ADVIA IMS VALPROIC ACID METHOD

K042807 · Bayer Healthcare, LLC · LEG · Feb 8, 2005 · Clinical Toxicology

Device Facts

• Record ID: K042807
• Device Name: ADVIA IMS VALPROIC ACID METHOD
• Applicant: Bayer Healthcare, LLC
• Product Code: LEG · Clinical Toxicology
• Decision Date: Feb 8, 2005
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.3645
• Device Class: Class 2

Indications for Use

The Bayer ADVIA IMS Valproic Acid method is for in vitro diagnostic use to measure the antiepileptic drug valproic acid in human serum and plasma. Measurements of valproic acid (2-propylpentanoic acid) are used as an aid in the diagnosis and treatment of valproic acid overdose, and in monitoring therapeutic levels of valproic acid to ensure appropriate therapy.

Device Story

ADVIA IMS Valproic Acid method is an in vitro diagnostic assay for quantitative measurement of valproic acid in human serum and plasma. Used on Bayer ADVIA IMS systems; operated by laboratory personnel. Input consists of patient serum or plasma samples; device performs chemical analysis to determine drug concentration. Output is a numerical concentration value (µg/mL) provided to clinicians. Results aid in monitoring therapeutic drug levels and managing overdose cases, facilitating appropriate patient therapy. Device is intended for clinical laboratory use.

Clinical Evidence

No clinical studies were performed. Evidence is based on analytical bench testing. Method comparison study (n=50) between ADVIA IMS and Centaur systems showed high correlation (r=0.997, slope=0.98). Precision evaluated over 10 days (n=79) showed total CVs ranging from 2.0% to 4.4%. Linearity established from 6.25 to 150 μg/mL. Interference testing confirmed no significant effect from common antiepileptic drugs or endogenous substances (hemoglobin, triglycerides, bilirubin, protein). Matrix equivalency confirmed for serum, heparinized plasma, and EDTA plasma.

Technological Characteristics

In vitro diagnostic reagent system for use on ADVIA IMS automated analyzers. Quantitative assay for valproic acid. Analytical range 0.57 to 150 µg/mL. System utilizes specific calibrators for standardization.

Indications for Use

Indicated for patients requiring therapeutic drug monitoring of valproic acid or assessment of valproic acid overdose. Used for quantitative measurement in human serum and plasma.

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

• Bayer Centaur Valproic Acid (K013488)

Submission Summary (Full Text)

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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE

A. 510(k) Number: k042807
B. Purpose for Submission: Notification of intent to manufacture and market the device: BAYER ADVIA IMS Valproic Assay with Calibrator.
C. Measurand: Valproic Acid
D. Type of Test: Competitive, homogenous, immunoassay with Chemiluminescence and paramagnetic particles.
E. Applicant: Bayer HealthCare LLC
F. Proprietary and Established Names: Proprietary name – ADVIA IMS Valproic Acid Assay, Valproic Acid Calibrator. Common name – Valproic Acid

G. Regulatory Information:

1. Regulation section: Valproic Acid Assay - 21 CFR 862.3645
Valproic Acid calibrator - 21 CFR 862.3200
2. Classification: Class II
Class II
3. Product code: Valproic Acid Assay – LEG
Valproic Acid Calibrator - DKB
4. Panel: 91 - Toxicology

H. Intended Use:

1. Intended use(s): The Bayer ADVIA IMS Valproic Acid is for in vitro diagnostic use to measure the antiepileptic drug valproic acid in human serum and plasma. Measurements of valproic acid (2-propylpentanoic acid) are used as an aid in the diagnosis and treatment of valproic acid overdose, and in monitoring therapeutic levels of valproic acid to ensure appropriate therapy.
2. Indication(s) for use: The Bayer ADVIA IMS Valproic Acid is for in vitro diagnostic use to measure the antiepileptic drug valproic acid in human serum and plasma. Measurements of valproic acid (2-propylpentanoic acid) are used as an aid in the diagnosis and treatment of valproic acid overdose, and in monitoring therapeutic levels of valproic acid to ensure appropriate therapy.

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3. Special conditions for use statement(s): For prescription use only.
4. Special instrument requirements: The BAYER ADVIA IMS Valproic Acid assay and calibrator are intended for use on the Bayer ADVIA IMS Analyzer.

I. Device Description: The Bayer ADVIA IMS Valproic Acid is for in vitro diagnostic use to measure the antiepileptic drug valproic acid in human serum and plasma. Measurements of valproic acid (2-propylpentanoic acid) are used as an aid in the diagnosis and treatment of valproic acid overdose, and in monitoring therapeutic levels of valproic acid to ensure appropriate therapy.

The device consists of liquid reagent used only on the Bayer ADVIA IMS for the determination of quantitative Valproic Acid results. Sold separately are liquid calibrators based on human serum with clinically significant levels of valproic acid added. These calibrators are tested and shown to be non-reactive for HBsAg, HIV, and anti-HCV using FDA approved tests.

J. Substantial Equivalence Information:

1. Predicate device name(s): ADVIA Centaur Valproic Acid assay.
2. Predicate 510(k) number(s): k013959
3. Comparison with predicate:

| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Intended Use | The Bayer ADVIA IMS Valproic Acid is for in vitro diagnostic use to measure the antiepileptic drug valproic acid in human serum and plasma. Measurements of valproic acid (2-propylpentanoic acid) are used as an aid in the diagnosis and treatment of valproic acid overdose, and in monitoring therapeutic levels of valproic acid to ensure appropriate therapy. | For in vitro diagnostic use in the determination of valproic acid in blood or serum using the Bayer CENTAUR system. |

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| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Principle | Competitive, homogenous, immunoassay with Chemiluminescence and paramagnetic particles. | Competitive, homogenous, immunoassay with Chemiluminescence and paramagnetic particles. |
| Reagents | Similar | Two liquid reagents contained in system specific packaging |
| | Differences | |
| Storage | 2-8 °C | 2-8 °C away from light |
| Stability | 14 days on system | 30 days on system |
| Calibrator | Six Level calibration | Two level calibration |

K. Standard/Guidance Document Referenced (if applicable):
NCCLS - How to define, determine, and utilize reference intervals in the clinical laboratory, C28-A.
NCCLS - Precision Performance of clinical chemistry devices, EP5-A.
NCCLS - Method comparison and bias using patient samples, EP9-A.
NCCLS - Procedures for the handling and processing of blood samples, H18-A2.
NCCLS – Interference testing in clinical chemistry, EP7-P.

L. Test Principle: The BAYER ADVIA IMS Valproic assay is based upon established competitive, homogenous, immunoassay with chemiluminescence and paramagnetic particles.

M. Performance Characteristics (if/when applicable):

1. Analytical performance:
a. Precision/Reproducibility: Within run and total run imprecision were evaluated for ten days by testing three levels of commercially available Bayer Ligand Controls. The imprecision study was performed on system B23 for ten days with two runs per day and two cups per run. The Day 1 calibration was used for all runs. Within run and Total Imprecision was calculated using analysis of variance.

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Imprecision Data

| Product | Days | Runs | N | Mean μg/mL | Within Run | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | | SD | %CV | SD | %CV |
| Ligand Control 1 | 10 | 20 | 79 | 34.0 | 0.9 | 2.7 | 1.5 | 4.4 |
| Ligand Control 2 | 10 | 20 | 79 | 70.2 | 1.3 | 1.9 | 2.0 | 2.9 |
| Ligand Control 3 | 10 | 20 | 79 | 98.9 | 1.3 | 1.4 | 1.9 | 2.0 |

b. Linearity/assay reportable range: 6.25 μg/mL up to valproic acid concentration in highest calibrator (Level 6) (approximately 150 μg/mL). The linearity of this method was evaluated by comparing the recovery of the six level Valproic Acid calibrators as unknowns. Recoveries ranged from 142 % at 6.25 μg/mL to 102 % at 150 μg/mL.

c. Traceability, Stability, Expected values (controls, calibrators, or methods): The calibrators are human serum based and stored at 2 – 8 °C. The calibrators are traceable to an internal standard manufactured using highly purified material. Standard reference, SRM, Antiepilepsy Drug Level Assay Standard from the National Institute of Standards and Technology were evaluated and found to recover at 109% of target concentrations.

The stability of the IMS Valproic Acid Calibration is based on real time stability studies. Six lots of calibrators manufactured according to final production and quality assurance procedures were tested. The analyte was tested using a single instrument.

Vials from each lot were stored at the recommended temperature of 2 – 8 °C (test samples) for the duration of the studies. At approximately 3 month intervals, samples of the test vials were tested for the recovery of valproic acid. Based on results from 6 lots, the product was assigned 18 months stability.

d. Detection limit: The lowest detectable signal, as determined by subtracting two times the within run SD from the zero calibrator is 0.57 μg/mL.

e. Analytical specificity: Pooled serum samples with valproic acid levels of 55.8 to 69.0 μg/mL were spiked with the compounds listed below to the concentrations as shown. ADVIA Valproic Acid assay results from the spiked samples were compared with those of unspiked control samples. These compounds did not have a significant effect on the

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ADVIA Valproic Acid measurement.

| Compound | Amount added (μg/mL) |
| --- | --- |
| Carbamazepine | 1000 |
| Clonazepam | 100 |
| Diazepam | 100 |
| Ethosuximide | 1000 |
| Phenobarbital | 750 |
| Phenytoin | 1000 |
| Primidone | 1000 |
| Aspirin | 1000 |

Heterophilic antibodies in human serum can react with reagent immunoglobulins, interfering with in vitro immunoassays. Patients routinely exposed to animals or animal serum products can be prone to this interference and value anomalies may be observed.

| Serum specimens that are... | Demonstrate <5% and/or statistically insignificant (p≥0.05, t-test) change in results up to |
| --- | --- |
| Hemolyzed | 500mg/dL of hemoglobin |
| Lipemic | 3000mg/dL of triglycerides |
| Icteric | 5mg/dL of bilirubin |
| Protonemic | 2 g/dL of protein |

f. Assay cut-off: N/A

2. Comparison studies:

a. Method comparison with predicate device: Fifty patient serum samples were tested on both the ADVIA IMS System and the Centaur System. The correlation is summarized as follows: $y =$ ADVIA IMS, $x =$ Centaur, Slope $= 0.98$ , Intercept $= 4.9$ , Sy.x $= 3.13$ , r $= 0.997$ , n $= 50$ , IMS Range ( $\mu g/mL$ ) 13.4 - 144.

b. Matrix comparison: The serum/plasma equivalency studys was run on ADVIA IMS with matched human serum, heparinized plasma and EDTS-plasma samples. The results are summarized as follows.

| Y | X | Slope | Intercept | Sy.x | R | N | IMS Range μg/mL |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Heparinized Plasma | Serum | 0.99 | 0.58 | 2.03 | 0.999 | 19 | 2.7 to 147.8 |
| EDTA Plasma | Serum | 1.00 | -0.20 | 2.60 | 0.998 | 19 | 3.8 to 147.5 |

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3. Clinical studies:
a. Clinical Sensitivity: N/A
b. Clinical specificity: N/A
c. Other clinical supportive data (when a. and b. are not applicable): N/A

4. Clinical cut-off: N/A

5. Expected values/Reference range: A therapeutic range of 50 to 100 µg/mL (347 to 693 µmol/L) has been reported for Valproic Acid by Tietz N. W. Clinical Guide to Laboratory Tests. Philadelphia, PA, WB Saunders; 1995; 884-885.

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.

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