(31 days)
No
The summary describes a fully automated, software-controlled system for in vitro quantitative analysis using established analytical methods (clinical chemistry, immunoassay, ISE). There is no mention of AI, ML, or related concepts in the intended use, device description, or performance studies. The software is described as unique but developed from previous generations, suggesting traditional programming rather than AI/ML.
No
This device is an in vitro diagnostic (IVD) system used for quantitative analysis of various analytes in body fluids, which aids in diagnosis and treatment monitoring. It does not directly provide therapy.
Yes
The "Intended Use / Indications for Use" section explicitly states that various measurements performed by the device are "used in the diagnosis and treatment" of specific conditions, indicating its role in the diagnostic process.
No
The device description explicitly states it is a "fully automated, random-access, software controlled system" that "consists of a high throughput sample distribution unit (core unit) and different analytical units for ISE, clinical chemistry, and immunoassay testing." It also mentions the "system hardware is comprised of new or previously cleared members of the Roche/Hitachi cobas c or Elecsys families of analyzers." This clearly indicates the device includes significant hardware components in addition to software.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use/Indications for Use: The document explicitly states the intended use is for the "quantitation of clinical chemistry and Ion Selective Electrolyte parameters from various biological fluids" and for the "in vitro quantitative determination" of specific analytes (glucose, sodium, TSH) in human biological fluids (serum, plasma, urine, CSF). This directly aligns with the definition of an in vitro diagnostic device, which is used to examine specimens derived from the human body to provide information for the diagnosis, prevention, monitoring, treatment, or alleviation of disease.
- Device Description: The description clearly states the cobas pro integrated solutions is a "fully automated, random-access, software controlled system intended for in vitro quantitative analysis of analytes in body fluids."
- Context: The document is structured like a submission for regulatory review (likely to the FDA), which is a process specifically for medical devices, including IVDs. The inclusion of sections like "Summary of Performance Studies," "Key Metrics," and "Predicate Device(s)" are standard components of such submissions for IVDs.
Therefore, based on the provided text, the cobas pro integrated solutions and the associated tests are clearly intended and described as In Vitro Diagnostic devices.
N/A
Intended Use / Indications for 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.
Product codes (comma separated list FDA assigned to the subject device)
CFR, JGS, JLW, JJE
Device Description
The cobas pro integrated solutions (cobas pro) is a fully automated, random-access, software controlled system intended for in vitro quantitative analysis of analytes in body fluids. It will typically be used in clinical laboratories with large workload. The system consolidates clinical chemistry, homogenous and heterogeneous immunoassays as well as electrolyte testing within one workplace. It consists of a high throughput sample distribution unit (core unit) and different analytical units for ISE (cobas pro ISE analytical unit), clinical chemistry (c 503 analytical unit) and immunoassay (e 801 analytical) testing. The system hardware is comprised of new or previously cleared members of the Roche/Hitachi cobas c or Elecsys families of analyzers. The instrument software is unique to the cobas pro and was developed from previous generations of Roche/Hitachi instrument systems.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
Not Found
Intended User / Care Setting
will typically be used in clinical laboratories with large workload.
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
4.1. Precision
- Study type: Repeatability and Intermediate Precision evaluated based on CLSI document EP05-A3.
- Glucose HK Gen.3:
- Sample size: 84 runs for serum, urine, and CSF applications.
- Data source: PreciControl ClinChem Multi 1 and 2, human serum, urine, and CSF (native, single donors, and pools).
- Key results: All samples met the predetermined acceptance criterion. Data presented is the worst precision result of 3 lots.
- Mean CV% for Repeatability (Serum): PCCC1 (0.6%), PCCC2 (0.4%), Serum 1 (9.2%), Serum 2 (0.5%), Serum 3 (0.4%), Serum 4 (0.6%), Serum 5 (0.5%).
- Mean CV% for Repeatability (Urine): LyQ_UR1 (2.0%), LyQ_UR2 (0.4%), Urine 1 (8.3%), Urine 2 (1.9%), Urine 3 (1.0%), Urine 4 (0.8%), Urine 5 (0.4%).
- Mean CV% for Repeatability (CSF): LiQ_CSF1 (0.4%), LiQ_CSF2 (0.6%), CSF 1 (3.0%), CSF 2 (0.8%), CSF 3 (0.5%), CSF 4 (0.4%), CSF 5 (0.5%).
- Mean CV% for Intermediate Precision (Serum): PCCC1 (1.0%), PCCC2 (0.8%), Serum 1 (10.0%), Serum 2 (0.6%), Serum 3 (0.5%), Serum 4 (0.7%), Serum 5 (0.6%).
- Mean CV% for Intermediate Precision (Urine): LyQ_UR1 (2.5%), LyQ_UR2 (0.7%), Urine 1 (8.5%), Urine 2 (2.4%), Urine 3 (1.2%), Urine 4 (2.1%), Urine 5 (0.8%).
- Mean CV% for Intermediate Precision (CSF): LiQ_CSF1 (0.5%), LiQ_CSF2 (0.7%), CSF 1 (3.5%), CSF 2 (1.0%), CSF 3 (0.6%), CSF 4 (0.5%), CSF 5 (0.6%).
- ISE indirect Na:
- Sample size: 84 runs for Li-Heparin plasma, serum, and urine.
- Data source: PreciControl ClinChem Multi 1 and 2, Li-Heparin plasma, serum and urine (native, single donors, and pools).
- Key results: All samples met the predetermined acceptance criterion.
- Mean CV% for Repeatability (Li Hep Plasma): PCCC1 (0.3%), PCCC2 (0.4%), Sample 1 (0.6%), Sample 2 (0.3%), Sample 3 (0.2%), Sample 4 (0.3%), Sample 5 (0.3%).
- Mean CV% for Repeatability (Serum): PCCC1 (0.3%), PCCC2 (0.3%), Sample 1 (0.5%), Sample 2 (0.3%), Sample 3 (0.3%), Sample 4 (0.3%), Sample 5 (0.4%).
- Mean CV% for Repeatability (Urine): Liquichek 1 (0.4%), Liquichek 2 (0.5%), Sample 1 (0.5%), Sample 2 (0.3%), Sample 3 (0.5%), Sample 4 (0.4%), Sample 5 (0.3%).
- Mean CV% for Intermediate Precision (Li Hep Plasma): PCCC1 (0.9%), PCCC2 (0.7%), Sample 1 (1.5%), Sample 2 (0.7%), Sample 3 (0.7%), Sample 4 (0.6%), Sample 5 (0.5%).
- Mean CV% for Intermediate Precision (Serum): PCCC1 (1.0%), PCCC2 (0.8%), Sample 1 (1.7%), Sample 2 (0.7%), Sample 3 (0.8%), Sample 4 (0.5%), Sample 5 (0.5%).
- Mean CV% for Intermediate Precision (Urine): Liquichek 1 (1.4%), Liquichek 2 (0.6%), Sample 1 (4.8%), Sample 2 (0.7%), Sample 3 (0.8%), Sample 4 (0.6%), Sample 5 (0.7%).
- Elecsys TSH:
- Sample size: 84 runs.
- Data source: PreciControl Universal and PC Thyro Sensitive, human sera (native, single donors, and pools).
- Key results: All samples met the predetermined acceptance criterion.
- Mean CV% for Repeatability: Human serum 1 (6.3%), Human serum 2 (1.7%), Human serum 3 (1.7%), Human serum 4 (2.6%), Human serum 5 (2.8%), PC Universal 1 (1.7%), PC Universal 2 (1.8%), PC Thyro Sensitive (1.6%).
- Mean CV% for Intermediate Precision: Human serum 1 (11.7%), Human serum 2 (2.8%), Human serum 3 (3.1%), Human serum 4 (3.9%), Human serum 5 (4.6%), PC Universal 1 (2.4%), PC Universal 2 (2.9%), PC Thyro Sensitive (2.9%).
4.2. Analytical Sensitivity
- Study type: Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) determination according to CLSI EP17 A2 requirements.
- Glucose HK Gen.3:
- Actual Results: LoB (0.2 mg/dL), LoD (0.4 mg/dL), LoQ (1.4 mg/dL).
- Labeling Claim: LoB (2 mg/dL), LoD (2 mg/dL), LoQ (2 mg/dL).
- ISE indirect Na for Gen.2:
- Actual Results: Plasma LoB (3.50 mmol/L), LoD (4.44 mmol/L), LoQ (11.8 mmol/L); Serum LoB (3.50 mmol/L), LoD (4.42 mmol/L), LoQ (12.1 mmol/L); Urine LoB (3.50 mmol/L), LoD (4.51 mmol/L), LoQ (12.2 mmol/L).
- Labeling Claim: LoB (3.5 mmol/L), LoD (4.5 mmol/L), LoQ (12.2 mmol/L).
- Elecsys TSH:
- Actual Results: LoB (0.0013 - 0.0015 µIU/mL across lots), LoD (0.00282 - 0.00348 µIU/mL across lots), LoQ (0.00386 - 0.00495 µIU/mL across lots).
- Labeling Claim: LoB (0.0025 µIU/mL), LoD (0.005 µIU/mL), LoQ (0.005 µIU/mL).
4.3. Linearity/Assay Reportable Range
- Study type: Linearity determination based on CLSI document EP06-A.
- Glucose HK Gen.3:
- Sample size: Not explicitly stated as a single number but "three high analyte human serum, urine and CSF samples were diluted to 12 levels".
- Key results: Linearity confirmed in the claimed measuring range from 2.0 to 750 mg/dL (0.11 to 41.6 mmol/L) for serum, urine, and CSF.
- Serum: Mean observed linear range 0.0 to 783.0 mg/dL. y = 0.999(x) + 0.00856; R2 = 0.9999.
- Urine: Mean observed linear range 0.0 to 788.4 mg/dL. y = 0.999(x) + 0.00435; R2 = 0.9997.
- CSF: Mean observed linear range 0.00 to 829.8 mg/dL. y = 0.998(x) + 0.0126; R2 = 0.9992.
- ISE indirect Na for Gen.2:
- Sample size: Not explicitly stated as a single number but "three high analyte human serum, urine and CSF samples were diluted to multiple aliquot concentrations".
- Key results: Linearity confirmed in the claimed measuring range from 80-180 mmol/L for Li-Heparin plasma and serum, and 20-250 mmol/L for urine.
- Plasma: Mean observed linear range 75.2 to 185 mmol/L. y = 1.000(x) + 0.0; R2 = 0.9998.
- Serum: Mean observed linear range 75.7 to 186 mmol/L. y = 1.000(x) + 0.0; R2 = 0.9998.
- Urine: Mean observed linear range 13.7 to 265 mmol/L. y = 1.000(x) + 0.0; R2 = 0.9999.
- Elecsys TSH:
- Sample size: Not explicitly stated as a single number but "Three high analyte human serum samples were diluted".
- Key results: The linear range for human serum samples is 0.004 - 118 uIU/mL. y = 1.082(x) -0.000156; R2 = 0.9972.
4.4. High Dose Hook Effect
- Study type: Assessment of high-dose hook effect.
- Elecsys TSH:
- Key results: No hook effect up to 1466 uIU/mL TSH.
4.5. Endogenous Interference
- Study type: Evaluation of endogenous substances for potential interference.
- Glucose HK:
- Sample type: Plasma and urine samples.
- Key results: All endogenous substances tested met the acceptance criteria of 100±10% recovery. Detailed list of substances and concentrations provided.
- ISE indirect Na:
- Sample type: Human plasma, serum, and urine samples.
- Key results: All endogenous substances tested showed no interference up to the stated concentrations. Detailed list of substances and concentrations provided.
- Elecsys TSH:
- Sample type: Human serum samples.
- Key results: No interference observed for tested compounds at indicated levels. Detailed list of substances and concentrations provided.
Exogenous Interference
- Study type: Evaluation of exogenous substances (drugs) for potential interference.
- ISE indirect Na:
- Sample type: Serum and urine applications.
- Key results: No interference observed for listed common drugs up to the specified concentrations. Detailed list of drugs and concentrations provided.
- Elecsys TSH:
- Sample type: Human serum samples.
- Key results: For all drugs tested, the specification of ± 10% of the reference value was met; each compound was found to be non-interfering at the drug concentration. Detailed lists of common and special drugs and concentrations provided.
4.6. Analytical Specificity/Cross-Reactivity
- Study type: Assessment of cross-reactivity.
- Elecsys TSH:
- Sample type: Native human serum sample pool.
- Key results: No cross reactivity was observed for hGH, hCG, LH, and FSH at the high concentrations tested (0.000%).
4.8. Method Comparison to Predicate
- Study type: Comparison of subject device assays to predicate devices.
- Glucose HK:
- Predicate: Glucose HK Gen.3 assay on the cobas c 501 analyzer (K060373).
- Sample size: 74 native human serum samples, 67 native human urine samples, and 75 native CSF samples.
- Key results:
- Serum: Slope 1.000, Intercept -0.0200 (Passing/Bablok); r=1.000 (Pearson).
- Urine: Slope 0.995, Intercept -0.0447 (Passing/Bablok); r=1.000 (Pearson).
- CSF: Slope 1.000, Intercept 0.00400 (Passing/Bablok); r=0.999 (Pearson).
- ISE indirect Na:
- Predicate: cobas c 501 ISE (K060373). Also compared to Flame Photometry.
- Sample size: 120 human Lithium heparin plasma samples, 118 human Lithium heparin plasma (vs Flame Photometer), 120 human serum, 120 human serum (vs Flame Photometer), and 120 human urine.
- Key results:
- cobas pro ISE vs cobas c 501 ISE (Plasma): Slope 1.003x, Intercept -1.72; r=1.000.
- cobas pro ISE vs Flame Photo. (Plasma): Slope 1.031x, Intercept -4.12; r=0.997.
- cobas pro ISE vs cobas c 501 ISE (Serum): Slope 1.027x, Intercept -4.38; r=1.000.
- cobas pro ISE vs Flame Photo. (Serum): Slope 1.016x, Intercept -1.11; r=0.996.
- cobas pro ISE vs cobas c 501 ISE (Urine): Slope 1.019x, Intercept -2.90; r=1.000.
- cobas pro ISE vs Flame Photo. (Urine): Slope 0.993x, Intercept -2.46; r=1.000.
- Elecsys TSH:
- Predicate: Elecsys TSH immunoassay on cobas e 801 in cobas 8000 core (K190773).
- Sample size: 138 samples (129 native human serum samples and 9 diluted human serum samples).
- Key results:
- Slope: 1.018 (LCL / UCL: 1.004 / 1.025)
- Intercept: -0.0018 µIU/mL (LCL / UCL: -0.0040 / -0.0001)
- Correlation coefficient, Pearson (r): 0.999
- Correlation coefficient, Kendall (tau): 0.977
- Bias at 0.27 µIU/mL: 1.2% (LCL / UCL: 0.0% / 1.8%)
- Bias at 4.2 µIU/mL: 1.8% (LCL / UCL: 0.4% / 2.5%)
4.9. Sample Matrix Comparison
- Study type: Evaluation of anticoagulant effects on analyte quantitation by comparing values from different tube types using Passing/Bablok regression analysis.
- Glucose HK:
- Sample size: At least 39 serum/plasma pairs for each anticoagulant.
- Key results: Correlation coefficient (r) for all comparisons (Serum vs variousPlasma Tubes) ranged from 0.998 to 0.999.
- ISE indirect Na:
- Sample size: 50 serum/Li-Heparin plasma pairs.
- Key results: Serum/Li-Heparin Plasma resulted in Slope 1.015, Intercept -2.69, and r=0.998.
- Elecsys TSH:
- Sample size: Minimum of 56 serum/plasma pairs for each anticoagulant.
- Key results:
- Serum/Li-Heparin Plasma: Slope 0.982, Intercept 0.0002 µIU/mL, r=0.999. Bias at 0.2 µIU/mL (-1.7%), Bias at 2.5 µIU/mL (-1.8%).
- Serum/K2-EDTA Plasma: Slope 0.977, Intercept -0.0015 µIU/mL, r=1.000. Bias at 0.2 µIU/mL (-2.8%), Bias at 2.5 µIU/mL (-2.3%).
- Serum/K3-EDTA Plasma: Slope 0.971, Intercept -0.0123 µIU/mL, r=1.000. Bias at 0.2 µIU/mL (-7.5%), Bias at 2.5 µIU/mL (-3.2%).
4.10. Stability
- Study type: Stability data provided by reference to previous clearances.
- Key results: Stability data supports Roche Diagnostic's claims as reported in the package inserts.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Key metrics reported are precision (SD, CV%), analytical sensitivity (LoB, LoD, LoQ), linearity (R2, slope, intercept), interference (recovery %), and method comparison (slope, intercept, Pearson r, Kendall tau, bias). No specificity, PPV, or NPV metrics are provided in the summary.
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Not Found (The text lists predicate devices but not their K/DEN numbers. It refers to a single K060373 number, but that is the submitter's previously cleared product, not a predicate device K-number in the same format as other predicate devices are listed here. The K-numbers K060373 and K190773 are mentioned later in the method comparison section as predicate for specific assay comparisons, but not as the initial predicate for the full system equivalence.)
However, based on the context in Table 2, 3, 4, 5 and the summary statement "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.", the following devices are listed as predicates within those tables:
cobas 6000 analyzer series, K060373
Glucose HK
ISE Indirect
Elecsys TSH, K190773
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 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.
0
Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health & Human Services logo on the left and the FDA acronym along with the full name of the agency on the right. The FDA part of the logo is in blue, with the acronym in a square and the full name written out to the right of the square.
August 16, 2019
Roche Diagnostics Khoa Tran Regulatory Affairs Principal 9115 Hague Road Indianapolis, IN 46250
Re: K191899
Trade/Device Name: Glucose HK Gen.3 ISE indirect Na for Gen.2 Elecsys TSH, cobas pro integrated solutions Regulation Number: 21 CFR 862.1345 Regulation Name: Glucose test system Regulatory Class: Class II Product Code: CFR, JGS, JLW, JJE Dated: July 15, 2019 Received: July 16, 2019
Dear Khoa Tran:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
1
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE(@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Kellie B. Kelm, Ph.D. Acting Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Ouality Center for Devices and Radiological Health
Enclosure
2
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) |
CONTINUE ON A SEPARATE PAGE IF NEEDED.This section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
3
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.
4
| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague Road |
| P.O. Box 50416 | |
| Indianapolis, IN 46250 | |
| Contact | Khoa Tran |
| Phone: (317) 521-3409 | |
| Fax: (317) 521-2324 | |
| Email: khoa.tran@roche.com |
Secondary Contact: Dave Tribbett
Phone: (317) 521-2964
Fax: (317) 521-2324
Email: david.tribbett@roche.com |
| Date Prepared | August 16, 2019 |
| Proprietary Name | cobas pro integrated solutions
Glucose HK Gen.3
ISE indirect Na for Gen.2
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,
Regulation Name, Regulatory
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
Glucose HK
ISE Indirect
Elecsys TSH |
| Establishment Registration | For the cobas pro integrated solutions, Glucose HK, ISE
indirect Na and Elecsys TSH, the establishment registration
number for Roche Diagnostics GmbH in Mannheim,
Germany is 9610126, and for Penzberg, Germany, 9610529.
The establishment registration number for Roche
Diagnostics in the United States is 1823260. |
5
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
6
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
7
(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
8
- . ISE Cleaning Solution: Sodium hydroxide solution, 3 mol/L with sodium hypochlorite solution 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.
12
- 2nd incubation: After addition of streptavidin-coated microparticles, the complex becomes . bound to the solid phase via interaction of biotin and streptavidin.
- . The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell/ProCell M. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier.
- . Results are determined via a calibration curve which is instrument specifically generated by 2- point calibration and a master curve provided via the reagent barcode or e- barcode.
| Topic | cobas 6000 Analyzer Series
(K060373) | cobas pro integrated
solutions
(K191899) |
|-----------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | Same | IVD device used for the
quantitation of clinical
chemistry/ immunochemistry
and Ion Selective Electrolyte
parameters from various
biological fluids |
| Software | cobas 6000 Analyzer Series System
Software | cobas pro integrated
solutions system Software |
| Configuration | Several analytical units with one PC and
one Core unit | Same as cobas 6000 |
| Function
performed | Data Input, Sample Processing, Result
Calculation, Result Reporting, Quality
Control, Infrastructure (power, water
supply) | Same |
| PC (Controller
Unit) Functions | Data Input (Keyboard, Disc), Data
Output (Screen, printer) | Data Input (Touch screen,
Disc), Data Output (Screen,
printer) |
| Core Unit
Functions | Real time database, data input and
output (via HOST communication),
control of sample conveyer | Same |
| Analytical Unit(s)
Functions | Control of analytic processes (pipetting,
incubation, detection) Primary Signal
processing | Same |
| Data Storage | Real time database in Core Unit (storage
of System and Application parameters,
Calibration Data, QC Data, Sample
Results, Alarm history) | Same |
Table 2: Substantial Equivalency System
13
| Topic | cobas 6000 Analyzer Series
(K060373) | cobas pro integrated
solutions
(K191899) |
|--------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|
| Result
Calculation | Automated measuring of signal using
various methods according to automated
calculation of concentration via
calibration curve | Same |
| Flagging of errors | Available | Same |
| Units Controlled | cobas c 501 (with integrated ISE) and
cobas e 601-analyzers | cobas c 503, cobas e 801,
and cobas pro ISE analyzers |
| Initial cassette
volume check
(ICVC) for
reagent pipetting | Available | Same |
| Data concept
(Application
parameter,
calibrator, control
value transfer) | Electronic transfer possible (user must
accept transfer before parameter applied) | Same |
Table 3: Substantial Equivalency Glucose HK Gen. 3
| Item | Glucose HK Gen. 3
( c 501 in cobas 6000 core)
K060373 | Glucose HK Gen. 3
(c 503 in cobas pro core)
K191899 |
|-------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|
| Proprietary name | Glucose HK Gen. 3 | Glucose HK Gen. 3 |
| Catalog number | 04404483190 | 08057800190 |
| Intended use | In vitro test for the
quantitative determination
of glucose in human serum,
plasma, urine and CSF on
Roche/Hitachi cobas c
systems. | In vitro test for the quantitative
determination of glucose in
human serum, plasma, urine and
CSF on Roche/Hitachi cobas c
systems. |
| Technology | Photometric | Same |
| Test format | Enzymatic | Same |
| Test type | Quantitative | Same |
| Assay protocol | R1+R2+Diluent+Sample,
incubation | Same |
| Pipetting volume sample | 15 µL | Same |
| Pipetting volume R1 | 28 µL | Same |
| Pipetting volume R2 | 10 µL | Same |
| | Serum, plasma, urine and
CSF | Same |
14
| Item | Glucose HK Gen. 3
(c 501 in cobas 6000 core)
K060373 | Glucose HK Gen. 3
(c 503 in cobas pro core)
K191899 |
|-----------------------|------------------------------------------------------------|-----------------------------------------------------------|
| Handling of R1 and R2 | Liquid, ready to use | Same |
| Measuring Range | 0.11-41.6 mmol/L | Same |
Table 4: Substantial Equivalency ISE indirect Na for Gen.2
| Item | cobas c 501 ISE
(in cobas 6000 core)
K060373 | cobas pro ISE
(in cobas pro core)
K191899 |
|---------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Proprietary name | ISE indirect Na | ISE indirect Na |
| Intended use | The ISE analytical unit of the
Roche/Hitachi cobas c systems
is intended
for the quantitative
determination of sodium in
serum, plasma or urine using | 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. | ion- selective electrodes. |
| Technology | ISE Potentiometry | Same |
| Test type | Quantitative | Same |
| Typical sample
volumes | 9.7 µL 15 µL | 9.7 µL 15 µL |
| Default ISE
Dilution ratio
1:31 | 1:31
(9.7uL sample + 291uL
Diluent) | Same
(15 uL sample + 450uLDiluent) |
| Sample types | Serum, plasma, urine | Same |
| Sample handling
system | Input of samples via core input
buffer using universal sample
racks | Same |
| Measuring Range | Serum/Plasma: 80-180
mmol/L
Urine: 20-250 mmol/L | Same |
Table 5: Substantial Equivalency Elecsys TSH
| Item | Elecsys TSH
(e 801 in cobas 8000 core)
K190773 | Elecsys TSH
(e 801 in cobas pro core)
K191899 |
|----------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Proprietary name | Elecsys TSH | Elecsys TSH |
| Catalog number | 08429324160 | 08429324160 |
| Item | Elecsys TSH
( e 801 in cobas 8000 core)
K190773 | Elecsys TSH
(e 801 in cobas pro core)
K191899 |
| Intended use | Elecsys TSH immunoassay 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 Elecsys TSH
immunoassay is an
electrochemiluminescence
immunoassay “ECLIA”,
which is intended for use on
the cobas e immunoassay
analyzers. | 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 the
cobas e immunoassay
analyzers. |
| Technology | ECLIA | Same |
| Test format | Sandwich | Same |
| Test type | Quantitative | Same |
| Assay protocol | R1+R2+sample, incubation,
+beads, incubation | Same |
| Pipetting volume
sample | 50 μL | Same |
| Pipetting volume
beads | 40 μL | Same |
| Pipetting volume R1 | 60 μL | Same |
| Pipetting volume R2 | 50 μL | Same |
| Handling of R1 and
R2 | Liquid, ready to use | Same |
| Buffer composition R1 | phosphate buffer 100 mmol/L | Same |
| Biotinylated antibody | MAKM-TU1.20-
F(ab')2-Bi(DDS*,mono) | MAKM-TU1.20-
F(ab')2-Bi(PEG24**,mono) |
| Buffer composition R2 | phosphate buffer 100 mmol/L
Anti-Biotin Antibody; specific
for free, unconjugated biotin
( | |
15
16
4. NON-CLINICAL PERFORMANCE EVALUATION
The non-clinical performance studies for the Glucose HK, ISE indirect Na and Elecsys TSH are summarized below.
4.1. Precision
Precision was performed based on guidance from the Clinical and Laboratory Standards Institute (CLSI) document EP05-A3. A summary of results for each assay is presented below.
Glucose HK Gen.3: Repeatability and Intermediate Precision
The precision of the Glucose HK Gen.3 was evaluated on one cobas c 503 analytical unit with one reagent lot. The protocol consisted of testing 2 replicates of each control (PreciControl ClinChem Multi 1 and PreciControl ClinChem Multi 2) and human serum per run, 2 runs per day for 21 days. The samples were run in randomized order on the analyzer. Human serum samples used were all native, single donors as well as pools. The protocol was repeated for urine and CSF applications. The Repeatability and Intermediate precision were calculated according to EP05-A3. All samples met the predetermined acceptance criterion. The data presented in the tables below is the worst precision result of the 3 lots.
| Repeatability and Intermediate Precision | |||||
|---|---|---|---|---|---|
| Repeatability | |||||
| Serum Application (N=84) | Mean Value | SD | CV % | ||
| Specimen | mmol/L | mg/dL | mmol/L | mg/dL | CV % |
| PreciControl ClinChem Multi 1 | |||||
| (PCCC1) | 5.61 | 101 | 0.0315 | 0.568 | 0.6 |
| PreciControl ClinChem Multi 2 | |||||
| (PCCC2) | 12.6 | 227 | 0.0523 | 0.942 | 0.4 |
| Serum 1 | 0.188 | 3.39 | 0.0174 | 0.313 | 9.2 |
| Serum 2 | 3.57 | 64.3 | 0.0181 | 0.326 | 0.5 |
| Serum 3 | 5.46 | 98.4 | 0.0233 | 0.420 | 0.4 |
| Serum 4 | 19.6 | 353 | 0.121 | 2.18 | 0.6 |
Table 6: Glucose HK Gen.3 Summary of Repeatability and Intermediate Precision Results
17
| Serum 5 | 38.6 | 696 | 0.188 | 3.39 | 0.5 |
|---|---|---|---|---|---|
| Urine Application (N=84) | Mean Value | SD | CV % | ||
| Specimen | mmol/L | mg/dL | mmol/L | mg/dL | |
| LyQ_UR1 | 1.09 | 19.6 | 0.0215 | 0.387 | 2.0 |
| LyQ_UR2 | 16.4 | 296 | 0.0655 | 1.18 | 0.4 |
| Urine 1 | 0.227 | 4.09 | 0.0188 | 0.339 | 8.3 |
| Urine 2 | 0.733 | 13.2 | 0.0143 | 0.258 | 1.9 |
| Urine 3 | 4.10 | 73.9 | 0.0418 | 0.753 | 1.0 |
| Urine 4 | 22.0 | 396 | 0.182 | 3.28 | 0.8 |
| Urine 5 | 40.6 | 732 | 0.173 | 3.12 | 0.4 |
| CSF Application (N=84) | Mean Value | SD | CV % | ||
| Specimen | mmol/L | mg/dL | mmol/L | mg/dL | |
| LiQ_CSF1 | 3.31 | 59.6 | 0.0119 | 0.214 | 0.4 |
| LiQ_CSF2 | 1.66 | 29.9 | 0.00970 | 0.175 | 0.6 |
| CSF 1 | 0.273 | 4.92 | 0.00831 | 0.150 | 3.0 |
| CSF 2 | 2.16 | 38.9 | 0.0180 | 0.324 | 0.8 |
| CSF 3 | 3.81 | 68.7 | 0.0172 | 0.310 | 0.5 |
| CSF 4 | 20.2 | 364 | 0.0824 | 1.48 | 0.4 |
| CSF 5 | 39.9 | 719 | 0.193 | 3.48 | 0.5 |
| Intermediate | |||||
| Serum Application (N=84) | Mean Value | SD | CV % | ||
| Specimen | mmol/L | mg/dL | mmol/L | mg/dL | |
| PreciControl ClinChem Multi 1 | |||||
| (PCCC1) | 5.61 | 101 | 0.0559 | 1.007 | 1.0 |
| PreciControl ClinChem Multi 2 | |||||
| (PCCC2) | 12.8 | 231 | 0.106 | 1.910 | 0.8 |
| Serum 1 | 0.188 | 3.39 | 0.0188 | 0.339 | 10.0 |
| Serum 2 | 3.57 | 64.3 | 0.0212 | 0.382 | 0.6 |
| Serum 3 | 5.46 | 98.4 | 0.0297 | 0.535 | 0.5 |
| Serum 4 | 19.6 | 353 | 0.136 | 2.45 | 0.7 |
| Serum 5 | 38.6 | 696 | 0.216 | 3.89 | 0.6 |
| Urine Application (N=84) | Mean Value | SD | CV % | ||
| Specimen | mmol/L | mg/dL | mmol/L | mg/dL | |
| LyQ_UR1 | 1.09 | 19.6 | 0.0278 | 0.501 | 2.5 |
| LyQ_UR2 | 16.4 | 296 | 0.122 | 2.20 | 0.7 |
| Urine 1 | 0.215 | 3.87 | 0.0183 | 0.330 | 8.5 |
| Urine 2 | 0.744 | 13.4 | 0.0180 | 0.324 | 2.4 |
| Urine 3 | 4.07 | 73.3 | 0.0478 | 0.861 | 1.2 |
| Urine 4 | 22.0 | 396 | 0.452 | 8.15 | 2.1 |
| Urine 5 | 40.4 | 728 | 0.344 | 6.20 | 0.8 |
| CSF Application (N=84) | Mean Value | SD | CV % | ||
| Specimen | mmol/L | mg/dL | mmol/L | mg/dL | CV % |
| LiQ_CSF1 | 3.34 | 60.2 | 0.0163 | 0.294 | 0.5 |
| LiQ_CSF2 | 1.66 | 29.9 | 0.0109 | 0.196 | 0.7 |
| CSF 1 | 0.273 | 4.92 | 0.00966 | 0.174 | 3.5 |
| CSF 2 | 2.16 | 38.9 | 0.0212 | 0.382 | 1.0 |
| CSF 3 | 3.81 | 68.7 | 0.0240 | 0.432 | 0.6 |
| CSF 4 | 20.2 | 364 | 0.0994 | 1.79 | 0.5 |
| CSF 5 | 39.9 | 719 | 0.230 | 4.14 | 0.6 |
18
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.
19
| 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
20
| Intermediate Precision | |||
|---|---|---|---|
| Specimen (Li Hep Plasma) | |||
| (N=84) | Mean Concentration (mmol/L) | SD (mmol/L) | CV (%) |
| PreciControl ClinChem Multi 1 | 111 | 0.967 | 0.9 |
| PreciControl ClinChem Multi 2 | 134 | 0.902 | 0.7 |
| Sample 1 | 84.7 | 1.25 | 1.5 |
| Sample 2 | 129 | 0.879 | 0.7 |
| Sample 3 | 135 | 0.931 | 0.7 |
| Sample 4 | 149 | 0.821 | 0.6 |
| Sample 5 | 174 | 0.950 | 0.5 |
| Specimen (Serum) (N=84) | Mean Concentration (mmol/L) | SD (mmol/L) | CV (%) |
| PreciControl ClinChem Multi 1 | 111 | 1.16 | 1.0 |
| PreciControl ClinChem Multi 2 | 134 | 1.07 | 0.8 |
| Sample 1 | 83.0 | 1.38 | 1.7 |
| Sample 2 | 131 | 0.930 | 0.7 |
| Sample 3 | 135 | 1.02 | 0.8 |
| Sample 4 | 150 | 0.802 | 0.5 |
| Sample 5 | 173 | 0.948 | 0.5 |
| Specimen (Urine) (N=84) | Mean Concentration (mmol/L) | SD (mmol/L) | CV (%) |
| Liquichek 1 | 78.1 | 1.06 | 1.4 |
| Liquichek 2 | 175 | 1.05 | 0.6 |
| Sample 1 | 24.8 | 1.19 | 4.8 |
| Sample 2 | 136 | 0.941 | 0.7 |
| Sample 3 | 111 | 0.941 | 0.8 |
| Sample 4 | 204 | 1.23 | 0.6 |
| Sample 5 | 241 | 1.63 | 0.7 |
Elecsys TSH: Repeatability and Intermediate Precision
Precision of the Elecsys TSH assay was evaluated on one cobas e 801 immunoassay analyzer with one reagent lot. The protocol consisted of testing 2 replicates of each control (PreciControl Universal and PC Thyro Sensitive) and human sera (HS) per run, 2 runs per day for 21 days. The samples were run in randomized order on the analyzer. Human serum samples used were all native, single donors as well as pools. Repeatability and Intermediate imprecision were calculated according to EP05-A3. All samples met the predetermined acceptance criterion. The following table summarizes the precision data for the Elecsys TSH.
21
Precision of the Elecsys TSH assay was evaluated on one cobas e 801 immunoassay analyzer with one reagent lot.
| Repeatability | Intermediate precision | ||||
|---|---|---|---|---|---|
| Sample (N=84) | Mean | ||||
| (µIU/mL) | SD | ||||
| (µIU/mL ) | CV (%) | SD | |||
| (µIU/mL ) | CV (%) | ||||
| Human serum 1 | 0.0133 | 0.000829 | 6.3 | 0.00155 | 11.7 |
| Human serum 2 | 0.262 | 0.00447 | 1.7 | 0.00722 | 2.8 |
| Human serum 3 | 3.95 | 0.0661 | 1.7 | 0.123 | 3.1 |
| Human serum 4 | 57.3 | 1.50 | 2.6 | 2.24 | 3.9 |
| Human serum 5 | 93.1 | 2.64 | 2.8 | 4.29 | 4.6 |
| PC Universal 1 | 1.32 | 0.023 | 1.7 | 0.0319 | 2.4 |
| PC Universal 2 | 8.00 | 0.142 | 1.8 | 0.234 | 2.9 |
| PC Thyro Sensitive | 0.168 | 0.00274 | 1.6 | 0.00488 | 2.9 |
Table 8: Summary of Repeatability and Intermediate Precision Results
4.2. Analytical Sensitivity
Limit of Blank (LoB), Limit of Detection (LoD) and Limit of Quantitation (LoQ)
The Limit of Blank, Limit of Detection and Limit of Quantitation were determined in accordance with the CLSI (Clinical and Laboratory Standards Institute) EP17 A2 requirements.
The Limit of Blank is the 95th percentile value from n ≥ 60 measurements of analyte- free samples over several independent series. The Limit of Blank corresponds to the concentration below which analyte- free samples are found with a probability of 95 %. The Limit of Blank was determined on the respective analytical unit, six runs on ≥ three days, with five blank samples with two replicates each per run. In total, 60 determinations for analyte free samples have been obtained.
The Limit of Detection was determined based on the Limit of Blank and the standard deviation of low concentration samples. The Limit of Detection corresponds to the lowest analyte concentration which can be detected (value above the Limit of Blank with a probability of 95%). The Limit of Detection was determined on the respective analytical unit, five samples
22
with low-analyte concentration was measured in two-fold determination in 6 runs, distributed over 3 days. In total 60 measurements were obtained per sample type.
LoQ determines the lowest amount of analyte that can be quantitatively determined with stated accuracy and stated experimental conditions. The LoO was determined as the lowest concentration of analyte which can be quantified with a total error of no more than 20% (Glucose and TSH) and 30% (Sodium).
Samples with low analyte concentration are measured over 3 to 5 days on the respective analyzer (n ≥ 60 per sample type). The mean value, SD, and %TE (total error) were calculated for each sample. The mean concentration is plotted versus the %TE, with LoQ determined at maximum allowable %TE.
A summary of empirical results for Glucose HK Gen. 3 is presented below in the following order: LoB, LoD and LoQ.
| Serum | Reagent Lot | LoB [mg/dL] |
|---|---|---|
| Lot 3 | 0.2 | |
| Lot 1 | 0.1 | |
| Lot 2 | 0.2 | |
| Urine | Reagent Lot | LoB [mg/dL] |
| Lot03 | 0.7 | |
| Lot01 | 0.3 | |
| Lot02 | 0.3 | |
| CSF | Reagent Lot | LoB [mg/dL] |
| Lot 3 | 0.2 | |
| Lot 1 | 0.2 | |
| Lot 2 | 0.2 |
23
| Serum | Reagent Lot | LoD [mg/dL] |
|---|---|---|
| Lot 3 | 0.4 | |
| Lot 1 | 0.3 | |
| Lot 2 | 0.4 | |
| Urine | Reagent Lot | LoD [mg/dL] |
| Lot03 | 1.0 | |
| Lot01 | 0.6 | |
| Lot02 | 0.6 | |
| CSF | Reagent Lot | LoD [mg/dL] |
| Lot 3 | 0.3 | |
| Lot 1 | 0.3 | |
| Lot 2 | 0.3 |
| Serum/Plasma | Reagent Lot | LoQ [mg/dL] |
|---|---|---|
| Lot 3 | 1.3 | |
| Lot 1 | 1.3 | |
| Lot 2 | 1.4 | |
| Urine | Reagent Lot | LoQ [mg/dL] |
| Lot03 | 1.4 | |
| Lot01 | 1.3 | |
| Lot02 | 1.5 | |
| CSF | Reagent Lot | LoQ [mg/dL] |
| Lot 3 | 1.1 | |
| Lot 1 | 1.1 | |
| Lot 2 | 1.2 |
The results and labeling Claim for Glucose HK Gen.3
| Result | Claim | |
|---|---|---|
| Limit of Blank (LoB) | 0.2 mg/dL (0.011 mmol/L) | 2 mg/dL (0.11 mmol/L) |
| Limit of Detection (LoD) | 0.4 mg/dL (0.022 mmol/L) | 2 mg/dL (0.11 mmol/L) |
| Limit of Quantitation (LoQ) | 1.4 mg/dL (0.078 mmol/L) | 2 mg/dL (0.11 mmol/L) |
A summary of empirical results for ISE indirect Na for Gen.2 is presented below in the following order: LoB, LoD and LoQ.
24
| Sample Type | Electrode Lot | LoB [mmol/L] |
|---|---|---|
| Plasma | E9012 | 3.50 |
| Serum | E9012 | 3.50 |
| Urine | E9012 | 3.50 |
| Sample Type | Electrode Lot | LoD [mmol/L] |
|---|---|---|
| Plasma | E9012 | 4.44 |
| Serum | E9012 | 4.42 |
| Urine | E9012 | 4.51 |
| Sample Type | Electrode Lot | LoQ [mmol/L] |
|---|---|---|
| Plasma | E9012 | 11.8 |
| Serum | E9012 | 12.1 |
| Urine | E9012 | 12.2 |
Labeling Claim for ISE indirect Na for Gen.2 as stated in the method sheet:
- Limit of Blank = 3.5 mmol/L .
- Limit of Detection = 4.5 mmol/L ●
- Limit of Quantitation = 12.2 mmol/L .
A summary of empirical results for Elecsys TSH is presented below in the following order: LoB, LoD and LoQ.
| Reagent Lot | LoB (µIU/mL) |
|---|---|
| 344546 | 0.0013 |
| 344548 | 0.0015 |
| 344550 | 0.0014 |
| Reagent Lot | LoD (μIU/mL) |
|---|---|
| ------------- | -------------- |
25
| 344546 | 0.00282 |
|---|---|
| 344548 | 0.00348 |
| 344550 | 0.00312 |
| Reagent Lot | LoQ (µIU/mL) |
|---|---|
| 344546 | 0.00410 |
| 344548 | 0.00386 |
| 344550 | 0.00495 |
Labeling Claim for Elecsys TSH as stated in the method sheet:
- Limit of Blank = 0.0025 µIU/mL .
- Limit of Detection = 0.005 µIU/mL .
- . Limit of Quantitation = 0.005 μIU/mL
4.3. Linearity/Assay Reportable Range
Glucose HK Gen.3 (GLUC3)
Linearity was determined based on guidance from Clinical and Laboratory Standards Institute (CLSI) document EP06-A. Three high analyte human serum, urine and CSF samples were diluted to 12 levels covering the measuring range and were then measured. The aliquots were assayed in 3-fold determination within a single run. All deviations were within predetermined acceptance criteria. Linearity for serum, urine and CSF samples was confirmed in the claimed measuring range from 2.0 to 750 mg/dL (0.11 to 41.6 mmol/L).
Glucose HK Gen.3 (GLUC3)
- Serum: The mean observed linear range concentrations ranged from 0.0 to 783.0 mg/dL ● for the sample set. The correlation with the expected concentrations according to the linear regression formulas: Serum: y = 0.999(x) + 0.00856; R2 = 0.9999.
26
- . Urine: The mean observed linear range concentrations ranged from 0.0 to 788.4 mg/dL for the sample set. The correlation with the expected concentrations according to the linear regression formulas: Urine: y = 0.999(x) + 0.00435; R2 = 0.9997.
- . CSF: The mean observed linear range concentrations ranged from 0.00 to 829.8 mg/dL for the sample set. The correlation with the expected concentrations according to the linear regression formulas: CSF: y = 0.998(x) + 0.0126; R2 = 0.9992
ISE indirect Na for Gen.2
Linearity was determined based on guidance from Clinical and Laboratory Standards Institute (CLSI) document EP06-A. Three high analyte human serum, urine and CSF samples were diluted to multiple aliquot concentrations covering the measuring range and were then measured. The aliquots were assayed in 3-fold determination within a single run. All deviations were within predetermined acceptance criteria. Linearity for Lithium heparin plasma and serum, and urine samples was confirmed in the claimed measuring range from 80-180 mmol/L and 20-250 mmol/L respectively.
- . Plasma: The mean observed linear range concentrations ranged from 75.2 to 185 mmol/L for the sample set. The correlation with the expected concentrations according to the linear regression formulas: Plasma: y = 1.000(x) + 0.0; R2 = 0.9998.
- . Serum: The mean observed linear range concentrations ranged from 75.7 to 186 mmol/L for the sample set. The correlation with the expected concentrations according to the linear regression formulas: Serum: y = 1.000(x) + 0.0; R2 = 0.9998.
- . Urine: The mean observed linear range concentrations ranged from 13.7 to -265 mmol/L for the sample set. The correlation with the expected concentrations according to the linear regression formulas: Urine: y = 1.000(x) + 0.0; R2 = 0.9999.
Elecsys TSH
Linearity of the Elecsys TSH assay was assessed on the cobas e 801 analytical unit according to CLSI EP06-A. Three high analyte human serum samples were diluted and concentrations covering the measuring range were measured. Samples were assayed in 3-fold determination within a single run.
27
- . Serum: The linear range for the three human serum samples is 0.004 - 118 uIU/mL. Elecsys TSH correlated with expected concentrations according to the linear regression formulas: Serum: y = 1.082(x) -0.000156; R2 = 0.9972
4.4. High Dose Hook Effect
The high-dose hook effect of the Elecsys TSH assay was assessed on the cobas e 801 analytical unit in one-fold determination. Three human serum samples were spiked with analyte to achieve high TSH concentrations. For each sample, a dilution series was performed. No hook effect up to 1466 uIU/mL TSH.
4.5. Endogenous Interference
The purpose of this study was to evaluate endogenous substances for potential interference with the parameters measured with the Glucose HK on cobas c 503, ISE indirect Na on cobas pro ISE, and Elecsys TSH on the cobas e 801 analytical units. All the endogenous substances met the acceptance criteria of recovery of 100±10%.
Glucose HK
The effect on quantitation of analyte in the presence of endogenous interfering substances using the Glucose HK Gen.3 (GLUC3) assay was determined on the cobas pro c 503 analytical unit using plasma and urine samples and conducted according to CLSI EP07-A2. Glucose levels of approximately 79.5 mg/dL and 116.3 mg/dL were tested and the summary of results is presented in the two tables below.
28
| Potential Interferent | No Interference up to approximately | |
|---|---|---|
| Plasma | Albumin | 74.3 g/L |
| Bilirubin | 78 mg/dL | |
| Ditaurobilirubin | 81 mg/dL | |
| Hemolysis | 1081 mg/dL | |
| IgG | 74.5g/L | |
| Lipemia | 1668 mg/dL | |
| Urine | Albumin | 2.50 g/L |
| Calcium | 12.0 mg/dL | |
| Citrate | 11.0 mg/dL | |
| Creatinine | 88.4 mg/dL | |
| Hemolysis | 1150 mg/dL | |
| IgG | 1.10 g/L | |
| Magnesium | 25.0 mg/dL | |
| Oxalate | 1.50 mg/dL | |
| Phosphate | 130 mg/dL | |
| Urea | 1800 mg/dL | |
| Uric Acid | 6.00 mg/dL | |
| Urobilinogen | 1.13 mg/dL |
ISE indirect Na
Endogenous interference
The effect on quantitation of analyte in the presence of endogenous interfering substances using the Sodium electrode was determined on the cobas pro ISE analytical unit using human plasma, serum, and urine samples. A low (approximately 124 mmol/L) and high (approximately 151 mmol/L) samples were tested. A low concentration of 26.3 mmol/L and a high concentration of 188 mmol/L were tested for urine application. The summary of results is presented in the table below.
| Potential Interferent | No Interference up to approximately | |
|---|---|---|
| Plasma | Bilirubin | 63 mg/dL |
| Ditaurobilirubin | 69 mg/dL | |
| Hemolysis | 1137 mg/dL | |
| Lipemia | 2326 mg/dL | |
| Serum | Bilirubin | 68.0 mg/dL |
| Ditaurobilirubin | 71.0 mg/dL | |
| Hemolysis | 1144 mg/dL | |
| Lipemia | 2206 mg/dL | |
| Urine | Hemolysis | 1141 mg/dL |
29
Exogenous interference
The effect on quantitation of analyte in the presence of exogenous interfering substances was determined at 125 and 158 mmol/L for Serum and at 30 and 200 mmol/L for Urine applications.
Two sample pools, containing a low and high concentration of ISE indirect Na are used. These sample pools are divided into an appropriate number of aliquots. One aliquot is not spiked with the drugs and it is used as the reference sample for ISE indirect Na concentration. The ISE indirect Na concentration in the sample is determined with n=3 measurements on a cobas pro ISE analytical unit.
The other sample aliquots, with either the high or low ISE indirect Na concentrations, are spiked with the respective amount of drug. The ISE indirect Na concentration of the spiked aliquots are determined in triplicate and the mean of the triplicate determinations is compared to the ISE indirect Na concentration determined for the reference aliquot (mean of n=3).
| Serum application | ||
|---|---|---|
| Interference | No Interference up to | |
| Acetaminophen (paracetamol) | 200 mg/L | |
| Acetylcysteine | 1660 mg/dL | |
| Acetylsalicylic acid | 1000 mg/L | |
| Ampicillin- Na | 1000 mg/L | |
| Ascorbic acid | 300 mg/L | |
| Cefoxitin | 2500 mg/L | |
| Cyclosporin | 5 mg/L | |
| Doxycycline | 50 mg/L | |
| Heparin | 5000 IU/L | |
| Ibuprofen | 500 mg/L | |
| Intralipid | 10000 mg/L | |
| L- Dopa | 20 mg/L | |
| Methyldopa | 20 mg/L | |
| Metronidazol | 200 mg/L | |
| Phenylbutazone | 400 mg/L | |
| Rifampicin | 60 mg/L |
30
| CENTRAL CONSULT CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONS
| l'heophylline | 100 mg/L |
|---|---|
| Urine application | ||
|---|---|---|
| Interference | No Interference up to | |
| Acetaminophen (paracetamol) | 3000 mg/L | |
| Acetylcysteine | 10 mg/dL | |
| Ascorbic acid | 4000 mg/L | |
| Gentamycin sulfate | 400 mg/L | |
| Ibuprofen | 4000 mg/L | |
| Levodopa | 1000 mg/L | |
| Methyldopa | 2000 mg/L | |
| Cefoxitin | 12000 mg/L | |
| Ofloxacine | 900 mg/L | |
| Phenazopyridine | 300 mg/L | |
| Salicyluric acid | 6000 mg/L | |
| Tetracycline | 300 mg/L |
Elecsys TSH
The serum samples may contain substances that could potentially interfere with the test. The following compounds were added to human serum samples with a low (approximately 0.462 uIU/mL), a mid (approximately 3.95 µIU/mL) and a high (approximately 7.54 µIU/mL) TSH concentration. One aliquot of each serum sample was spiked with the interfering substance, another aliquot was spiked with the same volume of isotonic NaCl solution (dilution pool). The interfering pool was then dilution pool in 10 % increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample. None of the serum samples showed any deviation from the expected results. No interference was observed for these compounds at the levels indicated below.
31
| Interference | Interference Substance |
|---|---|
| Biotin | 1200 mg/dL |
| Lipemia (Intralipid) | 2000 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Bilirubin | 66 mg/dL |
| Rheumatoid Factor (RF) | 1500 IU/mL |
| Immunoglobulin (IgG) | 3.98 g/dL |
| Immunoglobulin (IgM) | 0.730 g/dL |
Analytical Specificity/Cross-Reactivity 4.6.
The effect on quantitation of analyte in the presence of potential cross-reacting compounds using the Elecsys TSH was determined on the cobas e 801 analytical unit using a native human serum sample pool. For each potential cross-reacting compound a human serum sample with a low concentration level of TSH was tested. Results from these spiked serum samples were matched against the unspiked references and the % cross-reactivity was calculated. No cross reactivity was observed at the concentration tested.
Table 9: Summary of Cross-Reactivity
| Cross-reactant | Concentration tested (µIU/mL) | Cross-reactivity % |
|---|---|---|
| hGH | 10000000 | 0.000 |
| hCG | 50000000 | 0.000 |
| LH | 10000000 | 0.000 |
| FSH | 10000000 | 0.000 |
4.7. Exogenous Interferences - Drugs
The effect on quantitation of TSH in the presence of drugs was determined by comparing values obtained from samples spiked with 17 commonly and 13 specially used pharmaceutical compounds with the reference sample (unspiked). Two human serum samples (native serum pools) with analyte concentration approximately 0.5 and 8 uIU/mL were used and tested on the cobas e
32
801 analytical unit. The drug concentrations tested correspond at least to the three times maximum daily doses (or the one-time maximum daily dose, respectively). Drug interferences are measured based on recommendations given in CLSI guidelines EP07-ED3 and EP37-ED1 and other published literature. For all drugs tested, the specification of ± 10% of the reference value was met as each compound was found to be non-interfering at the drug concentration.
Table 10: Common Drugs
| Potential interfering commonly used
drugs | Highest interferent concentration tested at which no significant
interference was observed (mg/L) |
|----------------------------------------------|------------------------------------------------------------------------------------------------------|
| Acetylcysteine | 150 |
| Ampicillin - Na | 75 |
| Ascorbic acid | 52.5 |
| Cyclosporine | 1.8 |
| Cefoxitin | 750 |
| Heparin | 3300 IU/mL |
| Levodopa | 7.5 |
| Methyldopa | 22.5 |
| Metronidazole | 123 |
| Phenylbutazone | 321 |
| Doxycycline | 18 |
| Acetylsalicylic acid | 30 |
| Rifampicin | 48 |
| Acetaminophen | 156 |
| Ibuprofen | 219 |
| Theophylline | 60 |
| Itraconazole | 10 |
33
Table 11: Special Drugs
| Drug | Highest interferent concentration tested at which no
significant interference was observed (mg/L) |
|------------------|------------------------------------------------------------------------------------------------------|
| Amiodarone | 200 |
| Carbimazole | 30 |
| Fluocortolone | 100 |
| Hydrocortisone | 200 |
| Iodide | 0.2 |
| Levothyroxine | 0.25 |
| Liothyronine | 0.075 |
| Methimazole | 80 |
| Octreotide | 0.3 |
| Prednisolone | 100 |
| Propranolol | 240 |
| Propylthiouracil | 300 |
| Perchlorate | 2000 |
Method Comparison to Predicate 4.8.
Glucose HK
A method comparison was performed using the Glucose HK Gen.3 (GLUC3) assay (c 503, Y) and the predicate, Glucose HK Gen.3 (GLUC3) assay on the cobas c 501 analyzer(X) to assess the bias between the two analytical units in two different cores. A total of 74 native human serum samples, 67 native human urine samples and 75 native CSF samples were measured in singlicate on the cobas c 503 analyzer in one run covering the entire measuring range.
A summary of results is presented in the table below.
34
| Method | Sample Type
(number of
samples) | Passing/Bablok
(Slope & Intercept)
and correlation
(Kendall tau ( t)) | Linear Regression
(Slope & Intercept)
and correlation
(Pearson ( r )) | Sample
concentration
range
(mg/dL) |
|--------------------------------|---------------------------------------|--------------------------------------------------------------------------------|--------------------------------------------------------------------------------|---------------------------------------------|
| cobas c 503 vs. cobas
c 501 | Serum (74) | 1.000x - 0.0200
t = 0.987 | 0.997x - 0.00454
r = 1.000 | 5.8 - 725.4 |
| cobas c 503 vs cobas
c 501 | Urine (67) | 0.995x - 0.0447
t = 0.982 | 0.995x - 0.0402
r = 1.000 | 3.1 - 736.2 |
| cobas c 503 vs cobas
c 501 | CSF (75) | 1.000x + 0.00400
t = 0.957 | 1.001x + 0.0287
r = 0.999 | 3.6 - 734.4 |
Table 12: Summary of Method Comparison
ISE indirect Na
A method comparison was performed using the ISE indirect Na assay (on cobas pro ISE in cobas pro core, Y) and the predicate device, cobas c 501 ISE, X) to assess the bias between the two test systems. Additionally, the results of the candidate test system were compared against flame photometry. A total of 120 human Lithium heparin plasma samples for cobas pro ISE versus cobas c 501 ISE, 118 human Lithium heparin plasma for cobas pro ISE vs Flame Photometer, 120 human serum for cobas pro ISE vs c 501 ISE, 120 human serum versus Flame Photometer and 120 human urine were measured in singleton on the cobas pro ISE analyzer in one run covering the entire measuring range.
| Table 13: Summary of Method Comparison | |||
|---|---|---|---|
| ---------------------------------------- | -- | -- | -- |
| cobas pro ISE vs | Sample Type
(number of
samples) | Passing/Bablok
(Slope &
Intercept) and
correlation
(Pearson ( r )) | Sample
concentration
range (mmol/L) |
|------------------|---------------------------------------|--------------------------------------------------------------------------------|-------------------------------------------|
| cobas c 501 ISE | Plasma (120) | $1.003x - 1.72$
r = 1.000 | 84.2-177 |
| Flame Photo. | Plasma (118) | $1.031x - 4.12$
r = 0.997 | 80.4-175 |
| cobas c 501 ISE | Serum (120) | $1.027x - 4.38$
r = 1.000 | 84.4 -175 |
| Flame Photo. | Serum (120) | $1.016x - 1.11$
r = 0.996 | 81.3 -174 |
| cobas c 501 ISE | Urine (120) | $1.019x - 2.90$
r = 1.000 | 25.5-241 |
| Flame Photo. | Urine (120) | $0.993x - 2.46$ | 22.5-249 |
35
| r = 1.000 | |||
|---|---|---|---|
| -- | -- | ----------- | -- |
Elecsys TSH
A method comparison was performed using the Elecsys TSH assay (on cobas e 801 in cobas pro core, Y) and the Elecsys TSH assay (on cobas e 801 in cobas 8000 core, X) to assess the bias between the two test systems. A total of 138 samples (129 native human serum samples and 9 diluted human serum samples, single donors as well as pools diluted) were measured in singleton on each cobas e 801 analytical unit in one run covering the entire measuring range.
| N | 138 |
|---|---|
| Range ( $\mu$ IU/mL) | 0.006 – 97.8 |
| Slope | 1.018 |
| (LCL / UCL) | (1.004 / 1.025) |
| Intercept ( $\mu$ IU/mL) | -0.0018 |
| (LCL / UCL) | (-0.0040 /- 0.0001) |
| Correlation coefficient, Pearson (r) | 0.999 |
| Correlation coefficient, Kendall (tau) | 0.977 |
| Bias at 0.27 $\mu$ IU/mL | 1.2% |
| (LCL / UCL) | (0.0%/ 1.8%) |
| Bias at 4.2 $\mu$ IU/mL | 1.8% |
| (LCL / UCL) | (0.4% / 2.5%) |
4.9. Sample Matrix Comparison
Glucose HK
The effect on quantitation of analyte in the presence of anticoagulants with the Glucose HK Gen. 3 assay was determined by comparing values obtained from samples (native human serum samples, single donors drawn into serum/gel separation tubes and K2-EDTA, Li-Heparin, NaF/K-Oxalate NaF/Na2-EDTA, NaF/Citrate/Na2-EDTA and KF/Na2-EDTA plasma tubes).
The recovery of analyte values in the presence of anticoagulants with the Glucose HK Gen.3 assay was determined on the cobas c 503 analytical unit by comparing values obtained from samples drawn into serum and plasma collection tubes. The recovery of each plasma sample to the matching
36
serum sample was calculated. At least 39 serum/plasma pairs were tested for each kind of anticoagulant in single determination.
| Table 15: Summary of Matrix Comparison | ||
|---|---|---|
| Matrix Comparison (Passing/Bablok) | ||
|---|---|---|
| Serum vs Serum Tube with | ||
| Separation Gel | N | |
| Range | ||
| Slope | ||
| Intercept | ||
| Correlation coefficient r | 39 | |
| 3.6 - 694.8 mg/dL | ||
| 1.000 | ||
| 0.00500 | ||
| 0.999 | ||
| Serum tube vs K2EDTA Plasma | ||
| Tube | N | |
| Range | ||
| Slope | ||
| Intercept | ||
| Correlation coefficient r | 52 | |
| 3.6 - 694.8 mg/dL | ||
| 1.005 | ||
| -0.0108 | ||
| 0.998 | ||
| Serum tube vs Lithium Heparin | ||
| Plasma Tube | N | |
| Range | ||
| Slope | ||
| Intercept | ||
| Correlation coefficient r | 51 | |
| 3.6 - 694.8 mg/dL | ||
| 1.007 | ||
| -0.0274 | ||
| 0.998 | ||
| Serum tube vs NaF/K-Oxalate | ||
| Plasma Tube | N | |
| Range | ||
| Slope | ||
| Intercept | ||
| Correlation coefficient r | 50 | |
| 3.6 - 694.8 mg/dL | ||
| 1.006 | ||
| -0.0100 | ||
| 0.998 | ||
| Serum tube vs NaF/ Na2-EDTA | ||
| Plasma Tube | N | |
| Range | ||
| Slope | ||
| Intercept | ||
| Correlation coefficient r | 50 | |
| 3.6 - 694.8 mg/dL | ||
| 1.020 | ||
| -0.0241 | ||
| 0.998 | ||
| Serum tube vs NaF/Citrate/ Na2- | ||
| EDTA Plasma Tube | N | |
| Range | ||
| Slope | ||
| Intercept | 50 | |
| 3.6 - 694.8 mg/dL | ||
| 1.035 | ||
| -0.104 |
37
| Matrix Comparison (Passing/Bablok) | ||
|---|---|---|
| Correlation coefficient r | 0.998 | |
| N | 52 | |
| Serum tube vs KF/Na2-EDTA | ||
| Plasma Tube | Range | 3.6 – 694.8 mg/dL |
| Slope | 0.996 | |
| Intercept | -0.0367 | |
| Correlation coefficient r | 1.000 |
ISE indirect Na
The effect on quantitation of analyte in the presence of anticoagulants with the ISE indirect Na was determined by comparing values obtained from samples drawn into serum and Li-Heparin plasma tubes. A total of 50 serum/ Li-Heparin plasma pairs per sample material were tested in singleton with one reagent lot on one cobas pro ISE analytical unit. Data were evaluated using a regression analysis according to Passing/Bablok.
Table 16: Summary of Matrix Comparison
| Matrix Comparison (Passing/Bablok) | ||
|---|---|---|
| N | 50 | |
| Range | 83.1 – 174 mmol/L | |
| Serum/Li-Heparin | Slope | 1.015 |
| Intercept | -2.69 | |
| Correlation coefficient r | 0.998 |
Elecsys TSH
The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys TSH immunoassay was determined by comparing values obtained from samples (native human serum samples, single donors as well as pools) drawn into serum and Li-Heparin, K2-EDTA, K3-EDTA plasma tubes. A minimum of 56 serum/plasma pairs per sample material were tested in singleton with one reagent lot on one cobas e 801 analyzer. Data were evaluated using a regression analysis according to Passing/Bablok. Serum separation tubes from 3 separate manufacturers and blood from five donors were used. Measurements were performed in duplicate with one reagent lot and
38
evaluated on the basis of recovery relative to the serum / plasma tube without separating gel (reference).
| Matrix Comparison (Passing/Bablok) | ||
|---|---|---|
| N | 50 | |
| Serum/Li-Heparin Plasma | Range | 0.006 – 97.1 µIU/mL |
| Slope | 0.982 | |
| Intercept | 0.0002 µIU/mL | |
| Correlation coefficient r | 0.999 | |
| Bias at 0.2 µIU/mL | -1.7 % | |
| Bias at 2.5 µIU/mL | -1.8 % | |
| N | 51 | |
| Serum/K2-EDTA Plasma | Range | 0.006 – 97.1 µIU/mL |
| Slope | 0.977 | |
| Intercept | -0.0015 µIU/mL | |
| Correlation coefficient r | 1.000 | |
| Bias at 0.2 µIU/mL | -2.8 % | |
| Bias at 2.5 µIU/mL | -2.3 % | |
| N | 51 | |
| Serum/K3-EDTA Plasma | Range | 0.006 – 97.1 µIU/mL |
| Slope | 0.971 | |
| Intercept | -0.0123 µIU/mL | |
| Correlation coefficient r | 1.000 | |
| Bias at 0.2 µIU/mL | -7.5 % | |
| Bias at 2.5 µIU/mL | -3.2 % |
Table 17: Summary of Matrix Comparison
4.10. Stability
The stability data for Glucose HK Gen.3, ISE indirect Na and Elecsys TSH was provided in K061048, K060373, and K190773 respectively. The stability data supports Roche Diagnostic's claims as reported in the package inserts.
39
Conclusion 4.11.
Based on the analytical testing results and acceptance characteristics including sensitivity, precision, specificity, interference and method comparison of the device, it is concluded that Glucose, ISE indirect Na, TSH and the cobas pro integrated solutions are substantially equivalent to the predicate devices.