21 CFR 801 Subpart C)

CONTINUE ON A SEPARATE PAGE IF NEEDED.

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510(k) #: K220134	510(k) Summary	Prepared on: 2022-09-09
Contact Details		21 CFR 807.92(a)(1)
Applicant Name	Roche Diagnostics
Applicant Address	9115 Hague Road Indianapolis IN 46250 United States
Applicant Contact Telephone	463-336-2546
Applicant Contact	Mr. Noel Mencias
Applicant Contact Email	noel.mencias@roche.com
Device Name		21 CFR 807.92(a)(2)
Device Trade Name	Glucose HK Gen.3;ISE indirect Na for Gen.2;ONLINE DAT Methadone II;Elecsys TSH;cobas pure integrated solutions
Common Name	GLUC3; ISE Na; MDN2; TSH; cobas pure integrated solutions
Classification Name	Hexokinase, glucose; Electrode, ion specific, sodium; enzyme immunoass
Regulation Number	862.1345; 862.1665; 862.3620; 862.1690; 862.2160
Product Code	CFR; JGS; DJR; JLW; JJE
Legally Marketed Predicate Devices 21 CFR 807.92(a)(3)
Predicate #	Predicate Trade Name (Primary Predicate is listed first)	Product Code
K191899	cobas pro integrated solutions	JJE
K191899	Glucose HK Gen.3	CFR
K191899	ISE indirect Na for Gen.2	JGS
K021505	ONLINE DAT Methadone II	DJR
K191899	Elecsys TSH	JLW
Device Description Summary 21 CFR 807.92(a)(4)
cobas pure integrated solutionsThe cobas pure integrated solutions is a fully automated, random-access, software controlled system intended for in vitro quantitative

and qualitative analysis of analytes in body fluids. It will typically be used in low to mid throughput clinical laboratories. The system consolidates clinical chemistry, homogenous immunoassays as well as electrolyte testing within one workplace. The cobas pure integrated solutions consists of a clinical chemistry analytical unit (cobas c 303) with an integrated ISE analytical unit, an immunoassay analytical unit (cobas e 402) and a core unit.

Glucose HK Gen. 3

Glucose is phosphorylated by hexokinase (HK) in the presence of adenosine triphosphate (ATP) and magnesium ions to produce

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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 (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.

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 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 diarrhed reabsorption in the kidney and excessive fluid retention. Common causes of include excessive fluid loss, high salt intake and increased kidney reabsorption.

ONLINE DAT Methadone II

Elecsys TSH

Intended Use/Indications for Use

21 CFR 807.92(a)(5)

cobas pure integrated solutions is an automated analyzer, intended for running qualitative and quantitative clinical chemistry and immunochemistry assays as well as ion selective measurements.

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, idiopathic hypoglycemia and pancreatic islet cell tumors.

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 insipids (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.

Methadone II (MDN2) is an in vitro diagnostic test for the qualitative detection of methadone in human urine on Roche/Hitachi cobas c systems at a cutoff concentration of 300 ng/mL. Semiquantitative test results may be obtained that permit laboratories to assess assay performance as part of a quality control program. Semiquantitative assays are intended to determine an appropriate dilution of the specimen for confirmatory method such as gas chromatography/mass spectrometry (GC-MS).

Elecsys TSH is an immunoassay 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.

Indications for Use Comparison

21 CFR 807.92(a)(5)

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Indications for use are the same as the predicate device.

Technological Comparison

21 CFR 807.92(a)(6)

21 CFR 807.92(b)

The cobas pure integrated solutions is a next generation of the cobas 6000 analyzer series (cobas 6000) which was cleared under K060373. The cobas pro integrated solutions, cleared in K191899, is the first of the next generation platforms and the predicate of cobas pure integrated solution. The cobas pure integrated solutions consists of a clinical chemistry analytical unit (cobas c 303) with an integrated ISE analytical unit, an immunoassay analytical unit (cobas e 402) and a core unit. The clinical chemistry (CC) and the ISE analytical units are part of the existing Roche/Hitachi/cobas c family of analyzers and the immunoassay (IM) analyzer are part of the existing Elecsys family of analyzers. These share technological characteristics with the predicate solutions, modified for lower throughput. The reagents and calibrators/controls to be applied on cobas pure integrated solutions will be existing devices already cleared on existing Roche/Hitachi cobas c or Elecsys instrumentation.

The representative reagents Glucose HK Gen.3, ISE indirect Na for Gen.2, ONLINE DAT Methadone II, and Elecsys TSH share the technological characteristics of their predicate devices.

Non-Clinical and/or Clinical Tests Summary & Conclusions

Glucose HK Gen.3

Precision experiments were performed in accordance with CLSI quideline EP05-A3. Two aliquots per run, two runs per day for ≥ 21 days were performed on the same cobas c 303 analytical unit using 1 lot of reagent. Repeatability (within run precision) and intermediate precision (within lab precision) were calculated.

The linearity study was performed according to CLSI quideline EP06-A on one cobas c 303 analyzer.

The Limit of Blank (LoB) of the Glucose HK Gen.3 assay on the cobas c 303 analytical unit assay was determined according to CLS EP 17-A2. The LoB is the highest observed measurement value for an analyte-free sample. The Limit of Blank was determined as the 95th percentile of measurements of blank samples.

The Limit of Detection (LoD) of the Glucose HK Gen.3 assay on the cobas c 303 analytical unit was determined according to CLSI EP 17-A. The LoD determines the lower limit for samples with analyte. The lowest amount of analyte in a sample that can be detected with a 95% probability.

The Limit of Quantitation (LoQ) of the Glucose HK Gen.3 assay was determined according to CLSI EP 17-A2. LoQ determines the lowest amount of analyte that can be quantitatively determined with stated experimental conditions. The LoQ was determined as the lowest concentration of analyte which can be quantified with a total error of no more than 20%.

Endogenous Interference studies were conducted to determine the effects of interference by hemoglobin, lipemia (Intralipid), albumin, Immunoglobulin (lgG) and bilirubin on the Glucose HK Gen.3 were determined on the cobas c 303.

Drug Interference studies were conducted to evaluate drugs for potential interference with Glucose Gen.3 HK assay measured on the cobas c 303 analytical unit.

Method Comparison experiments were performed for all sample types using the Gen.3 assay on the cobas c 303 versus the Glucose HK Gen.3 assay on the cobas c 503.

Matrix Comparison studies were performed to support the use of several different anticoagulant tube types.

On-board reagent stability was verified on the cobas c 303 for the specified time frame: 26 weeks on board.

Post Dilution Check experiments were run across the measuring range to verify the automatic rerun function of the analytical unit.

Recovery in Controls on cobas c 303 were tested.

ISE indirect Na for Gen.2

Precision experiments were performed in accordance with CLSI guideline EP05-A3. One run per day for ≥ 21 days with two parts, two aliquots per part were performed on the same cobas c 303 ISE analytical unit using one reagent lot. Repeatability (within run precision) and intermediate precision (within lab precision) were calculated.

The linearity study was conducted to demonstrate that measurements across the claimed measuring range for each parameter are linear. The study was performed according to CLSI quideline EP06-A.

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The Limit of Blank (LoB) of the ISE indirect Na for Gen. 2 assay on the cobas c 303 ISE analytical unit was determined according to CLSI EP 17-A2. The LoB is the highest observed measurement value for an analyte-free sample. The Limit of Blank was determined as the 95th percentile of measurements of blank samples.

The Limit of Detection (LoD) of the ISE indirect Na for Gen. 2 assay on the cobas c 303 ISE analytical unit was determined according to CLSI EP17-A2. The LoD determines the lower limit for samples with analyte. The lowest amount of analyte in a sample that can be detected with a 95% probability.

The Limit of Quantitation (LoQ) of the ISE indirect Na for Gen. 2 assay was determined according to CLSI EP 17-A2.

LoQ determines the lowest amount of analyte that can be quantitatively determined with stated experimental conditions. The LoQ was determined as the lowest concentration of analyte which a total error of no more than 30%.

The effects of interference by endogenous substances bilirubin, hemolysis and lipemia (htralipid) on the ISE Na test system were determined on the cobas c 303 ISE analyzer using pooled human plasma and serum samples spiked with varying levels of interferent.

A Drug Interference study was conducted to evaluate drugs for potential interference with ISE indirect Na for Gen.2 assay measured on the cobas c 303 ISE analytical unit.

Method Comparison experiments were performed for all sample types using ISE indirect Na for Gen2. on the cobas c 303 ISE versus ISE indirect Na for Gen2. on cobas pro ISE and flame photometry to assess the bias.

The effect of the presence of anticoagulants on analyte recovery was determined by matrix comparison on one cobas c 303 15E, obtained from samples drawn into Li-Heparin Plasma and Serum collection tubes.

A study verifying calibration frequency was performed.

Post Dilution Check experiments were run across the measuring range to verify the automatic rerun function of the cobas c 303 SE analytical unit.

Recovery in controls were measured on the cobas c 303 ISE analytical unit.

ONLINE DAT Methadone II

Precision was determined using human samples and controls in accordance with the CLSI (Clinical and Laboratory Standards Institute) EP05-A3 requirements with repeatability (n = 84) and intermediate precision (2 aliquots per run, 2 runs per day, 21 days).

To test endogenous interference, interfering substances were added to urine containing methadone at - 25 % of the cutoff level at specified concentrations. Samples were tested on the cobas c 303 analytical unit with the ONLINE DAT Methadone II assay.

The effects of drug interference were conducted on one cobas c 303. Aliguots of the drug in a human urine containing methadone at the control level concentrations were prepared. The compounds were added at the specified concentrations to pooled human urine containing methadone at a concentration of 225 ng/mL (negative control level) or 375 ng/mL (positive control level). For each compound, negative results relative to the 300 ng/mL cutoff were obtained for the samples containing methadone at a concentration of 225 ng/ml (negative control level) and positive results were obtaining methadone at a concentration of 375 ng/mL (positive control level), with the Methadone II assay.

Cross Reactivity studies were conducted by generating inhibition curves and determining the approximate quantity of each compound that is equivalent in assay reactivity to a 300 ng/mL assay cutoff.

Method Comparison studies were conducted with the Methadone II assay on the cobas c 303 and relative to GC-MS and relative to cobas c 503.

Recovery in Controls on cobas c 303 were tested.

Elecsys TSH

Precision measurements were conducted to evaluate repeatability (within-run precision) and the intermediate precision (withinlaboratory precision) according the CLSI guideline EP05-A3.

Linearity of the Elecsys TSH assay was assessed on the cobas e 402 Immunoassay analyzer according to CLSJ EP06-A.

LoB of the Elecsys TSH on the cobas e 402 analyzer was determined according to CLSJ EP17-A2. Limit of Blank determines the highest

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observed measurement values for samples The Limit of Blank was determined as the 95th percentile of measurements of blank samples.

LoD of the Elecsys TSH assay on the cobas e 402 Immunoassay analyzer has been determined according to CLSI EP17-A2. The LoD was determined as the lowest amount of analyte in a sample that can be detected with 95% probability.

The LoQ of the Elecsys TSH was determined on the cobas e 402 analyzer according to CLSI Guideline EP17-A2. LoQ determines the lowest amount of analyte that an be quantitatively determined with 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%.

The effect on quantitation of analyte in the presence of endogenous interfering substances using the Elecsys TSH was determined on the cobas e 402 immunoassay analyzer using human serum samples (native serum pools).

The effect on quantitation of analyte in the presence of drugs was determined by comparing values obtained from samples spiked with commonly and specially used pharmaceutical compounds with the reference sample (unspiked).

The effect on quantitation of analyte in the presence of potential cross-reacting compounds using the Elecsys TSH was determined on the cobas e 402 immunoassay analyzer using a native human serum sample pool.

On-board reagent stability for the Elecsys TSH assay was tested on one cobas e 402 immunoassay analyzer.

A method comparison was performed using the Elecsys TSH updated assay (candidate device, cobas e 402 in cobas pure integrated solution, Y) and the Elecsys TSH current assay (predicate device, cobas e 801 in cobas pro integrated solution, X) to assess the bias between the two assays.

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, Li-Heparin, K2-EDTA, K3-EDTA plasma tubes.

The high-dose hook effect of the Elecsys TSH assay was assessed on the cobas e 402 analyzer.

The analytical performance data for all representative assays meet specifications and support the substantial equivalence of Glucose HK Gen.3, ISE indirect Na for Gen.2, ONLINE DAT Methadone II, Elecsys TSH, and cobas pure integrated solutions 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.