Predicate Devices

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The device description and performance studies detail a standard immunoassay based on chemical reactions and optical measurements, with no mention of AI or ML algorithms for data processing or interpretation. The analysis of performance data uses traditional statistical methods like Deming Regression.

Therapeutic

No.
This device is an in vitro diagnostic test used to measure drug levels in accordance with therapy, not to provide therapy itself.

Diagnostic

Yes

The device is an in vitro test that quantitatively determines a substance (carbamazepine) in patient samples to monitor levels and help ensure appropriate therapy, which is a diagnostic purpose.

SaMD (Software as a Medical Device)

No

The device is an in vitro diagnostic assay that relies on chemical reactions and automated clinical chemistry analyzers, which are hardware components. It is not solely software.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Intended Use: The intended use explicitly states it is an "In vitro test for the quantitative determination of carbamazepine in serum and plasma". This clearly indicates the test is performed outside of the body using biological samples.
Device Description: The description details a "homogeneous microparticle agglutination immunoassay based on the kinetic interaction of microparticles in solution (KIMS)". This describes a laboratory-based test method using reagents and samples.
Sample Type: The test uses "human serum or plasma", which are biological specimens.
Purpose: The measurements are used "in monitoring levels of carbamazepine to help ensure appropriate therapy", which is a diagnostic or monitoring purpose.

All of these characteristics align with the definition of an In Vitro Diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

In vitro test for the quantitative determination of carbamazepine in serum and plasma on Roche/Hitachi cobas c systems.

Measurements obtained are used in monitoring levels of carbamazepine to help ensure appropriate therapy.

Product codes

KLT

Device Description

The ONLINE TDM Carbamazepine Gen. 4 assay is for the quantitative determination of carbamazepine in human serum or plasma on automated clinical chemistry analyzers. It is a homogeneous microparticle agglutination immunoassay based on the kinetic interaction of microparticles in solution (KIMS). Biotinylated drug hapten serves as the binding partner to anticarbamazepine antibody and streptavidin coated latex beads. A competitive reaction to a limited amount of specific anti-carbamazepine antibody takes place between the hapten and free carbamazepine in the sample. A decrease in the apparent signal produced by the microparticle agglutination is proportional to the amount of drug present in the sample.

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

Not Found

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

Detection Limit (LoB, LoD, LoQ) studies: Performed based on CLSI EP17-A2. LoB determined by measuring diluent 10-fold per run on one instrument for 6 runs over 3 days. LoD determined by measuring 5 low-analyte samples 2-fold per run for 6 runs over 3 days. LoQ determined by testing 9 samples over 3 days on one analyzer, 2 runs per day for 3 lots. Expected or target value determined with LC/MS.
- Representative Results (µg/mL): LoB = 0.3, LoD = 0.5, LoQ = 1.4
- Claimed in labeling (µg/mL): LoB = 0.5, LoD = 1.0, LoQ = 2.0
Precision according to CLSI EP5-A: Two runs per day for ≥ 21 days on the same analyzer. Repeatability (within run precision) and intermediate precision (within lab precision) calculated. Samples randomized in each run separately.
- Repeatability Summary (SD (ug/mL), CV (%)):
  - TDM Control 1: 0.08, 2.2
  - TDM Control 2: 0.14, 1.4
  - TDM Control 3: 0.20, 1.3
  - Human Serum 1: 0.08, 2.7
  - Human Serum 2: 0.09, 2.1
  - Human Serum 3: 0.17, 1.8
  - Human Serum 4: 0.19, 1.3
  - Human Serum 5: 0.27, 1.4
- Intermediate Precision Summary (SD (ug/mL), CV (%)):
  - TDM Control 1: 0.10, 2.8
  - TDM Control 2: 0.22, 2.3
  - TDM Control 3: 0.28, 1.8
  - Human Serum 1: 0.10, 3.3
  - Human Serum 2: 0.12, 2.9
  - Human Serum 3: 0.25, 2.6
  - Human Serum 4: 0.36, 2.4
  - Human Serum 5: 0.56, 2.9
Linearity according to CLSI EP6-A: Dilution series prepared from human serum sample pool and diluent to obtain eleven levels spanning the measuring range. Process repeated for plasma samples. Calculation according to CLSI guideline EP6-A.
- Serum: Linear Regression Equation: y = 1.000x - 0.0, Pearson correlation coefficient (R) = 0.997. Claimed Measuring Range: 2.0 to 20.0 µg/mL.
- K2-EDTA, Plasma: Linear Regression Equation: y = 1.013x - 0.195, Pearson correlation coefficient (R) = 0.999. Claimed Measuring Range: 2.0 to 20.0 µg/mL.
Matrix Comparison - Anticoagulants: Each pair of serum and plasma from a single donor spiked with carbamazepine. 33 full tubes included. Serum used as reference.
- Correlation:
  - Serum vs. Serum Gel Separation: y = 1.01x + 0.177, r = 0.989
  - Serum vs. Li-heparin: y = 1.01x -0.290, r = 0.991
  - Serum vs. Na-heparin: y = 1.02x -0.382, r = 0.990
  - Serum vs. K2-EDTA: y = 1.02x -0.059, r = 0.988
  - Serum vs. K3-EDTA: y = 0.993x + 0.147, r = 0.994
Interferences - H, L and I Indices: Effect of endogenous interfering substances determined at two carbamazepine concentrations and a dilution set of interfering substances.
- Highest Concentration shown not to interfere:
  - Hemolysis: up to an H index of 1000 (approximate hemoglobin concentration 1000 mg/dL)
  - Icterus/Bilirubin: up to an I index of 50 (approximate bilirubin concentration 50 mg/dL)
  - Lipemia: up to an L index of 2000 (approximate triglyceride concentration up to 1000 mg/dL)
  - Cholesterol: up to 600 mg/dL
  - Rheumatoid Factor: up to 1200 IU/mL
  - Total Protein: up to 13 g/dL
Interferences – Drugs: Sixteen commonly used drugs examined for potential interference.
- Highest Concentration Shown Not to Interfere with Carbamazepine (mg/L): Acetylcysteine (1660), Ampicillin-Na (1000), Ascorbic acid (300), Cefoxitin (2500), Heparin (5000 U/L), Levodopa (20), Methyldopa (20), Metronidazol (200), Doxycyclin (50), Acetylsalicylic Acid (1000), Rifampicine (60), Cyclosporine (5), Acetaminophen (200), Ibuprofen (500), Phenylbutazone (400), Theophyllin (100).
Cross-reactivity: Tested for various compounds at low (3 µg/mL) and high (12 µg/mL) carbamazepine concentrations. Results in % Cross reactivity presented in Table 8.
Method Comparison to Predicate: One hundred single native human samples from patients taking carbamazepine tested in singlicate on candidate and predicate device (cobas c 501). Data evaluated using Deming Regression analysis.
- y = 0.994x - 0.054 µg/mL
- r = 0.993

Key Metrics

Limit of Blank (LoB): 0.3 µg/mL (Representative Result), 0.5 µg/mL (Claimed in labeling)
Limit of Detection (LoD): 0.5 µg/mL (Representative Result), 1.0 µg/mL (Claimed in labeling)
Limit of Quantitation (LoQ): 1.4 µg/mL (Representative Result), 2.0 µg/mL (Claimed in labeling)

For Linearity:

Serum Pearson correlation coefficient (R): 0.997
K2-EDTA, Plasma Pearson correlation coefficient (R): 0.999

For Method Comparison to Predicate:

Correlation coefficient (r): 0.993

Predicate Device(s)

ONLINE TDM Carbamazepine, K031902

Reference Device(s)

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

Regulation Number and Section

§ 862.3645 Neuroleptic drugs radioreceptor assay test system.

(a)
Identification. A neuroleptic drugs radioceptor assay test system is a device intended to measure in serum or plasma the dopamine receptor blocking activity of neuroleptic drugs and their active metabolites. A neuroleptic drug has anti-psychotic action affecting principally psychomotor activity, is generally without hypnotic effects, and is a tranquilizer. Measurements obtained by this device are used to aid in determining whether a patient is taking the prescribed dosage level of such drugs.(b)
Classification. Class II.

Summary

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Image /page/0/Picture/1 description: The image shows the logo for the Department of Health & Human Services - USA. The logo is a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is an image of three stylized human profiles facing to the right, with a design that resembles an abstract bird or wing shape above them. The logo is black and white.

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

October 22, 2015

ROCHE DIAGNOSTICS OPERATIONS (RDO) DAVID TRIBBETT REGULATORY AFFAIRS PRINCIPAL 9115 HAGUE ROAD INDIANAPOLIS IN 46250

Re: K151578

Trade/Device Name: ONLINE TDM Carbamazepine Gen 4 Regulation Number: 21 CFR 862.3645 Regulation Name: Neuroleptic drugs radioreceptor assay test system Regulatory Class: II Product Code: KLT Dated: September 21, 2015 Received: September 22, 2015

Dear Mr. Tribbett:

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. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); 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.

1

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. 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

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours.

Courtney Hias -S

Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K151578

Device Name ONLINE TDM Carbamezapine Gen.4

Indications for Use (Describe)

In vitro test for the quantitative determination of carbamazepine in serum and plasma on Roche/Hitachi cobas c systems.

Measurements obtained are used in monitoring levels of carbamazepine to help ensure appropriate therapy.

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

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

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ONLINE TDM Carbamazepine Gen. 4 510(k) Summary

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

Submitter Name	Roche Diagnostics Operations (RDO)
Address	9115 Hague Road
Indianapolis, IN, 46250, USA
Contact	David Tribbett
Phone: (317)-521-2964
FAX: (317)-521-2324
Email: david.tribbett@roche.com
Date Prepared	October 22, 2015
Proprietary Name	ONLINE TDM Carbamazepine Gen. 4
Common Name	Enzyme immunoassay, Carbamazepine
Classification Name	Neuroleptic drugs radioreceptor assay test system
Product Codes	KLT, 21 CFR § 862.3645
Predicate Devices	ONLINE TDM Carbamazepine, K031902
Establishment Registration	1823260, Roche Diagnostics Corporation

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DEVICE DESCRIPTION 1.

The ONLINE TDM Carbamazepine Gen. 4 assay is for the quantitative determination of carbamazepine in human serum or plasma on automated clinical chemistry analyzers. It is a homogeneous microparticle agglutination immunoassay based on the kinetic interaction of microparticles in solution (KIMS). Biotinylated drug hapten serves as the binding partner to anticarbamazepine antibody and streptavidin coated latex beads. A competitive reaction to a limited amount of specific anti-carbamazepine antibody takes place between the hapten and free carbamazepine in the sample. A decrease in the apparent signal produced by the microparticle agglutination is proportional to the amount of drug present in the sample.

2. INDICATIONS FOR USE

In vitro test for the quantitative determination of carbamazepine in serum and plasma on Roche/Hitachi cobas c systems.

Measurements obtained are used in monitoring levels of carbamazepine to help ensure appropriate therapy.

TECHNOLOGICAL CHARACTERISTICS 3.

The ONLINE TDM Carbamazepine Gen. 4 assay is a homogeneous microparticle agglutination immunoassay.

It is a two-reagent system used for the detection of carbamazepine in serum. Kinetic interaction of microparticles in solution (KIMS) will be measured using automated analyzers. In this technology biotinylated drug hapten attached to streptavidin coated latex beads serves as the binding partner to anti-carbamazepine antibody. A competitive reaction to a limited amount of specific anti-carbamazepine antibody takes place between the latex bound hapten and free carbamazepine in the serum sample. A decrease in the apparent signal is proportional to the amount of drug present in the sample.

Reagents - working solutions which are ready for use, are packaged in a cassette labeled with their instrument positioning B (Reagent 1) and C (Reagent 2).

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R1, Anti-carbamazepine antibody (sheep monoclonal); MES® buffer, pH 6.4; . preservative
R2, Carbamazepine biotinylated hapten; streptavidin coated latex microparticles: 0.1 . %; HEPES") buffer, pH 7.4; preservative
- 2-(N-Morpholino) ethanesulfonic acid a.
- b. N-(2-Hydroxyethyl)piperazine-N' -(2-ethanesulfonic acid)

The following table compares the similarities and differences of the candidate device to the predicate device.

Assay Comparison Similarities
Feature	Predicate Device:
ONLINE TDM Carbamazepine (K031902)	Candidate Device:
ONLINE TDM Carbamazepine Gen. 4
Intended Use	The ONLINE TDM Carbamazepine assay is
for the quantitative determination of
carbamazepine in human serum or plasma
on automated clinical chemistry analyzers.	In vitro test for the quantitative
determination of carbamazepine in serum
and plasma on Roche/Hitachi cobas c
systems.
Sample Types	Serum: Collect serum using standard
sampling tubes.
Plasma: Potassium EDTA, sodium or
lithium heparin plasma.	Serum: Collect serum using standard
sampling tubes.
Plasma: K2- and K3-EDTA, sodium or
lithium heparin plasma.
Test Principle	Homogeneous microparticle
agglutination immunoassay.	Same
Reagent Shelf Life
Stability	2-8 °C until expiration date	2-8 °C until expiration date
Reagent On-Board
Stability	30 days opened and refrigerated on the
analyzer. Do not freeze.	On-board in use and refrigerated on the
analyzer: 4 weeks
Measuring Range	0.2-20 µg/mL	2-20 µg/mL (8.5-85 µmol/L)
Traceability	This method has been standardized against
USP reference standards.	Same
Calibrator	COBAS-FP Carbamazebine Calibrator,
CAL A-F	Preciset TDM I, calibrators B-F
(Previously cleared 510(k): K031856)
Calibration
frequency	After reagent cassette change, after reagent
lot change and as required following quality
control procedures	After reagent lot change and as required
following quality control procedures
Controls	TDM Control Set, levels I, II and III	Same

Table 1: Substantial Equivalence – Assay Similarities and Differences
-----------------------------------------------------------------------

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Assay Comparison Similarities
Feature	Predicate Device:
ONLINE TDM Carbamazepine (K031902)	Candidate Device:
ONLINE TDM Carbamazepine Gen. 4
Lower Limits of
Measurement	Lower Detection Limit = 0.2 µg/mL
(0.81 µmol/L)	LoB = 0.3 µg/mL (1.3 µmol/L)
LoD = 0.5 µg/mL (2.1 µmol/L)
LoQ = 1.4 µg/mL (5.9 µmol/L)
Test Principle	The ONLINE TDM Carbamazepine assay is
a homogeneous microparticle agglutination
immunoassay. It is a two-reagent system
used for the detection of
carbamazepine in serum. Kinetic interaction
of microparticles in solution (KIMS) will be
measured using RD/Hitachi families of
automated analyzers. In this technology
biotinylated drug hapten serves as the
binding partner to 1) anti-carbamazepine
antibody and 2) streptavidin coated latex
beads. A competitive reaction to a limited
amount of specific anti-carbamazepine
antibody takes place between the hapten
and free carbamazepine in the serum
sample. A decrease in the apparent signal
is proportional to the amount of drug
present in the sample.	The ONLINE TDM Carbamazepine Gen. 4
assay is a homogeneous microparticle
agglutination immunoassay. It is a two-
reagent system used for the detection of
carbamazepine in serum. Kinetic
interaction of microparticles (KIMS) will be
measured using automated analyzers. In
this technology biotinylated drug hapten
attached to streptavidin coated latex
beads serves as the binding partner to
anti-carbamazepine antibody. A
competitive reaction to a limited amount of
specific anti-carbamazepine antibody
takes place between the latex bound
hapten and free carbamazepine in the
serum sample. A decrease in the apparent
signal is proportional to the amount of
drug present in the sample.
Reagent Composition	R1 Conjugate Reagent/Buffer
Carbamazepine biotinylated hapten;
2-(N-Morpholino) ethanesulfonic acid (MES)
buffer, pH 6.4; preservative; surfactant
R2 Latex-Antibody Reagent/Buffer
Anti-carbamazepine antibody (mouse
monoclonal); streptavidin coated latex
microparticles: 0.08%; N-(2-Hydroxyethyl)
piperazine-N'-(2-ethanesulfonic acid)
(HEPES) buffer, pH 7.5; preservative	R1 Anti-carbamazepine antibody (sheep
monoclonal); MES) buffer, pH 6.4;
preservative
R2 Carbamazepine biotinylated hapten;
streptavidin coated latex microparticles:
0.1 %; HEPES) buffer, pH 7.4;
preservative

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NON-CLINICAL PERFORMANCE EVALUATION 4.

The following performance data were provided in support of the substantial equivalence determination:

Detection Limit: LoB, LoD and LoQ according to CLSI EP17-A2 Precision according to CLSI EP5-A2 Linearity according to CLSI EP6-A Matrix Comparison - Anticoagulants Interferences Interference - Drugs Method Comparison to Predicate

Detection Limit 4.1.

LoB, LoD, and LoQ studies were performed based upon CLSI EP17-A2.

LoB:

The diluent is measured with 10-fold determinations per run on one instrument. Six runs distributed over 3 days are performed. Data analysis will be based on determination of the 95th percentile of the 60 measured values.

LoD:

The 5 samples with low analyte content spiked with Carbamazepine (with concentrations ranging from LoB to approx. 4 times specified LoB) are measured with 2-fold determination per run. Six runs distributed over 3 days are performed.

LoD is defined as the concentration, at which there is a 95% probability that a sample contains analyte.

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LoQ is the lowest amount of analyte in a sample that can be detected quantitatively within specified precision and accuracy ranges.

Nine samples are prepared which cover the concentration range between LoB and 2x LoQ. Those samples are tested in two aliquots over at least three days on one analyzer, 2 runs per day for 3 lots.

Expected or target value is determined with LC/MS.

Table 2: LoB, LoD, and LoQ Experimental Determination

	Representative Result (µg/mL)	Claimed in labeling (µg/mL)
Limit of Blank (LoB)	0.3	0.5
Limit of Detection (LoD)	0.5	1.0
Limit of Quantitation (LoQ)	1.4	2.0

Precision according to CLSI EP5-A 4.1.

Two runs per day for ≥ 21 days on the same analyzer. Repeatability (within run precision) and intermediate precision (within lab precision) is calculated. The samples have to be randomized in each run separately.

The data set has to be complete for the 21 days.

				Table 3: Repeatability Summary
--	--	--	--	--------------------------------	--

Specimen	Mean (ug/mL)	SD (ug/mL)	CV (%)
TDM Control 1	3.4	0.08	2.2
TDM Control 2	9.7	0.14	1.4
TDM Control 3	15.7	0.20	1.3
Human Serum 1	2.9	0.08	2.7
Human Serum 2	4.2	0.09	2.1
Human Serum 3	9.4	0.17	1.8
Human Serum 4	14.6	0.19	1.3
Human Serum 5	19.5	0.27	1.4

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Specimen	Mean (ug/mL)	SD (ug/mL)	CV (%)
TDM Control 1	3.4	0.10	2.8
TDM Control 2	9.7	0.22	2.3
TDM Control 3	15.7	0.28	1.8
Human Serum 1	2.9	0.10	3.3
Human Serum 2	4.2	0.12	2.9
Human Serum 3	9.4	0.25	2.6
Human Serum 4	14.6	0.36	2.4
Human Serum 5	19.5	0.56	2.9

Table 4: Intermediate Precision Summary

Linearity according to CLSI EP6-A 4.2.

A dilution series was prepared from a human serum sample pool and diluent (Analyte-free serum). The dilution series are prepared to obtain eleven levels (including the high concentration pool and diluent). The diluted samples shall span the measuring range including a sample at the lower end of the measuring range, a sample over the measuring range and samples at the medical decision points. The process was repeated for plasma samples.

The calculation is according to the CLSI guideline EP6-A. All measurement data of the dilution steps are calculated by regression.

Sample Type	Linear Regression Equation	Claimed Measuring Range
Serum	$y = 1.000x - 0.0$
Pearson correlation coefficient (R) = 0.997	2.0 to 20.0 µg/mL
K2-EDTA, Plasma	$y = 1.013x - 0.195$
Pearson correlation coefficient (R) = 0.999	2.0 to 20.0 µg/mL

Table 5: Linearity Results

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4.3. Matrix Comparison - Anticoagulants

Each pair of serum and plasma of a single donor are spiked with carbamazepine. Included in the data are 33 full tubes as described below.

A matrix comparison is executed by taking the serum as reference. Only samples within the limit of icteric, lipemic and hemolytic interference are allowed to be used. Samples cover the measuring range.

The following matrix comparisons are provided:

Gel separation tubes .
K2-EDTA plasma vs serum .
K3-EDTA plasma vs serum .
Li-Heparin plasma vs serum .
Na-Heparin plasma vs serum .

Table 6: Matrix Comparison

Anticoagulant	Correlation
Serum vs. Serum Gel Separation	$y = 1.01x + 0.177, r = 0.989$
Serum vs. Li-heparin	$y = 1.01x -0.290, r = 0.991$
Serum vs. Na-heparin	$y = 1.02x -0.382, r = 0.990$
Serum vs. K2-EDTA	$y = 1.02x -0.059, r = 0.988$
Serum vs. K3-EDTA	$y = 0.993x + 0.147, r = 0.994$

Interferences - H, L and I Indices 4.4.

The effect on quantitation of analyte in the presence of endogenous interfering substances is determined at two carbamazepine concentrations and a dilution set of the added interfering substances. The following lists the potential interfering substances evaluated and the highest concentration which was shown to not interfere with the assay:

Hemolysis: up to an H index of 1000 (approximate hemoglobin concentration 1000 mg/dL)

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Icterus/Bilirubin: up to an I index of 50 (approximate bilirubin concentration 50 mg/dL) Lipemia: up to an L index of 2000 (approximate triglyceride concentration up to 1000 mg/dL) Cholesterol: up to 600 mg/dL Rheumatoid Factor: up to 1200 IU/mL

Total Protein: up to 13 g/dL

Test procedure:

High concentrated stock solutions of the interference substances are prepared in a suitable solvent. Two human sample pools are spiked with the defined carbamazepine concentrations and each divided into two aliguots. The potential interfering substance is added to one aliquot of each pool, while the other aliquot is mixed with the same amount of solvent without the interfering substance. A dilution series is prepared with at least 10 dilution steps for each interferent by mixing the two aliquots.

The parts containing the interfering substance have the same carbamazepine concentrations as the aliquots containing no interfering substance. When diluting those two aliquots, the carbamazepine concentration remains constant while the concentration of interferent varies. Thus, the effect of increasing concentrations of interferent can be determined.

Median of the measured results is compared to the expected result (aliquot with no interfering substance) and the recovery is determined (paired difference testing).

This procedure is repeated for each of the interfering substances.

Interferences – Drugs 4.5.

Sixteen commonly used drugs were examined for potential interference on measurement with ONLINE TDM Carbamazepine Gen. 4.

Two human sample pools spiked with the defined carbamazepine concentrations are divided into two aliquots. One aliquot of each concentration is used as the reference sample for carbamazepine concentration and is not spiked with the drugs but the solvent for the drug.

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The other aliquots, with either the high or low carbamazepine concentration, are spiked with the respective amount of drug. The carbamazepine concentration of the spiked aliquots is determined in triplicate and compared to the carbamazepine concentration determined for the reference aliquot.

The defined pharmaceutical compounds are spiked into samples with concentrations according to EP7-A2 or higher concentrations. The mean values are calculated as well as the % deviations from the interference samples compared to the reference sample (paired difference testing).

| Drug | Highest Concentration Shown
Not to Interfere with
Carbamazepine (drug
concentrations in (mg/L)) |
|----------------------|----------------------------------------------------------------------------------------------------------|
| Acetylcysteine | 1660 |
| Ampicillin-Na | 1000 |
| Ascorbic acid | 300 |
| Cefoxitin | 2500 |
| Heparin | 5000 U/L |
| Levodopa | 20 |
| Methyldopa | 20 |
| Metronidazol | 200 |
| Doxycyclin | 50 |
| Acetylsalicylic Acid | 1000 |
| Rifampicine | 60 |
| Cyclosporine | 5 |
| Acetaminophen | 200 |
| Ibuprofen | 500 |
| Phenylbutazone | 400 |
| Theophyllin | 100 |

Table 7: Common Drug Interferences

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4.6. Cross-reactivity

The following compounds were tested for cross-reactivity at low (3 µg/mL) and high (12 µg/mL) carbamazepine concentration:

Table 8: Cross-reactivity Testing

| Compound | Concentrat tested
(µg/mL) | % Cross
reactivity at 3
µg/mL | % Cross
reactivity at 12
µg/ml |
|-----------------------------------------|----------- | Carbamazepine-10,11-
epoxide | 29.6 µg/mL | Oxcarbazepine (Oxc) | 100 µg/mL | 10-Hydroxycarbamaze-
pine (MHD) | 100 µg/mL | Nortriptyline | 50 µg/mL | Amitriptyline | 100 µg/mL | Imipramine | 200 µg/mL | Phenothiazine | 200 µg/mL | Phenylbutazone | 450 µg/mL | Promethazine | 1000 µg/mL | Phenytoin | 1000 µg/mL | Mephenytoin | 1000 µg/mL | 2-Phenyl-2-
ethylmalonamide | 1000 µg/mL | Ethotoin | 1000 µg/mL | Valproic acid | 1000 µg/mL | Amobarbital | 1000 µg/mL | Chlordiazepoxide | 30 µg/mL | Clonazepam | 12 µg/mL | Ethosuximide | 1000 µg/mL | Diazepam | 25 µg/mL | Gluthethimide | 1000 µg/mL | Methosuximide | 100 µg/mL | p-Hydroxypheno-
barbital | 100 µg/mL | 5-(p-Hydroxyphenyl)-
phenylhydantoin | 1000 µg/mL | Phenobarbital | 1000 µg/mL | Primidone | 1000 µg/mL | Probenecid | 500 µg/mL | Secobarbital | 1000 µg/mL ion
-------------------------|-------------------------------------|--------------------------------------|
| 2.87 | 1.4 |
| 0.88 | 0.2 |
| 0.63 | 0.2 |
| 0 | 0.3 |
| 0 | 0 |
| 0 | 0 |
| 0 | 0 |
| 0.05 | 0 |
| 0.02 | 0 |
| 0 | 0 |
| 0.5 | 0.1 |
| 0.31 | 0.2 |
| 0.12 | 0.10 |
| 0.02 | 0 |
| 0 | 0 |
| 0.33 | 0.4 |
| 0.44 | 0.3 |
| 0.01 | 0 |
| 0.21 | 0.4 |
| 0 | 0 |
| 0.01 | 0 |
| 0.05 | 0.4 |
| 0.01 | 0 |
| 0.01 | 0 |
| 0.02 | 0 |
| 0.03 | 0 |
| 0.02 | 0 |

14

Method Comparison to Predicate 4.7.

One hundred single native human samples of patients taking carbamazepine covering the reportable range are tested.

The samples are tested in singlicate on the candidate and predicate device (cobas c 501).

The data was evaluated using Deming Regression analysis.

y = 0.994x - 0.054 µg/mL r = 0.993

CONCLUSIONS 5.

The submitted information in this premarket notification supports a substantial equivalence decision.