CARBAMAZEPINE, VALPROIC ACID, TDM CALIBRATION SET B AND ABTROL, NORTROL CONTROLS
Device Facts
| Record ID | K063131 |
|---|---|
| Device Name | CARBAMAZEPINE, VALPROIC ACID, TDM CALIBRATION SET B AND ABTROL, NORTROL CONTROLS |
| Applicant | Thermo Electron OY |
| Product Code | KLT · Clinical Toxicology |
| Decision Date | Oct 5, 2007 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.3645 |
| Device Class | Class 2 |
Indications for Use
For in vitro diagnostic use in the quantitative determination of the carbamazepine concentration in human serum on T60 analyzer. Measurements are used in the diagnosis and treatment of carbamazepine overdose and in monitoring levels of carbamazepine to help ensure proper therapy. For in vitro diagnostic use in the quantitative determination of the valproic acid concentration in human serum on T60 instrument. Measurements are used in the diagnosis and treatment of valproic acid overdose and in monitoring levels of valproic acid to help ensure proper therapy. For in vitro diagnostic use as a calibrator in the quantitative measurement of the kit code 981645 Carbamazepine and kit code 981650 Valproic acid assays on T60 Analyzer.
Device Story
The Carbamazepine and Valproic Acid test systems are in vitro diagnostic assays designed for use on T60 Clinical Chemistry Analyzers. The device utilizes a homogeneous enzyme immunoassay system based on recombinant DNA technology (US Patent 4708929). The system processes human serum samples to quantitatively measure drug concentrations. The output is a concentration value (µg/ml) provided to clinicians to assist in the diagnosis and treatment of drug overdose and to monitor therapeutic levels to ensure proper patient management. The device is intended for professional use in clinical laboratory settings.
Clinical Evidence
Performance was established through bench testing and method comparison studies. Precision was evaluated with total CVs ranging from 2.8% to 6.3% for Carbamazepine and 2.7% to 5.4% for Valproic Acid. Method comparison against predicate devices showed strong correlation (r=0.993 for both assays) with N=134 and N=136 respectively. Interference testing confirmed accuracy in the presence of hemoglobin, bilirubin, and lipemia up to specified concentrations.
Technological Characteristics
Homogenous enzyme immunoassay; bacterial beta-galactosidase fragments; spectrophotometric detection. Reagents include MOPS/MES/HEPES buffers, mouse monoclonal antibodies, enzyme donor/acceptor conjugates, and sodium azide. Storage 2-8°C. Analyzed on T60 Clinical Chemistry Analyzers. Calibrators are ready-to-use liquid, traceable to USP reference materials.
Indications for Use
Indicated for quantitative in vitro diagnostic determination of carbamazepine or valproic acid concentrations in human serum using T60 Clinical Chemistry Analyzers. Used for diagnosis/treatment of drug overdose and therapeutic drug monitoring. No specific age or gender contraindications provided.
Regulatory Classification
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.
Predicate Devices
- Cedia Carbamazepine II (k914857)
- Cedia Valproic Acid II (k930734)
- Cedia DAU 5-Drug Calibrators (k935792)
Related Devices
- K063145 — PHENOBARBITAL, PHENYTOIN, TDM CALIBRATION SET B AND ABTROL/NORTROL CONTROLS · Thermo Electron OY · Oct 17, 2007
- K964442 — VALPROIC ACID ASSAY FOR THE TECHNICON IMMUNO 1 SYSTEM · Bayer Corp. · Dec 18, 1996
- K042476 — VITROS CHEMISTRY PRODUCTS VALP REAGENT; VITRO CHEMISTRY PRODUCTS CALIBRATOR KIT 12; VITROS CHEMISTRY PRODUCTS TDM PERFOS · Ortho-Clinical Diagnostics, Inc. · Dec 1, 2004
- K042807 — ADVIA IMS VALPROIC ACID METHOD · Bayer Healthcare, LLC · Feb 8, 2005
Submission Summary (Full Text)
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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE
A. 510(k) Number:
k063131
B. Purpose for Submission:
New device
C. Measurand:
Carbamazepine and Valproic Acid
D. Type of Test:
Quantitative, homogenous enzyme immunoassay
E. Applicant:
Thermo Fisher Scientific Oy
F. Proprietary and Established Names:
Carbamezepine
Valproic Acid
TDM Calibration Set B
G. Regulatory Information:
1. Regulation section:
21 CFR 862.3645, Neuroleptic drugs radioreceptor assay test system.
(Carbamezepine and Valproic Acid)
21 CFR 862.3200, Calibrator Drug Mixture
2. Classification:
II
3. Product code:
KLT, Enzyme Immunoassay, Carbamazepine
LEG, Enzyme Immunoassay, Valproic Acid
DKB, Clinical Toxicology Calibrator
4. Panel:
Toxicology (91)
H. Intended Use:
1. Intended use(s):
See Indications for use.
2. Indication(s) for use:
Carbamazepine
The Carbamazepine is intended for the quantitative in-vitro diagnostic determination of the carbamazepine concentration in human serum using T60 Clinical Chemistry Analyzers. Measurements are used in the diagnosis and treatment of carbamazepine overdose and in monitoring levels of carbamazepine to help ensure proper therapy.
Valproic Acid
The Valproic Acid is intended for quantitative in-vitro diagnostic determination of the valproic acid concentration in human serum using T60 Clinical Chemistry Analyzers. Measurements are used in the diagnosis and treatment of valproic acid
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overdose and in monitoring levels of valproic acid to help ensure proper therapy.
**Calibrator**
TDM Calibration set B is intended for in vitro diagnostic use as a calibrator in the quantitative measurement of the kit code 981645 Carbamazepine and kit code 981650 Valproic acid assays on T60 Analyzer.
3. **Special conditions for use statement(s):**
Prescription use
4. **Special instrument requirements:**
T60 Clinical Chemistry Analyzers
I. **Device Description:**
**Carbamazepine**
The device consists of 4 reagents (Reagents A and B: buffer and lyophilizate).
**Reagent A:**
- buffer contains enzyme acceptor MOPS (3-(N-morpholino) propane sulfonic acid buffer, mouse monoclonal anti-carbamazepine antibodies, and NaN₃.
- lyophilizate contains enzyme acceptor (microbial), buffer salts and NaN₃.
**Reagent B:**
- buffer contains enzyme donor reconstitution MES (2-(N-morpholino) ethane sulfonic acid buffer and NaN₃.
- lyophilizate contains enzyme donor (microbial) conjugated to carbamazepine, Chlorophenol red-β-D-galactopyranoside, buffer salts, and NaN₃.
**Valproic Acid**
The device consists of 4 reagents (Reagents A and B: buffer and lyophilizate)
**Reagent A:**
- buffer contains enzyme acceptor HEPES - (N-[2-Hydroxyethyl] piperazine-N-[2-ethanesulfonic acid]) buffer) and NaN₃.
- lyophilizate contains enzyme acceptor (microbial), mouse monoclonal anti-valproic antibody, BSA, sodium salicylate, buffer salts, and NaN₃.
**Reagent B:**
- buffer contains enzyme donor reconstitution HEPES - (N-[2-Hydroxyethyl]piperazine-N-[2-ethanesulfonic acid]) buffer) and NaN₃.
- lyophilizate contains enzyme donor (microbial), conjugated to valproic acid, Chlorophenol red-β-D-galactopyranoside, goat anti-mouse antibodies, buffer salts, and NaN₃.
**Calibrator**
TDM Calibration set B consists of two levels of ready to use calibrators. The kit contains 1 vial/7.5 mL B0 calibrator and 1 vial/5.0 mL B1. These calibrators contain buffer salts, bovine serum albumin and <0.15% sodium azide; the B0 calibrator may also be used for dilution of high samples.
J. **Substantial Equivalence Information:**
1. **Predicate device name(s):**
Cedia Carbamazepine II
Cedia Valproic Acid II
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Cedia DAU 5-Drug Calibrators
2. Predicate 510(k) number(s):
k914857
k930734
k935792
3. Comparison with predicate:
| Carbamazepine – Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Indications | Measurements are used in the diagnosis and treatment of carbamazepine overdose and in monitoring levels of carbamazepine to ensure proper therapy. | Same |
| Storage | 2 to 8°C. | Same |
| Technology | Quantitative, homogenous enzyme immunoassay | Same |
| Carbamazepine – Differences | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Instrument | T60 Clinical Chemistry Analyzers | Roche Hitachi 911/912 Analyzers |
| Range | 1.0 to 19.0 μg/ml | 0.5 to ~20 μg/ml |
| Matrix | Serum | Serum and Plasma |
| Valproic Acid – Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Indications | Measurements are used in the diagnosis and treatment of valproic acid overdose and in monitoring levels of valproic acid to ensure proper therapy. | Same |
| Technology | Quantitative, homogenous enzyme immunoassay | Same |
| Storage | 2 to 8°C | Same |
| Valproic Acid – Differences | | |
| Item | Device | Predicate |
| Instrument | T60 Clinical Chemistry Analyzers | Roche Hitachi 912 |
| Range | 3.0 μg/ml to 142.5 μg/ml | 3.0 μg/ml to ~150 μg/ml |
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| Valproic Acid – Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Matrix | Serum | Serum or Plasma |
K. Standard/Guidance Document Referenced (if applicable):
CLSI - Evaluation of Precision Performance of Clinical Chemistry Devices - EP05-A2
CLSI - Evaluation of the Linearity of Quantitative Analytical Methods - EP06-A
CLSI - Method Comparison and Bias Estimation Using Patient Samples - EP09-A2
L. Test Principle:
The assays are based on the bacterial enzyme β-galactosidase which has been genetically engineered into two inactive fragments. These spontaneously reassociate to form fully active enzyme that in the assay formats, cleaves a substrate, generating a color change that can be measured spectrophotometrically.
M. Performance Characteristics (if/when applicable):
1. Analytical performance:
a. Precision/Reproducibility:
Carbamazepine
To evaluate precision, the within-lab and repeatability of the T60 Carbamazepine assay was calculated using the CLSI EP5-A2 method. Three commercially marketed controls (low, mid, high) were tested in duplicate during two runs per day over 21 days. The results are presented below:
| Mean Concentration (μg/mL) | 3.0 | | 9.5 | | 15.0 | |
| --- | --- | --- | --- | --- | --- | --- |
| | SD | CV% | SD | CV% | SD | CV% |
| Within-run | 0.09 | 2.8 | 0.14 | 1.5 | 0.16 | 1.1 |
| Between-run | 0.07 | 2.4 | - | - | 0.14 | 0.9 |
| Total | 0.19 | 6.3 | 0.32 | 3.3 | 0.42 | 2.8 |
Valproic Acid
To evaluate precision, the within-lab and repeatability of the T60 Valproic Acid assay was calculated using the CLSI EP5-A2 method. Three commercially marketed controls (low, mid, high) were tested in duplicate during two runs per day over 21 days. The results were as follows:
| Mean Concentration (μg/mL) | 35.0 | | 81.1 | | 113.6 | |
| --- | --- | --- | --- | --- | --- | --- |
| | SD | CV% | SD | CV% | SD | CV% |
| Within-run | 0.43 | 1.2 | 0.81 | 1.0 | 1.01 | 0.9 |
| Between-run | 0.61 | 1.8 | 1.08 | 1.3 | 1.07 | 0.9 |
| Total | 1.90 | 5.4 | 3.15 | 3.9 | 3.11 | 2.7 |
b. Linearity/assay reportable range:
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Carbamazepine
The linearity study was performed using CLSI EP6-A as a guideline. Dilution series were made from 7 human sera samples with low levels of carbamazepine spiked over a measured range of range of 1.2 to 18.9 ug/mL and analyzed on a T60 analyzer. Four parallel measurements were made in random order. The study was performed with one reagent lot. Observed error was ≤5.0%. The claimed measuring range is 1.0 to 19.0 ug/dL.
Valproic Acid
The linearity study was performed using CLSI EP6-A as a guideline. Dilution series were made from 9 human sera samples with low levels of valproic acid spiked over a measured range of range of 4.3 to 141 ug/mL and analyzed on a T60 analyzer. Four parallel measurements were made in random order. The study was performed with one reagent lot. Observed error was ≤5.8%. The claimed reportable range for this assay is 3.0-142.5 µg/mL.
The package insert instructs customers to manually dilute (1:1) samples with TDM Calibrator B0 when results exceed the measuring range.
To validate the extended measurement range for carbamazepine, the sponsor used a high serum sample and made seven dilutions from the highest concentration down to normal human sera. The data support an extended range up to 37.5 µg/ml.
To validate the extended measuring range for valproic acid, the sponsor used a high serum sample and made eleven dilutions from the highest concentration down to normal human sera. The data support an extended range up to 282 µg/ml.
c. Traceability, Stability, Expected values (controls, calibrators, or methods):
The TDM B Calibrators are purchased from another manufacturer and relabeled. The TDM B Calibrator target values are determined using assay specific methods on the T60. The target value is the median of all values obtained and traceable to USP reference materials. The product stability claims are as follows: Open vial at 2-8°C 60 days and Shelf life 2-8°C 24 months.
d. Detection limit
Carbamazepine
The lower limit of the assay (limit of blank - LOB) was determined by assaying 24 consecutive replicates of the analyte free (0 level) calibrator on the T60 Clinical Chemistry Analyzer. The LOB was calculated by multiplying the standard deviation by 3 and adding it to the absolute value of the mean. The limit of the blank was calculated to be 0.5 ug/mL.
The sponsor conducted a functional sensitivity study to determine the concentration at which acceptable assay precision is observed. A functional
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sensitivity study was performed using serum samples and the T60 Clinical Chemistry Analyzer. The functional sensitivity was defined as the lowest concentration that can be measured with an inter-assay CV of 20%. Serum samples were run in duplicates of 4 and the mean and SD were calculated based on the observed results. The sponsor claimed that the functional sensitivity of the candidate device is 1.0 ug/mL, which is the lower limit of the measuring range.
## Valproic Acid
The limit of detection (limit of blank -LOB) was determined by assaying 24 consecutive replicates of the analyte free (0 level) calibrator on the T60 Clinical Chemistry Analyzer. The LOB was calculated by multiplying the standard deviation by 3 and adding it to the absolute value of the mean. The limit of the blank was calculated to be 1.3 ug/mL.
The sponsor conducted a functional sensitivity study to determine the concentration at which acceptable assay precision is observed. A functional sensitivity study was performed using serum samples and the T60 Clinical Chemistry Analyzer. The functional sensitivity was defined as the lowest concentration that can be measured with an inter-assay CV of 20%. Serum samples were run in duplicates of 4 and the mean and SD were calculated based on the observed results. The sponsor claimed that the functional sensitivity of the candidate device is 3.0 ug/mL, the lower limit of the measuring range.
## e. Analytical specificity:
Interference studies were performed using CLSI EP7-A as a guideline. Non-interference was defined as deviations less than or equal to ± 10% of the initial value. The results are presented below:
## Carbamazepine:
Bilirubin (total): No interference found up to 58 mg/dl
Hemolysate: No interference found up to 1000 mg/dl
Lipemia: No interference found up to 1000 mg/dl
The sponsor evaluated the specificity of the carbamazepine assay by testing the following compounds:
| Compound | Concentration Tested (μg/ml) | Carbamazepine Concentration (μg/ml) | % Cross-reactivity |
| --- | --- | --- | --- |
| Amitryptiline | 100 | 17.7 | 18.6 |
| Carbamazepine-10,11-epoxide | 250 | 18.1 | 7.4 |
| Diazepam | 250 | 12.0 | 4.8 |
| Imipramine | 200 | 11.3 | 5.6 |
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| Compound | Concentration Tested (μg/ml) | Carbamazepine Concentration (μg/ml) | % Cross-reactivity |
| --- | --- | --- | --- |
| Methsuximide | 1000 | 10.0 | 1.0 |
| Nortriptyline | 50 | 16.4 | 17.2 |
| Phenothiazine | 200 | 16.4 | 8.6 |
| Probenecid | 500 | 10.1 | 2.0 |
The drugs listed below were spiked into normal human serum pools at the concentrations shown below. The manufacturer indicated that the drug levels evaluated were at a concentrations greater than what would be expected for a maximum daily dose. Results were compared to those of control samples without cross-reactant. The drugs and concentrations tested are shown below. Less than 1.0% cross-reactivity was observed for the following compounds:
| Compound | Concentration Tested (μg/ml) |
| --- | --- |
| 2-Phenyl-2-ethylmalonamide | 1000 |
| 5-(p-Hydroxyphenyl- phenylhydantoin | 1000 |
| Amobarbital | 1000 |
| Chlorazepate | 200 |
| Chlordiazepoxide | 1000 |
| Ethosuximide | 1000 |
| Ethotoin | 1000 |
| Glutethimide | 1000 |
| Mephenytoin | 1000 |
| p-Hydroxyphenobarbital | 1000 |
| Phenytoin | 1000 |
| Primidone | 200 |
| Promethazine | 1000 |
| Secobarbital | 1000 |
| Valproic Acid | 700 |
Interference studies for valproic acid were performed using CLSI EP7-A as a guideline. The results are presented below:
**Valproic Acid:**
Bilirubin (total): No interference found up to 58 mg/dl
Hemolysate: No interference found up to 1000 mg/dl
Lipemia: No interference found up to 1000 mg/dl
The following compounds were tested for cross-reactivity in serum samples. Results were compared to those of control samples without cross-reactant.
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| Compound | Concentration Tested (μg/ml) | Valproic Acid Concentration (μg/ml) | % Cross-reactivity |
| --- | --- | --- | --- |
| 3-Hydroxy-2-propylpentanoic acid | 660 | 28.8 | 4.4 |
| 4-Hydroxy-2-propylpentanoic acid | 660 | 28.8 | 4.4 |
| 5-Hydroxy-2-propylpentanoic acid | 660 | 38.2 | 5.8 |
| 3-Oxo-2-propylpentanoic acid | 1072 | 41.2 | 3.8 |
| PEMA | 1870 | 3.0 | <0.16 |
| 2-Propyl-2,3-pentadienoic acid | 300 | 42.7 | 14.2 |
| 2-Propyl-2-pentanoic acid | 2275 | 22.2 | 1.0 |
| 2-Propyl-4-pentanoic acid | 278 | 62.1 | 22.3 |
| 2-Propylglutaric acid | 735 | 3.0 | <0.4 |
| 2-Propyl-succinic acid | 333 | 3.0 | <0.9 |
| Carbamazepine | 7500 | 3.0 | <0.04 |
| Carbamazepine-10,11-epoxide | 333 | 3.0 | <0.9 |
| Clonazepam | 1000 | 3.0 | <0.3 |
| Diazepam | 1000 | 3.0 | <0.3 |
| Phenobarbital | 7500 | 4.5 | <0.06 |
| Phenytoin | 7500 | 3.0 | <0.04 |
| Primidone | 300 | 3.0 | <1.0 |
| Salicylic acid | 75000 | 3.0 | <0.004 |
f. Assay cut-off:
Not applicable
2. Comparison studies:
a. Method comparison with predicate device:
The T60 Carbamazepine assay was compared to the predicate device using CLSI Document EP9-A2 as a guideline for the method comparison study. One hundred thirty-four serum samples with Carbamazepine values ranging from 1.9 - 19.6 μg/mL as determined by the predicate device were split and run on the predicate and the proposed devices. The regression statistics are as follows:
Slope = 0.98
Intercept = 0.02 μg/mL
Correlation Coefficient = 0.993
The T60 Valproic Acid assay was compared to the predicate device using CLSI Document EP9-A2 as a guideline for the method comparison study. One hundred thirty-six serum samples with Valproic Acid values ranging from 3.2 - 143.4
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μg/mL as determined by the predicate device were split and run on the predicate and the proposed devices. The regression statistics are as follows:
Slope = 0.996
Intercept = 1.4 μg/mL
Correlation Coefficient = 0.993
b. Matrix comparison:
Not applicable.
3. Clinical studies:
a. Clinical Sensitivity:
Not applicable.
b. Clinical specificity:
Not applicable.
c. Other clinical supportive data (when a. and b. are not applicable):
Not applicable.
4. Clinical cut-off:
Not applicable; these are quantitative assays.
5. Expected values/Reference range:
Carbamazepine
A therapeutic range of 4 to 12 μg/mL has been reported for Carbamazepine.
See Tietz N. W. Fundamentals of Clinical Chemistry 4th edition, WB Saunders Co., Philadelphia, PA; 1996; 402-426.
Valproic Acid
A therapeutic range of 50 to 100 μg/mL has been reported for Valproic Acid.
See Tietz N. W. Fundamentals of Clinical Chemistry 4th edition, WB Saunders Co., Philadelphia, PA; 1996; 402-426.
N. Proposed Labeling:
The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.
O. Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
