K Number
K063744
Manufacturer
Date Cleared
2007-01-17

(30 days)

Product Code
Regulation Number
862.1110
Reference & Predicate Devices
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
Intended Use

In vitro test for the quantitative determination of total bilirubin in human serum and plasma on the cobas c 111 system.

Measurements of the levels of bilirubin and organic compound formed during normal and abnormal destruction of red cells, is used in the diagnosis of liver, hemolytic hematological and metabolic disorders, including hepatitis and gall bladder block.

Device Description

The Total Bilirubin Special reagent is intended for use on the cobas c 111 analyzer for the quantitative determination of total or direct bilirubin in serum and plasma.

The cobas c 111 analyzer is a partially automated, in-vitro diagnostic analyzer capable of performing clinical chemistry, specific protein and electrolyte tests. Analytes are measured photometrically or turbidimetrically; the analyzer also has an optional ISE module for measuring sodium, potassium and chloride.

The cobas c 111 instrument is a random access analyzer designed to be operated on a bench top in the professional environment using a combination of a photometric analysis unit and an optional ion selective electrodes (ISE).

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the Total Bilirubin Special reagent application to the cobas c 111 analyzer, based on the provided text:

Context: This submission is a Special 510(k) for a modification to an existing device. The modification involves applying the already cleared Total Bilirubin Special reagent to a new analyzer, the cobas c 111, which is itself a modification of the COBAS INTEGRA 400 plus. Therefore, the primary focus of the performance data is to demonstrate equivalence of the reagent's performance on the new analyzer compared to its performance on the predicate analyzer.


Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by demonstrating equivalence to the predicate device. The performance characteristics of the modified device (on cobas c 111) are compared to the predicate device (on COBAS INTEGRA Total Bilirubin Special, K063543).

Acceptance Criteria (Implicit: Equivalence to Predicate)Reported Device Performance (Modified Device: Total Bilirubin Special on cobas c 111)Predicate Device Performance (COBAS INTEGRA Total Bilirubin Special)
Precision (Within-run)1.79% @ 21.7 µmol/L2.44% @ 15.80 µmol/L
0.64% @ 64.2 µmol/L1.39% @ 54.00 µmol/L
2.94% @ 15.2 µmol/L(Not explicitly within-run for this level)
0.77% @ 60.0 µmol/L(Not explicitly within-run for this level)
Precision (Total)2.32% @ 21.6 µmol/L(Not explicitly "Total")
0.71% @ 67.4 µmol/L(Not explicitly "Total")
3.10% @ 16.2 µmol/L(Not explicitly "Total")
0.79% @ 83.0 µmol/L(Not explicitly "Total")
Precision (Between day)(Not explicitly stated for modified device)4.13% @ 14.7 µmol/L
(Not explicitly stated for modified device)2.15% @ 47.20 µmol/L
Measuring Range0.1-25.2 mg/dL0-25 mg/dL
Measuring Range (with postdilution)0.1-101 mg/dL0-250 mg/dL
Lower Detection Limit0.1 mg/dL0.063 mg/dL
Endogenous interferencesSame (as predicate)Hemolysis: No significant interference up to 1000 mg/dL, Lipemia: No significant interference up to 1400 mg/dL as Intralipid
Exogenous interferencesSame (as predicate)Ascorbic acid at 30 mg/dL causes artificially decreased total bilirubin values

Note on Acceptance Criteria: For a Special 510(k) like this, the implicit acceptance criterion is that the performance of the modified device is substantially equivalent to the predicate device, meaning it performs as well or better for the critical parameters. The table demonstrates this comparable performance.


Study Information

  1. Sample sizes used for the test set and the data provenance:

    • Test Set Sample Size: The document does not explicitly state the sample size used for the performance evaluation (precision, measuring range, detection limit, interference studies).
    • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective). This is a manufacturer's internal validation, likely conducted in a controlled lab environment.
  2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

    • This being an in-vitro diagnostic (IVD) chemistry analyzer, the "ground truth" for the test set is established by the reference method for total bilirubin (Doumas reference method, as mentioned in the traceability section) and highly controlled laboratory samples (e.g., control materials, spiked samples). There's no mention of human experts interpreting results in the way a radiologist interprets an image.
  3. Adjudication method for the test set:

    • Not applicable in the context of an IVD chemistry analyzer. Results are quantitative outputs from the instrument.
  4. If a multi-reader multi-case (MRMC) comparative effectiveness study was done:

    • No. This is a quantitative in-vitro diagnostic device, not an imaging device that requires human interpretation.
  5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

    • Yes, this is an algorithm-only (analyzer-only) performance study. The analyzer performs the test and provides a quantitative result. There is no human interpretation component in the direct measurement of bilirubin by this device.
  6. The type of ground truth used:

    • Reference Method: The device is standardized against the Doumas reference method for total bilirubin. This is the primary established ground truth for bilirubin measurement.
    • Control Materials: Performance is likely evaluated using assayed control materials (e.g., Precinorm U, Precipath U mentioned as quality controls) with known concentration values.
  7. The sample size for the training set:

    • Not applicable as this is not a machine learning/AI algorithm that requires a "training set" in the conventional sense. This is an analytical chemistry device where the "training" would be the initial development and calibration of the reagent and instrument platform.
  8. How the ground truth for the training set was established:

    • Not applicable. The "ground truth" for the development of such an IVD device is based on established clinical chemistry principles and standardization against internationally recognized reference methods (like Doumas). Calibrators are used to establish the measurement curve, and these calibrators are themselves traceable to a reference method.

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K063744

JAN 1 7 2007

Special 510(k) Summary

Purpose for Submission

Roche Diagnostics hereby submits this Special 510(k) to provide notification of modification to our Total Bilirubin Special test system. The reagent was originally cleared for use as:

  • . COBAS INTEGRA Total Bilirubin Special K981632/A001
    And modified as COBAS INTEGRA Total Bilirubin Special K063543 ● Modifications to the test systems include:

  • Reagent application to the cobas c 111 analyzer .

  • Other editorial labeling changes .

A full description of the differences and similarities between performance of Total Bilirubin Special on the COBAS INTEGRA 400 plus and cobas c 111 is described bclow.

The cobas c 111 analyzer is a new member of the COBAS INTEGRA® family of analyzers and will use reagents and calibrators identical to those of other INTEGRA analyzers. The cobas c 111 is a device modification of the current COBAS INTEGRA® 400 plus analyzer, cleared in a letter to file K951595. A full description of the differences and similarities between the two analyzers, software modifications and a summary of the design validation and verification activities for the modified software is included in this submission as part of the modifications to the Total Bilirubin Special test system.

In accordance with the FDA policy, new applications of previously cleared reagents to the cobas c 111 analyzer were completed, along with new labeling in the form of cobas c 111 package inserts. For all subsequent applications of previously cleared reagents, Roche Diagnostics is following the FDA guidance, Replacement Reagent and Instrument Family Policy - Dec 11, 2003, to demonstrate equivalence to the original reagent/instrument performance. Data will be available for FDA review upon request.

The additional labeling provided in this submission is for purposes of CLIA categorization.

Device Name Proprietary name: Total Bilirubin Special

Common name: Bilirubin total

Classification name: Bilirubin (total or direct) test system

Continued on next page

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EstablishmentRegistrationThe establishment registration number for Roche Diagnostics Gmbh Penzbergis 9610529.
The establishment registration number for Roche Diagnostics Corporation is1823260.
The establishment registration number for Roche instrument Center (RIC) is3003795116.
ClassificationThe FDA has classified a discrete photometric chemistry analyzer in Class I.
PanelClassificationNumberClassificationNameRegulationCitation
75 ClinicalChemistryCIGBilirubin (total ordirect) test system21 CFR 862.1110
DeviceDescriptionThe Total Bilirubin Special reagent is intended for use on the cobas c 111analyzer for the quantitative determination of total or direct bilirubin in serumand plasma.The cobas c 111 analyzer is a partially automated, in-vitro diagnosticanalyzer capable of performing clinical chemistry, specific protein andelectrolyte tests. Analytes are measured photometrically or turbidimetrically;the analyzer also has an optional ISE module for measuring sodium,potassium and chloride.The cobas c 111 instrument is a random access analyzer designed to beoperated on a bench top in the professional environment using a combinationof a photometric analysis unit and an optional ion selective electrodes (ISE).
PerformanceStandardsTo date, no performance standards that affect this device have been finalizedunder Section 514 of the Act.
Intended useIn vitro test for the quantitative determination of total bilirubin in humanserum and plasma on the cobas c 111 system.
PredicatedeviceWe claim substantial equivalence to the Total Bilirubin Special reagentcleared as K063543.

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Substantial equivalency-Similarities

The table below indicates the similarities and differences between the modified Bilirubin total reagent and its predicate device.

FeatureModified Device:Total Bilirubin SpecialPredicate device:COBAS INTEGRA Total BilirubinSpecial, K063543
GeneralIntended Use/Indications forUseIn vitro test for the quantitativedetermination of total bilirubin inhuman serum and plasma on thecobas c 111 system.The COBAS INTEGRA TotalBilirubin Special (BILTS) cassettecontains an in vitro diagnosticreagent system intended for use onCOBAS INTEGRA systems for thequantitative determination of totalbilirubin in serum and plasma ofadults and neonates (test BILTS, 0-985).
Specimenserum and plasmaserum and plasma
Test Principle
ReferencemethodSameDiazo method
Reagent information
ReagentcompositionSameR1: Sodium acetate buffer 85mmol/L, Sulfamic acid 110 mmol/LR2: Hydrochloric acid 100 mmol/L,Diazonium ion 3 mmol/L
Stability - shelflife and on-board2-8 °C until expiration dateOn-board 4 weeks2-8 °C until expiration dateCOBAS INTEGRA 400/400 plus:On-board at 10-15 °C 5 weeksCOBAS INTEGRA 700/800:On-board at 8 °C 5 weeks
CalibratorSameCalibrator f.a.s.
Quality controlSamePrecinorm U, Precipath UPrecinorm U plus, Precipath U plus
TraccabilitySameStandardized against the Doumasreference method
Performance characteristics
PrecisionWithin-run1.79% @ 21.7 µmol/L0.64% @ 64.2 µmol/L2.94% @ 15.2 µmol/L0.77% @ 60.0 µmol/LTotal2.32% @ 21.6 µmol/L0.71% @ 67.4 µmol/L3.10% @ 16.2 µmol/L0.79% @ 83.0 µmol/LWithin run:2.44% @ 15.80 µmol/L1.39% @ 54.00 µmol/LBetween day:4.13% @ 14.7 µmol/L2.15% @ 47.20 µmol/L
Measuring0.1-25.2 mg/dL0-25 mg/dL
Measuring range0.1-101 mg/dL (with postdilution)0-250 mg/dL (with postdilution)
Lower detectionlimit0.1 mg/dL0.063 mg/dL
Expected values(literaturereference)SameAdults and children: up to 1.0mg/dLNeonates:Age of newborn Premature24hrs: 1.0-6.0 mg/dL48hrs: 6.0-8.0 mg/dL3-5 days: 10.0-15.0 mg/dLAge of newborn Full Term24hrs: 2.0-6.0 mg/dL48hrs: 6.0-7.0 mg/dL
EndogenousSame3-5 days: 4.0-12.0 mg/dLHemolysis: No significant
interferencesinterference up to 1000 mg/dLLipemia: No significant interferenceup to 1400 mg/dL as Intralipid
ExogenousinterferencesSameAscorbic acid at 30 mg/dL causesartificially decreased total bilirubinvalues
Analyzer
Topiccobas c 111 Analyzer(Modified Device)COBAS INTEGRA® 400 pluswith ISE(K951595)
Analyzer Description
Intended UseThe Roche cobas c 111 analyzer isan in-vitro diagnostic analyzercapable of performing clinicalchemistry, specific protein andelectrolyte tests. Analytes aremeasured photometrically orturbidimetrically; the analyzer alsohas an optional ISE module formeasuring sodium, potassium andchloride.The Roche COBAS INTEGRA 400plus is an automated in vitrodiagnostic analyzer capable ofperforming general chemistry,specific protein, electrolyte tests,therapeutic drug, drug of abuse andthyroid analyses. It is equipped withmodules for absorption photometry,fluorescence polarizationphotometry and potentiometry (ISE)and works in conjunction with invitro diagnostic reagents.
Analyzer Description (continued)
Measurementprinciple• Absorbance Photometry(enzymes, substrates,proteins)• ISE Potentiometry(electrolytes)• Absorbance Photometry(enzymes, substrates,proteins, DAT)• Fluorescence Photometry(TDM)• ISE Potentiometry(electrolytes)
ReactionmodesSameEndpoint, kinetic, potentiometric
Software SIMILARITIES
Softwarecobas c 111 analyzer softwareCobas Integra® 400 plus AnalyzerSoftware
ConfigurationIntegrated bench top analyzer(including Absorbance Photometer)with optional ISE unitIntegrated benchtop analyzer (incl.Abs, FP-Photometer & ISE module)
FunctionsperformedSameData input, sample processing, resultcalculation, result reporting, qualitycontrol
ComputerData management & user interactionData management & user interaction
Infrastructureon cmbedded CPU with Linuxon PC based computer with
operating analyzerWindows XP operating analyzer
Instrument management and real-Instrument management and real-
time control on cmbedded CPU withtime control on embedded CPU with
vxWorks operating analyzervxWorks operating analyzer
AnalyticalSameControl of analytical processes
Functions(pipetting, incubation, detection),
primary signal processing
Data storageSame but no patient demographiesStorage of analyzer and application
are stored (due to less storagecapacity).parameters, calibration data, QC
data, sample results, alarms, patient
demographics, service actions and
ResultSamestatus information
calculationAutomated measuring of signal forkinetic and endpoint methods
according to cycle time and
automated calculation of
concentration via calibration curve
UserSameUser ID and password
management
Flagging ofSameAvailable
errors
Software DIFFFRENCES
Initial cassetteNot applicable:
volume checkAvailable
(ICVC) forInstead of cassettes single bottles
reagentwith liquid level detection are used
pipetting
Data conceptApplications via barcode
(ApplicationApplications via diskette
parameter
transfer)
Data conceptAutomatic QC when QC samplesAutomatic QC with on board QC
(Cal/QCare placed manuallysamples
assigned values)
Analyzer Features
ThroughputMax 100 tests per hourMax 400 tests per hour
Analyzer SizeSame but smallerIntegrated benchtop analyzer
Sample Handling
Typical sampleTypically 2 - 10 µL per test (same)Typically 2 - 10 µL per test
volumesISE (serum, plasma):ISE (serum, plasma):
25 µL (indirect mode)20 uL (indirect mode)
ISE (urine):97 uL (direct mode)
25 µL (indirect mode):ISE (urine):20 µL (indirect mode):
Sample TypesSame, but not CSFSerum, plasma, urine, CSF; whole blood and hemolysate for HbAlc
SampleHandlingAnalyzerSample area for samples, calibrators and controls.Rack analyzer for samples, calibrators and controls.
Sample capacityon board8 places for cups / tubes.Up to six racks with max. 15 sample cups/tubes per rack on board.
SampleidentificationSameID- Barcode
Reagent Handling
ReagentVolumeSame20 – 150 μL
ReagentContainerUnisys 20mL bottleIntegra cassette / cobas c pack
ReagentContainer(Electrolytes)SamePlastic bottles closed with screwcaps
Reagent AccessManual opening of bottle prior toplacement on boardReagent cassette caps pierced automatically inside the instrument.
OnboardstoragetemperatureRefrigerated 6-10 °C (43-50 °F)Refrigerated 10 - 15 °C (50-59 °F)
Reagentbottle/cassetteidentificationSameBarcode
On boardreagent storagecapacity27 reagent bottles32 cassettes
Analyzer cycletime18 sec10.6 sec
Reagent mixingStirring in cuvette with steel probeIntegrated cuvette vortex mixer
Auto rerunManual onlyAvailable
Pipetting Analyzer
Sample andreagent syringesXZ-Phi robotic syringeXYZ robotic syringe
Reagent probes1 polished steel probe with modifieddesign (used for sample & reagent)2 polished steel probes (used forsample & reagent)
Sample probes1 polished steel probe with modifieddesign (used for sample & reagent)2 polished steel probes (used forsample & reagent)
Probe cleaningSameAutomatic incl. carry over evasion
Liquid leveldetectionSame (+ reagent pipetting)Both probes conductance for samplepipetting
Clot detectionNot availableAvailable - pressure sensor
Test Reaction Chamber
TemperatureControlSameHeated air bath 37 °C (99 °F)
CuvettesSamePMMA acrylic plastic – for singleuse
ISE Module
ISE ModuleSerum, plasma indirect (1:6 dilution)Urine indirect (1:6 dilution)One-point calibration every samplemeasurement.Serum, plasma direct (undiluted)Serum, plasma indirect (1:6 dilution)Urine indirect (1:6 dilution)One-point calibration every samplemeasurement.
Ion SelectiveElectrodesSame but no lithium electrodePotentiometric: chloride, potassium,sodium, lithium and referenceelectrode
ISE throughput60 samples / h66 samples / h
Detection Information
SpectrophotometerSameGrating monochromator and diodearray
Light sourceTungsten / Halogen lamp, 20 WTungsten / Halogen lamp, 100 W
Light pathSame5 mm path length
Measuring unitSameIntensity (0 - 2.0 A)
Wavelengths340, 378, 409, 449, 480, 512,520, 552, 583, 629, 652, 659 nmmono- and bichromaticmeasurements340, 378, 409, 480, 512, 520,552, 583, 629, 652, 659, 800 nmmono- and bichromaticmeasurements
Calibration and quality control
CalibratorsSameMultiple use
CalibrationmodesSameLinear, non linear. Multiplestandards. Generation of multipointstandard curves by automaticdilution.
Calibration / onboard stabilitySameTypically each lot or 12 weeks forsame reagent on board
Control storageon instrumentTo be placed on demandWithin sample area possible
Calibrator /control valuetransferSameVia barcode transfer sheet or manualentry
Internal qualitymanagementanalyzerSameAvailable to monitor and validatetest results
Interfaces
Host interfaceSameRS232C bi-directional
PrinterInternal thermo paper printerStandalone LaserJet type
DisplayInternal LCD touch panel (1/4 VGA size)Standalone 17" computer display w. keyboard and mouse

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ProposedLabelingTotal Bilirubin Special reagent:Proposed labeling sufficient to describe the device, its intended use, and thedirections for use can be found in the separately attached document. Webelieve the proposed version of the device labeling presented contains all ofthe technical information required per 21 CFR 809.10.
cobas c 111 analyzer:Draft cobas c111 method manual sheets and example cassette labels forCLIA categorization purposes in this submission.
A complete User's Manual for the cobas c111 analyzer is provided inVolume II of this submission.
A CD-ROM containing the COBAS INTEGRA 400 plus Operator's Manual(the predicate device for cobas c 111 analyzer) is included with thissubmission.
We believe the proposed version of the device labeling presented contains allof the technical information required per 21 CFR 809.10.
Validation andDesign ControlDevelopment activities were conducted under appropriate design controlprocedures and the overall product specifications were met. The Results ofRisk Analysis and Declaration of Conformity with Design Controls areprovided with this submission.
ConfidentialityRoche Diagnostics requests that the FDA not disclose the nature or existenceof this submission until the substantial equivalence decision has beenreached.

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Closing Modification of the Bilirubin Total reagent does not affect the intended use or indications for use of the device as described in the labeling, nor does it alter the fundamental scientific technology of the device. Therefore, we trust the information provided in this Special 510(k) will support a decision of substantial equivalence to its predicate for the Total Bilirubin Special application to cobas c 111 analyzer.

An clectronic copy (scanned pdf version) of this submission can be provided upon request. If you have any questions or require further information, please do not hesitate to contact this office.

  • Phone: (317) 521-3831
  • · FAX: (317) 521-2324
  • · email: corina.harper(a roche.com

Sincerely,

Corina Harper, RAC Regulatory Affairs Consultant Roche Diagnostics Corporation

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Image /page/10/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle with three stripes forming its body and wings. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES - (USA)" are arranged in a circular pattern around the eagle.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Roche Diagnostics 9115 Hague Road Indianapolis, IN 46250 Attn: Corina Harper

JAN 17 2007

Re: K063744 Trade/Device Name: Total Bilirubin Special Regulation Number: 21 CFR §862.1110 Regulation Name: Bilirubin (total or direct) test system. Regulatory Class: Class II Product Code: CIG Dated: December 15, 2006 Received: December 18, 2006

Dear Ms. Harper:

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, youg, and Cosmetic Act (Act) that do not require approval of a premarket approval application(PMA), You may, therefore, market the device, subject to the general controls provisions of the Act . The general controls provisions of the Act include requirements for annual registration, l'inte of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your revire can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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 madon toos not incant or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Prt 820).

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Page 2 -

This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0490. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely vours.

Jean m. Cooper, M.S., D.V.M.

Yean M. Cooper, M.S., D.V.M. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known): K063744

Device Name: Total Bilirubin Special

Indications For Use:

In vitro test for the quantitative determination of total bilirubin in human serum and plasma on the cobas c 111 system.

Measurements of the levels of bilirubin and organic compound formed during normal and abnormal destruction of red cells, is used in the diagnosis of liver, hemolytic hematological and metabolic disorders, including hepatitis and gall bladder block.

Prescription Use XXX AND/OR (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

Page 1 of 1

Carol C. Bener
Vision Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

4062744

§ 862.1110 Bilirubin (total or direct) test system.

(a)
Identification. A bilirubin (total or direct) test system is a device intended to measure the levels of bilirubin (total or direct) in plasma or serum. Measurements of the levels of bilirubin, an organic compound formed during the normal and abnormal distruction of red blood cells, if used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.(b)
Classification. Class II.