Shenzhen K223690 Substantial Equivalence Determination Decision Summary Instructions

Shenzhen K223690 Substantial Equivalence Determination Decision Summary

Background Information

• A 510(k) Number
  K223690

• B Applicant
  Shenzhen YHLO Biotech Co., LTD.

• C Proprietary and Established Names
  iFlash-HCG; Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C)

• D Regulatory Information
  Product

Code(s)

| Classification| Regulation

Section

| Panel
---|---|---|---
DHA| Class II| 21 CFR 862.1155 – Human Chorionic

Gonadotropin (HCG) Test System

| CH – Clinical

Chemistry

JJE| Class I| 21 CFR 862.2160 – Discrete photometric

chemistry analyzer for clinical use

| CH – Clinical

Chemistry

Submission/Device Overview

• A Purpose for Submission:
  New Device

• B Measurand:
  Total beta human chorionic gonadotropin (intact hCG) and β -hCG.

• C Type of Test:
  Quantitative chemiluminescent immunoassay

Intended Use/Indications for Use

• A Intended Use(s):
  See Indications for Use below.

• B Indication(s) for Use:
  iFlash-HCG is a paramagnetic particle chemiluminescent immunoassay (CLIA) for quantitative detection of the intact human chorionic gonadotropin (hCG) molecule and the hCG β-subunit (β-hCG) in human serum and plasma using the automated Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C). The iFlash-HCG assay is to be used by laboratory professionals as an aid in early detection of pregnancy together with other clinical methods.
  Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) is a fully- automated, chemiluminescence immunoassay analyzer intended for quantitative or qualitative determination of analytes in human body fluids taken from clinical settings. It is used together with its supporting chemiluminescence immunoassay reagents. The Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) is intended for use in clinical laboratories.

• C Special Conditions for Use Statement(s):
  Rx – For Prescription Use Only

• D Special Instrument Requirements:
  Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C)

Device/System Characteristics

Device Description:
The iFlash hCG is provided in kits comprised of 100 tests, 2 packs, 50 tests/pack, Catalog # C86012 contain the following:

R1 (2 x 3.5 mL)| Anti-HCG antibody-coated paramagnetic micro-particles (mouse, 0.1 mg/mL), 0.05% ProClin 300 as preservative.
---|---
R2 (2 x 4.0 mL)| Acridinium-ester-labeled anti-HCG antibody

conjugate (mouse, 0.4 μg/mL), 0.1% ProClin 300 as preservative.

CAL1 (1 x 1.0

mL)

| Calibrator 1, TRIS buffer with protein stabilizer (BSA), 0.05% ProClin 300 as preservative, lyophilized.
CAL2 (1 x 1.0

mL)

| Calibrator 2, HCG protein (human) in TRIS buffer with protein stabilizer (BSA), 0.05% ProClin 300 as preservative, lyophilized.
CAL3 (1 x 1.0

mL)

| Calibrator 3, HCG protein (human) in TRIS buffer with protein stabilizer (BSA), 0.05% ProClin 300 as preservative, lyophilized.

Chemiluminescence immunoassay analyzer (Model: iFlash 3000-C) is a fully- automated, analyzer intended for quantitative or qualitative determination of analytes in human body fluids. It is intended for use in clinical laboratories. The Chemiluminescence immunoassay analyzer (Model: iFlash 3000-C) measures analytes in samples using the reagents, calibrators, quality control materials and other consumables that can be in the iFlash-HCG instruction for use manual. Components of the Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) include the components in the sample/reagent area, components in the consumables area, and components in the measurement area:

• Components in the sample/reagent area include:
  • Sample loading unit
  • Sampling unit
  • Reagent processing system
• Components in the consumables area include:
  • Reaction vessel system
  • System reagent bin (Pre-trigger Solution and Trigger Solution)
  • Wash buffer tank
  • Waste tank
  • Solid waste container
• Components in the measurement area include:
  • Incubation assembly
  • Magnetic separation washing assembly
  • Photon detection system

Principle of Operation

The iFlash-HCG assay is a sandwich immunoassay using a direct chemiluminometric technique. The hCG in the sample reacts with anti-HCG antibody-coated paramagnetic microparticles and acridinium-labeled anti-HCG antibody conjugate to form a sandwich complex. After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then the pre-trigger and trigger solutions are added to the reaction mixture. The
resulting chemiluminescent reaction is measured as relative light units (RLUs) by the iFlash optical system. The RLUs detected production is directly proportional to the analyte in the sample. Analyte concentration is determined from a calibration curve, which is generated by 3-point calibration and a master curve provided via the reagent QR code.

Instrument Description Information:

1. Instrument Name:
   Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C)

2. Specimen Identification:
   Human serum and lithium heparin, sodium heparin and K2-EDTA specimens are identified using the built-in barcode reader.

3. Specimen Sampling and Handling:
   Specimen sampling and handling procedures are described in the Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) Analyzer’s instruction for use manual
   Assay-specific specimen collection and preparation procedure can be found in the iFlash-HCG instruction for use manual.

4. Calibration:
   Calibration methods and procedures are described in the Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) Analyzer’s instruction for use manual. Assay-specific specimen collection and preparation procedure can be found in the iFlash-HCG instruction for use manual.

5. Quality Control:
   YHLO Immunoassay Multi Control, EVER-BLUE Immunoassay Multi Control are recommended.

Substantial Equivalence Information

1. A Predicate Device Name(s):
   Elecsys Hcg And Beta Test System, Elecsys TSH assay, cobas e 801 Immunoassay analyzer

2. B Predicate 510(k) Number(s):
   K003178, K162606

3. C Comparison with Predicate(s):

Assay

Intended Use/Indications For Use

| For the quantitative determination of intact human chorionic gonadotropin (hCG) and the hCG β-subunit (β-hCG) in human serum and plasma to aid in the early detection of pregnancy| ****

Same

Type of Test| Quantitative| Same
Technology| Sandwich Immunoassay| Same
Method| Automated| Same
Specimen Type| Human Serum and Plasma| Same
General Device Characteristic Differences|  |
---|---|---
Assay Range| 0.5-10000 mIU/mL| 0.2 – 10000 mIU/mL
Calibrator| Three-level Calibrators| Five-level Calibrators

Traceability

| WHO International Standard 5th WHO IS

Chorionic Gonadotrophin 07/364

| ****

4th International Standard (NIBSC) code 75/589

Instrument

Device & Predicate

Device(s):

| K223690| K162606
---|---|---

Device Trade Name

| Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C)| ****

Cobas e 801 analyzer

General Device Characteristic Similarities|  |

Intended Use/Indications For Use

| For quantitative or qualitative determination of analytes in human body fluids.| ****

Same

Calibration| Utilizes a stored calibration curve| Same
General Device Characteristic Differences|  |
Detection System| Chemiluminescent| Electrochemiluminescent

Standards/Guidance Documents Referenced:

• CLSI EP05- A3 Evaluation of Precision of Quantitative Measurement Methods-Approved Guideline-Third Edition
• CLSI EP06 2nd Edition – Evaluation of the Linearity of Quantitative Measurement Procedures
• CLSI EP07 3rd Edition – Interference Testing in Clinical Chemistry
• CLSI EP37 1st Edition – Supplemental Tables for Interference Testing in Clinical Chemistry
• CLSI EP17-A2 – Evaluation of Detection capability for Clinical Laboratory Measurement Procedures; Approved Guideline 2nd Edition
• CLSI EP09c 3rd Edition – Measurement Procedure Comparison and Bias Estimation Using Patient Samples
• CLSI EP34 1st Edition – Establishing and Verifying an Extended Measuring Interval Through Specimen Dilution and Spiking
• CLSI EP28-A3c – Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline, Third Edition

Performance Characteristics (if/when applicable):

Analytical Performance:

Precision/Reproducibility:
Precision of the iFlash-HCG Assay was evaluated according to CLSI EP05-A3 using nine serum samples and two levels of controls. Each sample was measured in two replicates per run with two runs per day over 20 days by three different operators at three different sites using three lots of the reagents on three different Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) resulting in a total of 240 test results per level. Results from one analyzer are provided in the table below

Sample

| Mean

(mIU/mL)

| Repeatability| Between- Run| Between- Day| Total

imprecision

---|---|---|---|---|---
N=240| SD| %CV| SD| %CV| SD| %CV| SD| %CV
Sample 1| 0.57| 0.028| 4.9| 0.015| 2.6| 0.013| 2.3| 0.041| 7.2
Sample 2| 4.68| 0.199| 4.3| 0.072| 1.5| 0.045| 1.0| 0.216| 4.6
Sample 3| 14.9| 0.589| 3.9| 0.078| 0.5| 0.172| 1.2| 0.978| 6.6
Sample 4| 23.5| 0.838| 3.6| 0.269| 1.1| 0.116| 0.5| 0.914| 3.9
Sample 5| 91.5| 1.98| 2.2| 0.213| 0.2| 0.382| 0.4| 4.18| 4.6
Sample 6| 957| 13.9| 1.5| 6.61| 0.7| 6.31| 0.7| 22.5| 2.4
Sample 7| 2823| 34.8| 1.2| 0.000| 0.0| 14.3| 0.5| 46.6| 1.6
Sample 8| 5627| 63.1| 1.1| 26.5| 0.5| 11.9| 0.2| 86.0| 1.5
Sample 9| 9023| 100| 1.1| 33.8| 0.4| 14.1| 0.2| 138| 1.5
Control 1| 2.71| 0.127| 4.7| 0.045| 1.7| 0.029| 1.1| 0.200| 7.4
Control 2| 101| 1.96| 1.9| 0.486| 0.5| 0.620| 0.6| 5.44| 5.4

Linearity:

Linearity of the iFlash-HCG Assay was evaluated following recommendations in CLSI EP06-Ed2. Three linearity studies were performed using eleven serum samples each. Varying concentrations of hCG were obtained by mixing low level serum samples and high level serum samples. All three studies were performed using three lots of reagents on one Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C).
In the first study, linearity was established by testing samples with concentrations ranging from 0.43 to 11786.53 mIU/mL. Each sample was tested in four replicates.

A regression analysis was conducted resulting in the following linear regression equation:

• y = 0.9824x + 38.719, R2 = 0.9994

In the second study, mid-range linearity was established by testing samples with hCG concentrations ranging from 0.45 to 1,050.30 mIU/mL. Each sample was tested in four replicates. A regression analysis was conducted resulting in the following linear regression equation: y = 0.9994x – 0.545, R2 = 0.9996
In the third study, low-range linearity was established by testing samples with concentrations ranging from 0.46 to 128.02 mIU/mL. Each sample level was tested in four replicates.
A regression analysis was conducted resulting in the following linear regression equation: y = 1.014x -2.857, R2 = 0.9995
The results from the linearity studies and limit of quantitation studies (LOQ = 0.50 ng/mL, see below), supports the sponsor’s claimed analytical measuring interval of 0.50 to 10,000 mIU/mL.

Dilution Studies
Dilution studies were performed to determine the sample recovery after a 1:100 dilution either manually or automatically by the Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C). The dilution study results support labeling claims that samples with hCG concentrations above 10,000 mIU/mL may be diluted 1:50 or 1:100 with sample diluent either manually or automatically on-onboard the analyzer

Analytical Specificity/Interference

Interference
The potential interference of certain exogenous and endogenous substances was assessed using female human serum pool samples containing approximately 6 mIU/mL and 5000 mIU/mL (“low” and “high” respectively) hCG spiked with various concentrations of substances based on recommendations in CLSI EP7-A2. The following endogenous substances do not interfere with this assay at the levels tested (less than 10% bias between the test sample and the control sample).
The following table lists the concentration of each endogenous substance at which no significant interference was found in the study.

The following table lists the concentration of each exogenous substance at which no significant interference was found in the study

Cross-Reactivity
Cross-reactivity of the iFlash-HCG assay was determined with three lots of reagent on one Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) using female human serum samples with approximately 0.1, 5, and 4000 mIU/mL (“low”, “medium”, and “high” respectively) hCG concentrations that were spiked with the following potential cross-reactants: luteinizing hormone (LH), follicle stimulating hormone (FSH), or thyroid stimulating hormone (TSH). Samples were tested in replicates of five using three lots of reagents on one iFlash 3000-C analyzer. The results demonstrated no cross-reactivity from potential cross-reactants up to 500 mIU/mL LH, 200 mIU/mL FSH, and 10000 mIU/mL TSH

Hook Effect
No high dose hook effect was observed for hCG concentrations in female human serum up to 1,250,000 mIU/mL hCG

Assay Reportable Range:
The reportable range is 0.50 – 10,000 mIU/mL.

Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
Traceability: This assay is traceable to the World Health Organization (WHO) 5th International Standard Chorionic Gonadotropin, Human, National Institute for Biological Standards and Control (NIBSC), code 07/364

Detection Limit:
The limit of blank (LoB), limit of detection (LoD) and limit of quantitation (LoQ) of the iFlash-HCG Assay were evaluated based upon recommendations in CLSI EP17-A2.

• Limit of Blank
  For determination of limit of blank (LoB), five analyte-free samples were tested with three lots of reagents over at least three days on one Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) in four runs with five replicates per run over three days. In total 60 measured values of analyte-free samples were obtained per lot. The LOB was determined to be 0.10 mIU/mL.

• Limit of Detection
  For determination of limit of detection (LoD), five serum samples containing low – analyte concentration (approximately 1-5 times LoB) were tested with three lots of reagents on one Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) in four runs with five replicates per run over three days. In total 60 measured values of samples with low analyte concentrations were obtained per lot. The LoD was determined to be 0.20 mIU/mL.

• Limit of Quantitation
  For determination of limit of quantitation (LoQ), five human serum samples covering the range between 0.30 and 70 mIU/mL were tested with three lots of reagents on one Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) in four runs with five replicates per run over three days. The limit of quantitation (LoQ) is the lowest concentration which is the design requirement of TEa%(Total Error Allowance) of ≤30%. The LoQ was determined to be 0.50 mIU/mL.

Assay Cut-Off:
Not applicable; this is a quantitative assay

Accuracy (Instrument):
Not applicable.

Carry-Over:
Samples with high hCG (1,250,000 mIU/mL) and low hCG (3.03 mIU/mL) hCG were tested alternating five times (i.e. HH,LL,HH,LL, etc.) in replicates of three, using one reagent lot on one Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C). No significant sample carryover effect was observed

Comparison Studies:
Method Comparison with Predicate Device:
Method comparison studies were conducted following recommendations in CLSI EP09-A3 Guideline. A total of 110 female human serum samples were tested in singlicate using iFlash- HCG Assay on Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) (candidate device) and Elecsys HCG+β (comparator device). The regression results are shown in the following table:

Matrix Comparison:
A matrix comparison study was performed to evaluate matrices suitable for use with the iFlash-HCG assay. Serum samples were compared to matched Lithium Heparin, Sodium Heparin, and K2-EDTA plasma samples using three lots of reagents on one Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C). The results were assessed using Passing/Bablok regression analysis.

Serum/Lithium-Heparin Plasma Summary Results

Serum/Sodium Heparin Plasma Summary Results

Serum/K2-EDTA Plasma Summary Results

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

Clinical Cut-Off:
Not applicable.

Expected Values/Reference Range:
Serum samples from 130 healthy, non-pregnant premenopausal women and 125 healthy, postmenopausal women were tested using the iFlash-HCG on the Chemiluminescence Immunoassay Analyzer (Model: iFlash 3000-C) according to CLSI EP28-A3c. The reference interval was calculated using the nonparametric method according to CLSI C28-A3, and was determined to be 0.05 – 0.85 mIU/mL for women ≤ age 50, and 0.1 – 4.4 mIU/mL for women over age 50. The central 95% reference interval was established to be 0.6 mIU/mL for premenopausal women and 5.4 mIU/mL for post-menopausal women.
It is recommended that each laboratory establish its own expected reference range for the specific population.

Other Supportive Instrument Performance Characteristics Data:
Not applicable.

Proposed Labeling:
The labeling supports the finding of substantial equivalence for this device.

Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

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