TBI Flex® reagent cartridge: The TBI method for the Dimension® clinical chemistry system is an in vitro diagnostic test intended to quantitatively measure total bilirubin in human serum and plasma. Measurements of total bilirubin are used in the diagnosis and treatment of liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gallbladder disease.

DBI Flex® reagent cartridge: The DBI method for the Dimension® clinical chemistry system is an in vitro diagnostic test intended to quantitatively measure direct bilirubin in human serum and plasma. Measurements of direct bilirubin are used in the diagnosis and treatment of liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gall bladder disease.

TBI/DBI Calibrator: The Dimension® Bilirubin Calibrator is an in vitro diagnostic product intended to be used to calibrate the Direct Bilirubin (DBI) and Total Bilirubin (TBI) methods for the Dimension® clinical chemistry system. This product was designed to meet the needs of users to assure accurate results over the assay range of these methods.

Device Description

Total Bilirubin and Direct Bilirubin Flex® reagent cartridge. There are no changes in the device operating principle or reagents which comprise the total and direct Flex® reagent cartridges with this revision.

A. TBI Flex® reagent cartridge: Diazotized sulfanilic acid is formed by combining sodium nitrite and sulfanilic acid at low pH. Bilirubin (unconjugated) in the sample is solubilized by dilution in a mixture of caffeine/benzoate/acetate/EDTA. Upon addition of the diazotized sulfanilic acid, the solubilized bilirubin including conjugated bilirubins (mono and diglucoronides) and the delta form (billiprotein-bilirubin covalently bound to albumin) is converted to diazo-bilirubin, a red chromophore representing the total bilirubin which absorbs at 540 nm and is measured using a bichromatic (540, 700 nm) endpoint technique. A sample blank correction is used.

B. DBI Flex® reagent cartridge: Diazotized sulfanilic acid is formed by combining sodium nitrite and sulfanilic acid at low pH. The sample is diluted in 0.5M HC1. A blank reading is taken to eliminate interference from non-bilirubin pigments. Upon addition of the diazotized sulfanilic acid, the conjugated bilirubin is converted to diazobilirubin, a red chromophore which absorbs at 540 nm and is measured using a bichromatic (540, 700 nm) endpoint technique.

Total bilirubin and Direct bilirubin calibrator. Purified water will be used as the low level calibrator instead of a low concentration of ditauro-bilirubin. This change was made to prevent lot to lot shifts in quality control recovery at the low end of the assay.

AI/ML Overview

The provided 510(k) summary (K060628) details the acceptance criteria and the study that proves the device meets these criteria for the TBI Flex® reagent cartridge, DBI Flex® reagent cartridge, and the associated TBI/DBI Calibrator.

1. Table of Acceptance Criteria and Reported Device Performance:

The document refers to Design Input Requirements (DIRs) and states that "All goals were achieved." However, the exact quantitative acceptance criteria are not explicitly detailed in the main body but are referenced as being in "Appendix D." Without Appendix D, a precise table of acceptance criteria versus reported performance cannot be generated. Based on the provided text, the qualitative acceptance criteria for "Performance studies" are:

Acceptance Criteria Category	Reported Device Performance
Method Comparison	Achieved (Study performed)
Open-Well Stability	Achieved (Study performed)
Interference	Achieved (Study performed)
Recovery	Achieved (Study performed)
Analytical Sensitivity	Achieved (Study performed)
Precision	Achieved (Study performed)
Reference Range	Achieved (Study performed)
Shelf Life Stability	Achieved (Study performed)

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

Sample Size for Test Set:
- Method Comparison: "more than 100 frozen serum samples"
- Analytical Sensitivity: "20 replicate batches"
- For other tests (Open-Well Stability, Interference, Recovery, Precision, Reference Range, Shelf Life Stability), specific sample sizes for the test set are not explicitly stated within the provided text, beyond the general statement that "Performance studies were conducted internally versus the DIR goals described above. All goals were achieved."
Data Provenance:
- Method Comparison: "frozen serum samples obtained from clinical laboratories." The country of origin is not specified, but the submission is to the US FDA, implying U.S. or internationally acceptable clinical laboratory samples.
- The studies are described as "conducted internally," suggesting they were done by Dade Behring Inc. There's no indication of prospective or retrospective studies, but given the nature of the tests (e.g., method comparison against a commercial control lot, testing for interference, stability), they would generally be prospective experiments conducted to validate the modified device.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications:

This device is an in vitro diagnostic chemistry system for measuring bilirubin. The "ground truth" for such devices is typically established through a combination of:

Reference Methods: Comparison to established, highly accurate reference methods or clinical laboratory standards.
Predicate Device Performance: Comparison to the legally marketed predicate device (as done here).
Known Concentrations: Use of samples with known concentrations of the analyte (e.g., for recovery, analytical sensitivity, and calibrator validation).

The concept of "experts establishing ground truth" in the context of radiologists or similar interpretive medical professionals is not applicable here. The "experts" involved would be the qualified laboratory personnel conducting the studies and verifying the results against established laboratory standards and the predicate device. Their specific number and qualifications (e.g., "radiologist with 10 years of experience") are not detailed in the document, as it falls under standard laboratory practices and personnel qualifications for an IVD manufacturer.

4. Adjudication Method for the Test Set:

Adjudication methods (e.g., 2+1, 3+1) are typically used in clinical trials involving subjective interpretations (like imaging) where multiple readers assess cases and a consensus or tie-breaking mechanism is needed. This is not applicable to an in vitro diagnostic device for quantitative measurement like a bilirubin assay, where the "ground truth" is determined by objective analytical measurements, comparison to reference materials, or predicate device performance.

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

No, a Multi Reader Multi Case (MRMC) comparative effectiveness study was not conducted for this device. MRMC studies are specific to diagnostic devices where human readers interpret outputs (e.g., medical images) and AI assistance might improve their performance. This device is an automated, quantitative chemical assay and does not involve human readers interpreting "cases" in the clinical sense that an MRMC study would measure.

6. Standalone Performance Study:

Yes, a standalone performance study was implicitly done. The "Performance studies" described under "Design Testing and Evaluation" (Method Comparison, Open-Well Stability, Interference, Recovery, Analytical Sensitivity, Precision, Reference Range, Shelf Life Stability) are all evaluating the algorithm/device's performance independently against predefined analytical goals and the predicate device. These studies assess the device's accuracy, precision, linearity, and stability in a standalone manner. The comparison to the predicate device serves as the primary benchmark for demonstrating substantial equivalence.

7. The Type of Ground Truth Used:

The ground truth used for performance evaluation can be inferred from the study types:

Predicate Device Performance: The primary ground truth is the performance of the legally marketed predicate devices (Dade Behring TBIL Flex® reagent cartridge (K861700), Dade Behring DBIL Flex® reagent cartridge (K862359), and Dade Behring TBIL/DBIL Calibrator (K861700)). The studies aimed to demonstrate that the revised device is "substantially equivalent in principle and performance" to these predicates.
Known Concentrations/Reference Materials: For tests like Recovery, Analytical Sensitivity, and calibrator production (e.g., using purified water for the low level), samples with known or traceable concentrations of bilirubin or reference materials are used to establish ground truth for quantitative accuracy.
Clinical Laboratory Samples: For Method Comparison, "frozen serum samples obtained from clinical laboratories" are tested against a "commercial control lot" (presumably using a well-established method, possibly the predicate itself).

8. Sample Size for the Training Set:

The document describes this as a revision to an existing product, and the studies mentioned are for verification and validation (V&V) of the revised device, not for the training of an AI algorithm. There is no mention of an AI component or machine learning model that would require a "training set." This is an in vitro diagnostic reagent and calibrator kit for a chemical analysis system.

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

As there is no mention of an AI component requiring a training set, this question is not applicable in the context of the provided 510(k) summary. The "ground truth" establishment described in this submission pertains to the analytical performance validation of the chemical assays and calibrators.

Summary

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K060628

510(k) Summary of Safety and Effectiveness Information

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

Submitter's Name:	George M. PlummerDade Behring Inc.P.O. Box 6101Newark, DE 19714-6101
Date of Preparation:	March 8, 2006
Name of Products:	TBI Flex® reagent cartridgeDBI Flex® reagent cartridgeTBI/DBI Calibrator
FDA Classification Name:	Bilirubin (total or direct) test systemBilirubin Calibrator
Predicate Device:	Dade Behring TBIL Flex® reagent cartridge (K861700)Dade Behring DBIL Flex® reagent cartridge (K862359)Dade Behring TBIL/DBIL Calibrator (K861700)

Device Description

Total Bilirubin/Direct Bilirubin reagents.

There is no change in the device operating principle or reagents which comprise the total and direct Flex® reagent cartridges with this revision.

TBI Flex® reagent cartridge

Diazotized sulfanilic acid is formed by combining sodium nitrite and sulfanilic acid at low pH. Bilirubin (unconjugated) in the sample is solubilized by dilution in a mixture of caffeine/benzoate/acetate/EDTA. Upon addition of the diazotized sulfanilic acid, the solubilized bilirubin including conjugated bilirubins (mono and diglucoronides) and the delta form (biliprotein-bilirubin covalently bound to albumin) is converted to diazobilirubin, a red chromophore representing the total bilirubin which absorbs at 540 nm and is measured using a bichromatic (540, 700 nm) endpoint technique. A sample blank correction is used.

Solubilized bilirubin + Diazotized sulfanilic acid ---------------------------------------------------------------------------------------------------------------------------

DBI Flex® reagent cartridge

Diazotized sulfanilic acid is formed by combining sodium nitrite and sulfanilic acid at low pH. The sample is diluted in 0.5M HCI. A blank reading is taken to eliminate interference from non-bilirubin pigments. Upon addition of the diazotized sulfanilic acid, the conjugated bilirubin is converted to diazo-bilirubin, a red chromophore which absorbs at 540 nm and is measured using a bichromatic (540, 700 nm) endpoint technique.

Conjugated bilirubin + Diazotized sulfanilic acid ----------------------------------------------------------------------------------------------------------------------------

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Total bilirubin and Direct bilirubin calibrator.

Purified water will be used as the low level calibrator instead of a low concentration of ditauro-bilirubin. This change was made to prevent lot to lot shifts in quality control recovery at the low end of the assay.

Intended Use:

TBI Flex® reagent cartridge:

The TBI method for the Dimension® clinical chemistry system is an in vitro diagnostic test intended to quantitatively measure total bilirubin in human serum and plasma. Measurements of total bilirubin are used in the diagnosis and treatment of liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gallbladder disease.

DBI Flex® reagent cartridge:

The DBI method for the Dimension® clinical chemistry system is an in vitro diagnostic test intended to quantitatively measure direct bilirubin in human serum and plasma. Measurements of direct bilirubin are used in the diagnosis and treatment of liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gall bladder disease.

TBI/DBI Calibrator:

The Dimension® Bilirubin Calibrator is an in vitro diagnostic product intended to be used to calibrate the Direct Bilirubin (DBI) and Total Bilirubin (TBI) methods for the Dimension® clinical chemistry system. This product was designed to meet the needs of users to assure accurate results over the assay range of these methods.

Comparison to the predicate device:

The TBI, DBI Flex® reagent cartridges and TBI/DBI Calibrator are substantially equivalent in intended use, principle and performance to the original Dade Behring TBIL, DBIL assays, K861700 and K862359 respectively and TBIL/DBIL Calibrator, k 861700. See Appendix A and B for copies of the product inserts. The assays are in vitro assays with intended uses for the measurement of total and direct bilirubin in human serum and plasma. Both calibrators are for use of calibration of the total and direct bilirubin in vitro assays.

A summary of the features of the Dade Behring Dimension TBI and DBI Flex® reagent cartridge and the predicate Dade Behring TBIL and DBIL Flex® reagent cartridge assays is provided in the following chart. Although the intended use statements have been modified to align with CFR 862.1110, there are no new claims for the assay.

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Attribute	TBIL (originalassay)	TBI (revisedassay)	DBIL (originalassay)	DBI (revisedassay)
Intended Use	The TBILmethod used onthe Dimension®clinicalchemistry systemis an in vitrodiagnostic testintended for thequantitativedetermination oftotal bilirubin inserum andplasma.	The TBI methodfor theDimension®clinicalchemistry systemis an in vitrodiagnostic testintended toquantitativelymeasure totalbilirubin inhuman serumand plasma.Measurements oftotal bilirubin areused in thediagnosis andtreatment ofliver, hemolytic,hematological,and metabolicdisorders,includinghepatitis andgallbladderdisease.	The DBILmethod used onthe Dimension®clinicalchemistry systemis an in vitrodiagnostic testintended for thequantitativedetermination ofdirect(conjugated)bilirubin inserum andplasma.	The DBI methodfor theDimension®clinicalchemistry systemis an in vitrodiagnostic testintended toquantitativelymeasure directbilirubin inhuman serumand plasma.Measurements ofdirect bilirubinare used in thediagnosis andtreatment ofliver, hemolytic,hematological,and metabolicdisorders,includinghepatitis and gallbladder disease.
Sample type	Human serumand plasma	Human serumand plasma	Human serumand plasma	Human serumand plasma
Methodology	Photometric(diazo chemistry)	Photometric(diazo chemistry)	Photometric(diazo chemistry)	Photometric(diazo chemistry)
Detection	Bichromatic(540, 700 nm)	Bichromatic(540, 700 nm)	Bichromatic(540, 700 nm)	Bichromatic(540, 700 nm)
Sample volume	28 uL	10 uL	31 uL	10 uL
HemoglobinCorrection	Up to 500 mg/dL	Up to 1000mg/dL	No	Up to 100 mg/dL
Hemoglobin Flag	Yes	Yes	No	Yes

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A summary of the features of the Dade Behring Dimension TBI/DBI calibrator cartridge and the predicate Dade Behring TBIL/DBIL calibrator is provided in the following chart.

Attribute	Original Calibrator	Revised Calibrator
Intended Use	The Dimension® BilirubinCalibrator is an in vitrodiagnostic product to be usedto calibrate the Dimension®clinical chemistry system forthe Direct Bilirubin (DBIL)and Total Bilirubin (TBIL)methods. This product wasdesigned to meet the needs ofusers to assure accurate resultsover the assay range of thesemethods.	The Dimension® BilirubinCalibrator is an in vitrodiagnostic product intendedto be used to calibrate theDirect Bilirubin (DBI) andTotal Bilirubin (TBI)methods for the Dimension®clinical chemistry system.This product was designed tomeet the needs of users toassure accurate results overthe assay range of thesemethods.
Analyte	Ditauro-bilirubin	Ditauro-bilirubin
Matrix	Human serum	Human serum
Levels	Three	Three
Bilirubin concentration (mg/dL)Total	L1 (0.8), L2 (10), L3 (22)	L1 (0), L2 (10), L3 (25)
Direct	L1 (0.6), L2 (7), L3 (15)	L1 (0), L2 (7), L3 (17.5)
Form	Lyophilized	Lyophilized
Volume	6 vials, 2 vials each level, 1mL each vial (hydratedvolume)	4 vials, 2 vials each level, 1ml each vial (hydratedvolume). Purified water isused for level 0 and notsupplied by Dade Behring.

Comments on Substantial Equivalence:

Testing versus the design input criteria and the results of the risk analysis demonstrate that the revised TBI Flex® reagent cartridge, DBI Flex® reagent cartridge and the associated TBIDBI Calibrator are equivalent to the predicate devices, the current design products.

Conclusion:

The revised TBI Flex® reagent cartridge, DBI Flex® reagent cartridge and the associated TBVDBI Calibrator are substantially equivalent in principle and performance to the current design products.

George M. Plummer Quality Assurance and Compliance Manager Date: March 8, 2006

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Revised Product Premarketing Notification [Ref: F, D &C Act, Section 510(k)]

Device Name: TBI Flex® reagent cartridge DBI Flex® reagent cartridge TBI/DBI Calibrator
Applicant: George M. Plummer Regulatory Affairs and Compliance Manager Dade Behring Inc. Building 500, Mailbox 514 P.O. Box 6101 Newark, DE 19714-6101 (302) 631-9798 (302) 631-6299 (Fax)
Manufactured By: Dade Behring Inc. 1717 Deerfield Road P.O. Box 778 Deerfield, IL 60015-0778 Owner/Operator No. 9017031
Manufactured At: Dade Behring Inc. Chemistry/Immunochemistry Group Route 896 P.O. Box 6101 Newark, DE 19702 Establishment Registration No. 2517506

Date of Submission: March 8, 2006

Original Device 510 (k) Numbers:

TBIL Flex® reagent cartridge: K861700 DBIl Flex® reagent cartridge: K862359 TBIL/DBIL Calibrator: K861700

Classification:

The FDA has classified total and direct Bilirubin Test Systems as Class II in 21 CFR 862.1110 and Bilirubin Calibrators as Class II in 21 CFR 862.1150.

Standards and Guidance Documents:

The following voluntary standards or guidance documents were used in determining safety and effectiveness of the devices:

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CLSI/NCCLS EP5-A2, 2004, Evaluation of Precision Performance of Clinical . Chemistry Devices; Approved Guideline-Second Edition
CLSI/NCCLS EP9-A2, 2002, Method Comparison and Bias Estimation Using . Patient Samples; Approved Guideline - Second Edition
CLSI/NCCLS C28-A2, 2002 How to Define and Determine Reference Intervals in . the Clinical Laboratory; Approved Guideline-Second Edition
CLSI/NCCLS EP7- A, 2002, Interference Testing in Clinical Chemistry; Approved . Guideline
General Principles of Software Validation: Final Guidance for Industry and FDA . Staff, January, 11, 2002.
ISO 14971-2000, Medical devices Application of risk management to medical . devices

Proposed Labels/Labeling:

A copy of the labels and labeling for the revised TBI and DBI Flex® reagent cartridges and TBI/DBI Calibrator is provided in Appendix A. A copy of the predicate labeling is provided in Appendix B.

Intended Use:

TBI Flex® reagent cartridge:

DBI Flex® reagent cartridge:

TBI/DBI Calibrator:

Comparison to the predicate device:

The TBI, DBI Flex® reagent cartridges and TBVDBI Calibrator are substantially equivalent in intended use, principle and performance to the original Dade Behring TBIL, DBIL assays, K861700 and K862359 respectively and TBIL/DBIL Calibrator, k 861700. See Appendix A and B for copies of the product inserts. The assays are in vitro assays with intended uses for the measurement of total and direct bilirubishin human

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serum and plasma. Both calibrators are for use of calibration of the total and direct bilirubin in vitro assays.

A summary of the features of the Dade Behring Dimension TBI and DBI Flex® reagent cartridge and the predicate Dade Behring TBIL and DBL Flex® reagent cartridge assays is provided in the following chart. Although the intended use statements have been modified to align with CFR 862.1110, there are no new claims for the assay.

Attribute	TBIL (originalassay)	TBI (revisedassay)	DBIL (originalassay)	DBI (revisedassay)
Intended Use	The TBILmethod used onthe Dimension®clinicalchemistry systemis an in vitrodiagnostic testintended for thequantitativedetermination oftotal bilirubin inserum andplasma.	The TBI methodfor theDimension®clinicalchemistry systemis an in vitrodiagnostic testintended toquantitativelymeasure totalbilirubin inhuman serumand plasma.Measurements oftotal bilirubin areused in thediagnosis andtreatment ofliver, hemolytic,hematological,and metabolicdisorders,includinghepatitis andgallbladderdisease.	The DBILmethod used onthe Dimension®clinicalchemistry systemis an in vitrodiagnostic testintended for thequantitativedetermination ofdirect(conjugated)bilirubin inserum andplasma.	The DBI methodfor theDimension®clinicalchemistry systemis an in vitrodiagnostic testintended toquantitativelymeasure directbilirubin inhuman serumand plasma.Measurements ofdirect bilirubinare used in thediagnosis andtreatment ofliver, hemolytic,hematological,and metabolicdisorders,includinghepatitis and gallbladder disease.
Sample type	Human serumand plasma	Human serumand plasma	Human serumand plasma	Human serumand plasma
Methodology	Photometric(diazo chemistry)	Photometric(diazo chemistry)	Photometric(diazo chemistry)	Photometric(diazo chemistry)
Detection	Bichromatic(540, 700 nm)	Bichromatic(540, 700 nm)	Bichromatic(540, 700 nm)	Bichromatic(540, 700 nm)
Sample volume	28 uL	10 uL	31 uL	10 uL
HemoglobinCorrection	Up to 500 mg/dL	Up to 1000mg/dL	No	Up to 100 mg/dL
Hemoglobin Flag	Yes	Yes	No	Yes

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A summary of the features of the Dade Behring Dimension TBI/DBI calibrator cartridge and the predicate Dade Behring TBIL/DBIL calibrator is provided in the following chart.

Attribute	Original Calibrator	Revised Calibrator
Intended Use	The Dimension® BilirubinCalibrator is an in vitrodiagnostic product to be usedto calibrate the Dimension®clinical chemistry system forthe Direct Bilirubin (DBIL)and Total Bilirubin (TBIL)methods. This product wasdesigned to meet the needs ofusers to assure accurateresults over the assay rangeof these methods.	The Dimension® BilirubinCalibrator is an in vitrodiagnostic product intended tobe used to calibrate the DirectBilirubin (DBI) and TotalBilirubin (TBI) methods for theDimension® clinical chemistrysystem. This product wasdesigned to meet the needs ofusers to assure accurate resultsover the assay range of thesemethods.
Analyte	Ditauro-bilirubin	Ditauro-bilirubin
Matrix	Human serum	Human serum
Levels	Three	Three
Bilirubin concentration (mg/dL)
Total	L1 (0.8), L2 (10), L3 (22)	L1 (0), L2 (10), L3 (25)
Direct	L1 (0.6), L2 (7), L3 (15)	L1 (0), L2 (7), L3 (17.5)
Form	Lyophilized	Lyophilized
Volume	6 vials, 2 vials each level, 1mL each vial (hydratedvolume)	4 vials, 2 vials each level, 1 mleach vial (hydrated volume).Purified water is used for level0 and not supplied by DadeBehring.

Device Description

1. Total Bilirubin and Direct Bilirubin Flex® reagent cartridge. There are no changes in the device operating principle or reagents which comprise the total and direct Flex® reagent cartridges with this revision.
- A. TBI Flex® reagent cartridge
  - Diazotized sulfanilic acid is formed by combining sodium nitrite and sulfanilic acid at low pH. Bilirubin (unconjugated) in the sample is solubilized by dilution in a mixture of caffeine/benzoate/acetate/EDTA. Upon addition of the diazotized sulfanilic acid, the solubilized bilirubin including conjugated bilirubins (mono and diglucoronides) and the delta form (billiprotein-bilirubin covalently bound to albumin) is converted to diazo-bilirubin, a red chromophore representing the total bilirubin which absorbs at 540 nm and is measured using a bichromatic (540, 700 nm) endpoint technique. A sample blank correction is used.

Solubilized bilirubin + Diazotized sulfanilic acid ---------------------------------------------------------------------------------------------------------------------------

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B. DBI Flex® reagent cartridge
Diazotized sulfanilic acid is formed by combining sodium nitrite and sulfanilic acid at low pH. The sample is diluted in 0.5M HC1. A blank reading is taken to eliminate interference from non-bilirubin pigments. Upon addition of the diazotized sulfanilic acid, the conjugated bilirubin is converted to diazobilirubin, a red chromophore which absorbs at 540 nm and is measured using a bichromatic (540, 700 nm) endpoint technique.

Conjugated bilirubin + Diazotized sulfanilic acid ----------------------------------------------------------------------------------------------------------------------------

1. Total bilirubin and Direct bilirubin calibrator. Purified water will be used as the low level calibrator instead of a low concentration of ditauro-bilirubin. This change was made to prevent lot to lot shifts in quality control recovery at the low end of the assay.

Design Control Activities

1. Design Development
  For the revised TBIL, DBIL assays and the associated TBIL/DBIL calibrator, we followed the standard Dade Behring new/revised product development process, an integrated structured approach to product development that ensures products will meet design goals, customer needs and global regulatory and compliance requirements. A cross-functional product development team (R&D, Manufacturing, Marketing, Technical Support and Regulatory), referred to as the Core Team, was assigned to develop the revised assays and calibrator. The design control processes that were followed for the revised assays and calibrator are described in the following bullet points:
A. Development proceeds through set stage gates with deliverables required to proceed to the next stage. A review is conducted at each stage gate with the Product Approval Committee (PAC) comprised of functional management to assess readiness to advance to the next stage. The review is conducted versus standard and project specific deliverables.
B. A risk analysis is conducted to asses the impact of the modification on the device and its components. The risk analysis is reviewed periodically throughout the development process to ensure progress is attained on any required verification and/or validation activities resulting from the analysis.
C. Product design input requirements (DIR) and acceptance criteria are identified.
D. Technology is validated to produce the product and initial design in the early product development stages.
E. Design improvement, design verification, design validation and development of support processes are completed in subsequent development stages.
Design reviews are conducted periodically to ensure continued compliance to r design goals and review status of progress of the project.
1. Risk Analysis

The Dade Behring risk management process is designed to align with ISO 14971-2000, Medical devices - Application of risk management to medical devices. A summary of the

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risk analysis process, the verification, validation, and test activities, and the acceptance criteria and results is provided in Appendix C.

3. Design Testing and Evaluation

Design Input Requirements (DIRs) are developed early in the product development process. The product is evaluated versus the DIR throughout the development process. Three validation lots of the revised TBI and DBI Flex® reagent cartridges and associated TBI/DBI calibrator were manufactured at full commercial scale under standard manufacturing conditions. These qualification lots were evaluated versus the DIR requirements as described below:

A. Method Comparison: Split-sample correlation study designed to compare the accuracy of the qualification lots to that of a commercial control lot using more than 100 frozen serum samples obtained from clinical laboratories.
B. Open-Well Stability: Comparison of results with reagents after Flex® well puncture vs. fresh reagents to challenge the open-well stability requirement.
C. Interference: Tests the affect of a specific set of potential interfering materials that are listed in the product insert in Appendix A.
D. Recovery: Tests the recovery across the assay range using a set of samples prepared by mixing a high concentration of total bilirubin or direct bilirubin and a blank sample at various ratios.
E. Analytical Sensitivity: Tests the analytical sensitivity of the method (defined as 2 times the standard deviation obtained with a sample that contains 0 mg/dL bilirbuin) by running 20 replicate batches to estimate the standard deviation.
F. Precision: Tests within-run and total reproducibility using an ANOVA approach in compliance with CLIS/NCCLS EP-5A2.
G. Reference Range: Tests that confirm the existing predicate product reference range.
H. Shelf Life Stability: Tests that demonstrate the real time product stability at normal product temperature storage conditions

Details of the DIR acceptance criteria may be found in Appendix D.

Verification and Validation Activities 4.

Performance studies were conducted internally versus the DIR goals described above. All goals were achieved.

5. Declaration of Conformity

A declaration of conformity is provided in Appendix E. This declaration provides a statement that:

A. all verification and validation activities were performed by the designated individuals and the results demonstrated that the predetermined acceptance criteria were met
B. the manufacturing facility is in conformance with the design control procedure requirements as specified in 21 CFR 820.30 and the records are available for review.

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Comments on Substantial Equivalence/Conclusion:

Testing versus the design input criteria and the results of the risk analysis demonstrate that the revised TBI Flex® reagent cartridge, DBI Flex® reagent cartridge and the associated TBI/DBI Calibrator are equivalent to the predicate devices, the current design products. The revised products are substantially equivalent in principle and performance to the current design products.

George M. Plummer Regulatory Affairs and Compliance Manager Date: March 8, 2006

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Image /page/11/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with its head turned to the right and its wings outstretched. The eagle is enclosed in a circle, and the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is written around the circle. The logo is black and white.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

AUG - 3 2006

George Plummer Dade Behring, Inc. Glasgow Business Community Bldg 500, MS 514 P.O. Box 6101 Newark, DE 19714 6101

Re: K060628

Trade/Device Name: Dade Behring Dimension Total and Direct Bilirubin Assays. Regulation Number: 862.1110 Regulation Name: Bilirubin (total or direct) test system. Regulatory Class: II Product Code: CIG, JIS Dated: March 8, 2006 Received: March 9, 2006

Dear Mr. Plummer:

This letter corrects our substantially equivalent letter of April 6, 2006.

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 (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, listing 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 additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition. FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA`s issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not

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limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (sections 531-542 of the Act); 21 CFR 1000-1050.

This letter will allow you to continue 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 advice for your device on our labeling regulation (21 CFR Part 801), please contact the Office of Compliance at (240) 276-0450. 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 (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html

Sincerely yours,

Alberto Gutierrez, Ph.D. 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 Statement

510(k) Number (if known):

Image /page/13/Picture/2 description: The image shows the alphanumeric string 'K060628' in a bold, handwritten style. The characters are closely spaced and have a consistent stroke width. The string appears to be a code or identifier, possibly a serial number or reference code.

Device Name:

TBI Flex® reagent cartridge; DBI Flex® reagent cartridge;TBI/DBI Bilirubin Calibrator

Indications for Use:

TBI Flex® reagent cartridge:

DBI Flex® reagent cartridge:

TBI/DBI Calibrator:

George M. Plummer Regulatory Affairs and Compliance Manager

March 8, 2006

Prescription Use
(Per 21 CRF 801 Subpart D)

AND/OR

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)

	Carol Benson
	Division Sign-Off

Office of in Vitro Diagnostic
Device Evaluation and Safety

	K060628
--	---------

Regulation Number and Section

§ 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.