Acetaminophen
Device Facts
| Record ID | K202644 |
|---|---|
| Device Name | Acetaminophen |
| Applicant | Sekisui Diagnostics P.E.I., Inc. |
| Product Code | LDP · Clinical Toxicology |
| Decision Date | Feb 18, 2022 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.3030 |
| Device Class | Class 2 |
Indications for Use
The Acetaminophen assay is used for the quantitative determination of acetaminophen in human serum or plasma on the ARCHITECT c Systems. The Acetaminophen assay is to be used as an aid in the diagnosis and treatment of acetaminophen overdose toxicity.
Device Story
The Acetaminophen assay is an enzymatic, spectrophotometric in vitro diagnostic test for measuring acetaminophen concentration in human serum or plasma. It utilizes an enzyme reagent containing aryl acylamidase to cleave the amide bond of acetaminophen, producing p-aminophenol. This product reacts with 2,5-dimethylphenol in the presence of manganese to generate a color change, resulting in increased absorbance at 660 nm. The absorbance is directly proportional to the acetaminophen concentration in the sample. The assay is performed on ARCHITECT c8000 clinical chemistry analyzers by laboratory professionals. The output is a quantitative concentration value (µg/mL or µmol/L), which clinicians use to assess toxicity levels and guide treatment decisions for patients suspected of overdose. The device provides a rapid diagnostic aid to manage potential liver toxicity.
Clinical Evidence
No clinical data. Performance was established through bench testing, including precision (CLSI EP05-A3), reproducibility, analytical sensitivity (LoB, LoD, LoQ), linearity (CLSI EP06-A), and interference studies (CLSI EP07-A2). Method comparison against the predicate device on 119 patient specimens showed a correlation coefficient of 0.9993.
Technological Characteristics
Enzymatic/colorimetric assay using aryl acylamidase and 2,5-dimethylphenol. Reagents include manganese (II) chloride, aryl acylamidase, and 2,5-dimethylphenol. Measuring range: 3–377 µg/mL (up to 3770 µg/mL with 1:10 dilution). Analyzed on ARCHITECT c8000. Complies with CLSI guidelines EP05-A3, EP06-Ed2, EP17-A2, EP25-A, and EP34.
Indications for Use
Indicated for the quantitative determination of acetaminophen in human serum or plasma to aid in the diagnosis and treatment of acetaminophen overdose toxicity.
Regulatory Classification
Identification
An acetaminophen test system is a device intended to measure acetaminophen, an analgestic and fever reducing drug, in serum. Measurements obtained by this device are used in the diagnosis and treatment of acetaminophen overdose.
Predicate Devices
- SEKURE Acetaminophen L3K Assay (K081938)
Related Devices
- K180835 — SEKURE Acetaminophen L3K Assay · Sekisui Diagnostics P.E.I., Inc. · Feb 8, 2019
- K110726 — ROCHE ACETAMINOPHEN ASSAY · Roche Diagnostics · Dec 23, 2011
Submission Summary (Full Text)
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FDA
U.S. FOOD & DRUG
ADMINISTRATION
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
ASSAY ONLY
## I Background Information:
A 510(k) Number
K202644
B Applicant
Sekisui Diagnostics P.E.I. INC.
C Proprietary and Established Names
Acetaminophen
D Regulatory Information
| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| LDP | Class II | 21 CFR 862.3030 - Acetaminophen Test System | TX - Clinical Toxicology |
## II Submission/Device Overview:
A Purpose for Submission:
New Device
B Measurand:
Acetaminophen
C Type of Test:
Quantitative enzymatic / colorimetric assay
## III Intended Use/Indications for Use:
A Intended Use(s):
See Indications for Use below.
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
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K202644 - Page 2 of 9
B Indication(s) for Use:
The Acetaminophen assay is used for the quantitative determination of acetaminophen in human serum or plasma on the ARCHITECT c Systems.
The Acetaminophen assay is to be used as an aid in the diagnosis and treatment of acetaminophen overdose toxicity.
C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
D Special Instrument Requirements:
ARCHITECT c8000 analyzer
IV Device/System Characteristics:
A Device Description:
The assay consists of two reagents:
Reagent 1 (Enzyme Reagent) 8.6 mL
Active Ingredients: manganese (II) chloride (0.3 mmol/L), aryl acylamidase (0.9 KU/L).
Preservatives: gentamicin sulfate, p-hydroxybenzoic acid, sodium azide.
Reagent 2 (Color Reagent) 22.3 mL
Active ingredient: 2,5-dimethylphenol (31 mmol/L).
B Principle of Operation:
The Acetaminophen assay is an automated clinical chemistry assay. In the reaction, aryl acylamidase is the enzyme that hydrolyzes acetaminophen to p-aminophenol and acetate. Next, p-aminophenol reacts with 2,5-dimethylphenol in the presence of a manganese catalyst to create the chromophore, 4-(4-iminophenol)-2,5-dimethylcyclohexadiene-1-one. Generation of this reaction product is measured at 660 nm and its production is proportional to the concentration of acetaminophen in the patient sample.
V Substantial Equivalence Information:
A Predicate Device Name(s):
Acetaminophen L3K Assay
B Predicate 510(k) Number(s):
K081938
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C Comparison with Predicate(s):
| Device & Predicate Device(s): | Candidate K202644 | Predicate K081938 |
| --- | --- | --- |
| Device Trade Name | Acetaminophen | Genzyme Diagnostics Acetaminophen L3K Assay |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | Same | For the quantitative measurement of acetaminophen in serum and plasma. Measurement of acetaminophen is used in the diagnosis and treatment of acetaminophen overdose toxicity. |
| Methodology | Same | Enzymatic (Aryl acylamidase) and Spectrophotometric (2,5-dimethylphenol Chromophore) |
| General Device Characteristic Differences | | |
| Analyzer platform | ARCHITECT c8000 System | Hitachi 717 |
| Acceptable matrices | Serum Lithium heparin plasma Sodium heparin plasma | Serum Lithium heparin plasma |
| Measuring range | 3 to 377 μg/mL | 0.6 to 377.5 μg/mL |
VI Standards/Guidance Documents Referenced:
- Clinical Laboratory and Standards Institute (CLSI) EP06 Evaluation of Linearity of Quantitative Measurement Procedures - 2nd Edition
- CLSI EP05-A3 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition
- CLSI EP17-A2 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition
- CLSI EP25-A Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline
- CLSI EP34 Establishing and Verifying an Extended Measuring Interval Through Specimen Dilution and Spiking – First Edition
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VII Performance Characteristics (if/when applicable):
A Analytical Performance:
1. Precision/Reproducibility:
The sponsor provided a within-laboratory precision study using one ARCHITECT c8000 analyzer, two reagent lots, two calibrator lots, and one control lot.
The samples included control materials, serum pools spiked with acetaminophen, and pooled serum samples. Samples were tested in a minimum of 2 replicates (target of 3 replicates, 2 times per day separated by a minimum of 2 hours), on at least 20 different days, for a minimum of 80 required measurements. Results are summarized in the table below.
| | | | | Within-Run | | Between-Run | | Between-Day | | Within-Lab | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Sample | Rgt Lot | N | Mean (μg/mL) | SD | % CV | SD | % CV | SD | % CV | SD | % CV |
| Level 1 (control) | 1 | 127 | 15 | 0.2 | 1.2 | 0.2 | 1.5 | 0.0 | 0.0 | 0.3 | 1.9 |
| | 2 | 120 | 15 | 0.1 | 0.9 | 0.2 | 1.0 | 0.0 | 0.0 | 0.2 | 1.3 |
| Level 2 (control) | 1 | 125 | 72 | 0.4 | 0.5 | 0.3 | 0.4 | 0.4 | 0.6 | 0.7 | 0.9 |
| | 2 | 119 | 73 | 0.5 | 0.6 | 0.2 | 0.3 | 0.3 | 0.4 | 0.6 | 0.8 |
| Level 3 (control) | 1 | 127 | 226 | 0.8 | 0.4 | 0.8 | 0.4 | 1.4 | 0.6 | 1.8 | 0.8 |
| | 2 | 120 | 227 | 0.8 | 0.3 | 0.6 | 0.3 | 0.9 | 0.4 | 1.3 | 0.6 |
| Panel A (spiked) | 1 | 126 | 5 | 0.2 | 4.4 | 0.2 | 4.3 | 0.3 | 5.9 | 0.5 | 8.6 |
| | 2 | 120 | 5 | 0.3 | 5.6 | 0.4 | 6.6 | 0.1 | 2.7 | 0.5 | 9.1 |
| Panel B (pooled) | 1 | 126 | 51 | 0.3 | 0.7 | 0.2 | 0.5 | 0.2 | 0.4 | 0.5 | 0.9 |
| | 2 | 120 | 51 | 0.3 | 0.6 | 0.1 | 0.1 | 0.2 | 0.4 | 0.4 | 0.7 |
| Panel C (pooled) | 1 | 126 | 83 | 0.4 | 0.5 | 0.3 | 0.4 | 0.4 | 0.5 | 0.7 | 0.8 |
| | 2 | 120 | 84 | 0.4 | 0.4 | 0.2 | 0.3 | 0.3 | 0.4 | 0.6 | 0.7 |
| Panel D (spiked) | 1 | 138 | 277 | 1.0 | 0.4 | 0.8 | 0.3 | 1.2 | 0.4 | 1.7 | 0.6 |
| | 2 | 120 | 278 | 1.0 | 0.4 | 1.1 | 0.4 | 1.3 | 0.5 | 2.0 | 0.7 |
| Panel E (spiked) | 1 | 141 | 361 | 1.4 | 0.4 | 1.0 | 0.3 | 1.5 | 0.4 | 2.3 | 0.6 |
| | 2 | 120 | 362 | 1.6 | 0.4 | 1.1 | 0.3 | 1.7 | 0.5 | 2.6 | 0.7 |
2. Linearity:
The sponsor performed a study to evaluate the linearity of the candidate assay on the ARCHITECT c8000 by referencing the CLSI EP06-Ed2 guideline. A linearity series of 11 samples was prepared by making admixtures of a sample of known high concentration with an acetaminophen-free normal human serum. The evaluation samples had concentrations of 2, 5, 46, 91, 138, 182, 226, 276, 315, 364, and $394~\mu \mathrm{g / mL}$ .
K202644 - Page 4 of 9
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The maximum deviation from linearity was 1 µg/mL for samples with acetaminophen concentrations less than 20 µg/mL and the maximum % deviation from linearity ranged from -0.9% to 0.8% for samples with acetaminophen concentrations greater than or equal to 20 µg/mL
Linear regression of the data produced the following:
| Slope | 0.9916 |
| --- | --- |
| Intercept | 0.1964 |
| Correlation Coefficient | 0.999 |
The results of the linearity studies support the sponsor's claimed measuring interval of 3 – 377 µg/mL. Samples with a concentration greater than 377 µg/mL will be reported as > 377 µg/mL without dilution.
The sponsor also performed a study to evaluate the accuracy of the auto-dilute feature for samples with a concentration greater than 377 µg/mL. Five samples with acetaminophen concentrations within the range of 450 µg/mL to 3,000 µg/mL were prepared by spiking USP Reference Standard Acetaminophen Stock solution into five human serum specimens which had acetaminophen levels of 0 µg/mL as screened by a commercially available assay. The acetaminophen concentration of each sample was assigned using the mean concentration of ten replicates tested by a commercially available assay. Each sample was either manually or automatically diluted at a 1:10 dilution. The results of the study demonstrated that the dilution recoveries for the auto dilute feature were all within +/- 2% of the expected value. The dilution study results support the sponsor's labeling claims that samples with acetaminophen concentrations above 377 µg/mL may be diluted 1:10 either manually or on-onboard the analyzer to obtain results up to 3770 µg/mL.
3. Analytical Specificity/Interference:
The sponsor performed a study to evaluate potential interference from endogenous and exogenous compounds. The study used one ARCHITECT c8000 analyzer, one reagent lot, one calibrator lot, and one control lot.
Each potential interferent was tested at acetaminophen concentrations of approximately 5, 30, and 150 µg/mL.
The sponsor defined significant interference as ± ≤ 7.5% interference for acetaminophen samples ≥ 20 µg/mL or ± ≤ 1.50 µg/mL interference for acetaminophen samples < 20 µg/mL. By these criteria, no interference was observed at the following concentrations:
Potential Endogenous Interferents
| Potential Interferent | Interferent Concentration |
| --- | --- |
| Bilirubin – conjugated | 14 mg/dL |
| Bilirubin – unconjugated | 28 mg/dL |
| Hemoglobin | 570 mg/dL |
| Intralipid | 2000 mg/dL |
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| Potential Interferent | Interferent Concentration |
| --- | --- |
| Total Protein | 10 g/dL |
| Triglycerides | 933 mg/dL |
Potential Exogenous Interferents
| Potential Interferent | Interferent Concentration |
| --- | --- |
| Amitriptyline | 0.048 mg/dL |
| Ampicillin | 7.5 mg/dL |
| Benzocaine | 560 mg/L |
| Cefoxitin | 660 mg/dL |
| Codeine | 0.141 mg/dL |
| Cyclosporine | 0.18 mg/dL |
| Cysteamine | 220 μmol/L |
| Dapsone | 5.9 mg/L |
| 2,5-Dihydroxybenzoic acid | 117 μmol/L |
| Dipyrone/Metamizole | 100 mg/L |
| Doxycycline | 1.8 mg/dL |
| 4-Ethoxyaniline | 1.0 mmol/L |
| Ibuprofen | 21.9 mg/dL |
| Imipramine | 0.0315 mg/dL |
| L-Ascorbic acid | 170 μmol/L |
| L-Cysteine | 18 mg/dL |
| Levodopa | 0.75 mg/dL |
| L-Methionine | 500 μg/mL |
| Methyldopa | 2.25 mg/dL |
| Metoclopramide | 1.5 μmol/L |
| Metronidazole | 12.3 mg/dL |
| N-Acetylcysteine | 1663 mg/L |
| N-Acetylprocainamide | 16 μg/mL |
| p-Aminosalicylic acid | 5.3 mmol/L |
| Phenacetin | 14 μg/mL |
| Phenylbutazone | 32.1 mg/dL |
| Procainamide | 102 μmol/L |
| Rifampicin | 80 μmol/L |
| Salicylic acid | 4.4 mmol/L |
| Tetracycline | 34 μmol/L |
| Theophylline | 6.0 mg/dL |
4. Assay Reportable Range:
The reportable range of the assay is 3 – 377 μg/mL without dilution and 3 – 3770 μg/mL when the automatic x 10 dilution factor is applied. Samples with an acetaminophen concentration less than 3 μg/mL are reported as “< 3 μg/mL”.
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5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
The Acetaminophen Calibrator is prepared gravimetrically from USP grade reference acetaminophen material to a concentration of 151 µg/mL (1000 µmol/L). The calibrator preparation is verified against the master calibrator (an internal reference standard).
6. Detection Limit:
The sponsor performed studies in accordance with CLSI EP17-A2 guideline to determine the limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) of the candidate device. Two lots of reagent were evaluated on the ARCHITECT c8000 analyzer.
The testing was performed using one zero-analyte sample (normal human serum) and ten low-level samples (2 samples at each of the 5 acetaminophen target concentrations of approximately 1, 2, 3, 4 and 5 µg/mL). The low-level samples were prepared by volumetrically spiking acetaminophen stock solution into normal human serum. A total of 60 replicates were collected per concentration per reagent lot.
The results of the studies supported the following detection limit claims:
| | µg/mL |
| --- | --- |
| LoB | 0.0 |
| LoD | 1.0 |
| LoQ | 3.0 |
7. Assay Cut-Off:
Not Applicable
B Comparison Studies:
1. Method Comparison with Predicate Device:
The sponsor performed a method comparison study comparing results from the candidate device to those from the predicate device. A total of 119 human serum specimens were evaluated with the predicate and candidate devices. The concentration range evaluated was 3.5 – 356.3 µg/mL by the predicate device.
Contrived samples made up 4% of the total and were prepared by spiking serum specimens with a stock solution of acetaminophen material to the desired concentration range. The contrived samples were spiked to acetaminophen concentrations at the upper end of the measuring range where it is difficult to obtain unaltered clinical samples.
For the candidate method, one ARCHITECT c8000 analyzer, two reagent lots, two calibrator lots, and one control lot were used. For the predicate method, one ARCHITECT c8000 analyzer, two reagent lots, two calibrator lots, and one control lot were used.
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A Passing-Bablok linear regression model was performed by comparing the first replicate result from the investigational method versus the mean result from the comparator method. Linear regression statistics from a representative lot were as follows:
Predicate Method vs Candidate Method
| Correlation Coefficient | 0.9993 |
| --- | --- |
| Slope | 1.042 |
| Intercept | -0.034 |
2. Matrix Comparison:
The sponsor performed a matrix comparison study to verify which specimen tube types (matrices) may be used with the assay. A total of 78 samples were analyzed. Of those 78 samples, 45 native samples covered the claimed therapeutic range of $10 - 30~\mu \mathrm{g / mL}$ and 18 samples were spiked to cover the assay reportable range.
The data was collected using Serum (with gel in plastic, Serum Separator Tube), Lithium heparin (with gel in plastic, Plasma Separator Tube), Lithium heparin (without gel in plastic), and Sodium heparin (without gel in plastic) vs serum (without gel in plastic) as the comparator matrix. All percent recoveries were within $\pm 10\%$.
Linear regression produced the following:
| Matrix | Concentration Range | Slope - Deming | Slope - Passing-Bablok | Correlation Coefficient |
| --- | --- | --- | --- | --- |
| Serum Separator Tube | 3.52 – 342.51 μg/mL | 1.004 | 1.005 | 0.999 |
| Plasma Separator Tube | 3.52 – 342.51 μg/mL | 1.009 | 1.004 | 0.999 |
| Lithium heparin (without gel in plastic) | 3.52 – 342.51 μg/mL | 1.017 | 1.009 | 0.999 |
| Sodium heparin (without gel in plastic) | 3.52 – 342.51 μg/mL | 1.018 | 1.009 | 1.000 |
Therefore, the sponsor concluded that the following matrices are suitable for use with the assay and has claimed them as sample types in the labeling:
- Plain serum
- Serum separator tube
- Plasma separator tube
- Lithium heparin tube (without gel in plastic)
- Sodium heparin tube (without gel in plastic)
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C Clinical Studies:
1. Clinical Sensitivity:
Not Applicable
2. Clinical Specificity:
Not Applicable
3. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):
Not Applicable
D Clinical Cut-Off:
Not Applicable
E Expected Values/Reference Range:
The sponsor’s labeling lists the following therapeutic and toxic acetaminophen concentrations:
aTherapeutic 10–30 µg/mL
bToxic Levels
4 hours > 150 µg/mL
24 hours > 4.7 µg/mL
aBurtis CA, Ashwood ER, Bruns DE, editors. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 5th ed. St. Louis, MO: Elsevier; 2012:2176.
bRowden AK, Norvell J, Eldridge DL, et al. Acetaminophen poisoning. Clin Lab Med 2006;26(1):49-65.
VIII Proposed Labeling:
The labeling supports the finding of substantial equivalence for this device.
IX Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
