ABX MICROS ES 60 CT; (OPEN TUBE MODEL), (CLOSE TUBE MODEL)

K141161 · HORIBA ABX SAS · GKZ · Dec 20, 2014 · Hematology

Device Facts

• Record ID: K141161
• Device Name: ABX MICROS ES 60 CT; (OPEN TUBE MODEL), (CLOSE TUBE MODEL)
• Applicant: HORIBA ABX SAS
• Product Code: GKZ · Hematology
• Decision Date: Dec 20, 2014
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 864.5220
• Device Class: Class 2

Intended Use

The ABX MICROS ES 60 (OT and CT models) is a quantitative multi-parameter, automated hematology analyzer for in vitro diagnostic use in clinical laboratories to identify and enumerate the following parameters: WBC, RBC, HGB, HCT, MCV, MCH, MCHC, RDW, PLT, MPV, LYM%, LYM#, MON%, MON#, GRA%, GRA#, in K₂EDTA and K₃EDTA anticoagulated venous whole blood samples of adult patient population. It is not intended to be used for pediatric subjects.

Device Story

Automated hematology analyzer for clinical laboratories; performs complete blood count (CBC) and leukocyte differential (DIFF). Inputs: whole blood samples (K₂EDTA/K₃EDTA). Operation: uses focused flow impedance for cell counting/sizing and spectrophotometry (550 nm) for hemoglobin measurement. System processes electrical pulses from aperture impedance to determine cell volume and count; lysing reagent releases hemoglobin for optical measurement. Output: quantitative values for WBC, RBC, HGB, HCT, MCV, MCH, MCHC, RDW, PLT, MPV, and differential counts (LYM, MON, GRA). Available in Closed Tube (CT) with cap-piercing or Open Tube (OT) versions. Data managed by internal microprocessor; results displayed on 8-inch LCD touch screen. Assists clinicians in hematological assessment and diagnosis of blood-related conditions.

Clinical Evidence

Performance validated via analytical and clinical studies. Analytical testing included precision (repeatability/reproducibility), linearity, carry-over, and interference (CLSI EP05, EP06, EP07, EP09, EP17). Clinical comparability study (n=179) against predicate showed acceptable bias. Sampling method comparison (OT vs CT, n=237) and anticoagulant comparison (K2EDTA vs K3EDTA, n=52) confirmed equivalence. Clinical sensitivity/specificity evaluated against manual microscopy (gold standard, n=200) per CLSI H20-A2, demonstrating acceptable performance in detecting abnormal samples.

Technological Characteristics

Bench-top hematology analyzer; impedance-based cell counting; spectrophotometric hemoglobin measurement (550 nm). Dimensions: 43x36x36 cm. Connectivity: barcode reader, printer. Software: Linux-based. Reagents: ABX Minidil LMG, Minilyse LMG, Miniclean. Standards: CLSI EP05-A2, EP06-A, EP07-A2, EP09-A3, EP17-A2, EP28-A3c, H20-A2, H26-A2; IEC/UL 61010 safety; EN 61326 EMC.

Indications for Use

Indicated for adult patients requiring quantitative multi-parameter hematology analysis of K2EDTA or K3EDTA anticoagulated venous whole blood. Not indicated for pediatric subjects.

Regulatory Classification

Identification

An automated differential cell counter is a device used to identify one or more of the formed elements of the blood. The device may also have the capability to flag, count, or classify immature or abnormal hematopoietic cells of the blood, bone marrow, or other body fluids. These devices may combine an electronic particle counting method, optical method, or a flow cytometric method utilizing monoclonal CD (cluster designation) markers. The device includes accessory CD markers.

Special Controls

*Classification.* Class II (special controls). The special control for this device is the FDA document entitled “Class II Special Controls Guidance Document: Premarket Notifications for Automated Differential Cell Counters for Immature or Abnormal Blood Cells; Final Guidance for Industry and FDA.”

Predicate Devices

• Horiba ABX Micros 60 (k030799)

Submission Summary (Full Text)

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Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is a stylized image of three human profiles facing to the right, stacked on top of each other.

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

December 20, 2014

Horiba ABX SAS/Horiba Medical c/o Ms. Caroline Ferrer, Regulatory Affairs Manager Parc Euromedecine Rue du Caducee - BP7290 34184 Montpellier Cedex 4 - France

Re: k141161

Trade/Device Name: ABX Micros ES 60 OT and ABX Micros ES 60 CT Regulation Number: 21 CFR 864.5220 Regulation Name: Automated differential cell counter Regulatory Class: Class II Product Code: GKZ Dated: November 14, 2014 Received: November 17, 2014

Dear Ms. Ferrer:

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

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comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); 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.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Division of Industry and Consumer Education at its toll-free number [phone] or [phone] 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" (21CFR 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 [phone] or [phone] or at its Internet address

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

Sincerely vours.

# Leonthena R. Carrington -A

Maria M. Chan, Ph.D. for Director Division of Immunology and Hematology Devices Center for Devices and Radiological Health

Enclosure

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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

# Indications for Use

510(k) Number (if known) k141161

#### Device Name

ABX MICROS ES 60 OT (Open Tube model) ABX MICROS ES 60 CT (Close Tube model)

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

#### Indications for Use (Describe)

The ABX MICROS ES 60 (OT and CT models) is a quantitative multi-parameter, automated hematology analyzer for in vitro diagnostic use in clinical laboratories to identify and enumerate the following parameters: WBC, RBC, HCT, MCV, MCH, MCHC, RDW, PLT, MPV, LYM%, LYM#, MON%, MON#, GRA%, GRA#, in K2EDTA and K3EDTA anticoagulated venous whole blood samples of adult patient population. It is not intended to be used for pediatric subjects.

| <span> <span style="text-decoration: underline;"> <b> Prescription Use (Part 21 CFR 801 Subpart D) </b> </span> </span> | <span>Over-The-Counter Use (21 CFR 801 Subpart C)</span> |
|----------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|
|----------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|

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# Premarket Notification [510(k)] Summary

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

The assigned 510(k) number is : k141161

1.0 Sumitted by : Company: HORIBA ABX SAS HORIBA MEDICAL Parc Euromédecine Rue du Caducée - BP 7290 34184 Montpellier cedex 4 FRANCE

Contact Person: Caroline Ferrer ([e-mail]) Telephone: + (33) 4 67 14 1843 Fax: + (33) 4 67 14 1517

2.0 Date Submitted :

14th November 2014

3.0 Device Name and Classification : Trade/Proprietary Name: ABX MICROS ES 60

### Classification:

| Device: | Counter, differential cell |
|--------------------|----------------------------|
| Panel: | 81 Hematology |
| Regulation number: | 864.5220 |
| Product Code: | GKZ |
| Class: | 2 |

# 4.0 System description :

4.1 Device Description

The ABX MICROS ES 60 is a quantitative, automated hematology analyzer and leukocyte differential counter for in vitro diagnostic use in clinical laboratories. The instrument system is comprised of the analyzer and a suite of analytical reagents that allow for simultaneous quantitative determination of hemoglobin measurement, cell counting, quality control, calibration, and cleaning. The system is a microprocessor controlled hematology analyzer used for the in vitro diagnostic testing of whole blood specimens. It operates in complete blood count (CBC) and Differential (DIFF) mode

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using a combination of focused flow impedance and light transmission technologies. It is available in Closed (CT) or Open Tube (OT) sampling versions.

# 4.2 Principles of Operation

The ABX Micros ES 60 principle of automated cell counting and sizing is used in the analysis of the whole blood. Each cell suspended in a conductive liquid (diluent) acts as an insulator. As each cell goes through the aperture, it momentarily increases the resistance of the electrical path between two submerged electrodes on either side of the aperture. This causes a measurable electronic pulse. While the number of pulses indicates particle count, the amplitude of the electrical pulse is proportional to the cell volume. These pulses are sent to the Signal Conditioner for analog to digital conversion. Pulse counts and digitized pulse measurements are sent to the System Manager for processing by the algorithms where the reported parameter values, flags and histograms are generated.

The diluted sample is processed through two different chambers:

- The RBC / PLT chamber, for the Red Blood Cell (RBC) and Platelet (PLT) detection .
- The WBC / HGB chamber, for the White Blood Cell (WBC) and Hemoglobin (HGB) counts

Image /page/4/Figure/8 description: This image shows a schematic diagram of a blood analysis system. The diagram includes components such as WBC/HGB, RBC/PLT, and ABX Diluent/Lyse. The diagram also shows the flow of samples and reagents through the system, with arrows indicating the direction of flow. The image includes labels such as CT and OT.

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# Red Blood Cells (RBC) and Platelets (PLT) Detection:

The blood specimen is diluted in the electrolytic (current conductor) ABX Minidil LMG and pulled through the 50 um calibrated micro-aperture in the mini flow-cytometer. Two electrodes are placed on either side of the aperture. Electric current passes through the electrodes continuously. When a cell passes through the aperture, the electric resistance between the two electrodes increases proportionately to the cell volume.

The impedance variation is measured and allows for the RBC and PLT quantification.

#### Hemoglobin Measurement:

The lysing reagent breaks down the RBC cell membrane and releases the hemoglobin contained by the cell. The hemoglobin, released by the lysing reagent, combines with the potassium cyanide from the lysing reagent to form a chromogenous cyanmethemoglobin compound. This compound is then measured through the optical part of the WBC/HGB chamber by spectrophotometry at a wavelength of 550 nm.

#### Hematocrit Measurement:

All the RBC pulses are grouped into various sizes. Each group pulse height is then averaged. All the pulse height averages are then averaged one final time for a mean average of all the RBC pulse heights. This function is a numeric integration of the MCV. The HCT results are given as a percentage of this integration.

#### Red Distribution Width (RDW) Calculation:

The RDW is calculated from the RBC histogram. It allows to follow the evolution of the width of the RBC histogram in relation to the number of cells and their average volume.

# Mean Cell Volume (MCV), Mean Cell Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC) Calculations:

The MCV is calculated directly from the entire RBC histogram. The MCH is calculated from the HGB value and the RBC count. The MCHC is calculated according to the HGB and HCT values.

#### Mean Platelet Volume (MPV):

The MPV is directly derived from the analysis of the platelet distribution curve.

### White Blood Cell (WBC) Count:

The WBC count is carried out in the WBC/HGB chamber. The detection principle is the same as for RBC.

ABX Minidil LMG reagent preserves and prepares the WBC cell membrane for the differential reaction. The lysing reagent has a differential mode of action on the WBC cytoplasmic membranes.

- When the lysing reagent reacts with the lymphocytes, the cytoplasm and the . membrane are destroyed. At the end of the lysing action, only the nucleous remains intact and this action results in a smaller volume detected by the instrument.

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- When the lysing reagent reacts with the monocyte cytoplasmic membrane, it has an intermediate reaction that empties the cytoplasm from the cell. At the end of the lysing action, the monocyte cells obtained have an intermediate size between the lymphocytes and the granulocytes.
- When the lysing reagent reacts with the granulocytes, it has a limited reaction due ● to a molecule in their cytoplasmic structure which protects them from the shrinking action of the lyse. This in turn makes the granulocytes the larger of the WBC sub-populations in the cell differentiation.

The three sub-populations of WBCs are placed according to the number of cells and the size of the cells in each group. The lymphocyte, monocyte and granulocyte results are given as a percentage of the entire WBC count.

The granulocytes subpopulation of the WBC contains three sub-populations that contain cytoplasmic granular material which stain various colors when viewed microscopically. They are as followed:

- Neutrophils
- Eosinophils
- Basophils

The distribution of these cells depends on the pathological and physiological conditions of the individuals analyzed.

Pathological cells are placed in different zones within the WBC distribution curve and trigger alarms.

### 4.3 Modes of Operation

Two models of ABX Micros ES 60 are available.

- . The Closed Tube (CT) instrument: it has a cap-piercing mechanism. The blood collection tube is placed directly in the analyzer without removing the cap.
- . The Open Tube (OT) instrument: the cap form the blood collection tube must be removed before analyzing the sample.

### 4.4 Specimen Identification

Specimen identification is by manual sample identification with the use of a hand held barcode scanner.

### 4.5 Calibration

Calibration is a procedure that is performed during specific situations such as installation. maintenance or service intervention. It is performed by a HORIBA ABX SAS representative. It ensures that the precision and accuracy of the analyzer are acceptable, so that accurate measurements are performed by the analyzer.

ABX Minocal calibrator (k955925) is used for the ABX Micros ES 60 calibration procedure. Assigned assay values are traceable to reference methods.

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# 4.6 Quality Control

Quality control allows the user to monitor a set of analyses based on known sample values and ranges over a period of several months. Statistical computation performed on these populations allows the extraction of qualitative information related to the stability of the instrument.

ABX Minotrol 16 Control (k850755) enables monitoring of system performance for all directly measured and calculated CBC and Diff parameters. Assigned assay values are determined on validated instruments using the appropriate reagents.

### 4.7 Software

HORIBA ABX SAS's Hazard Analysis and Software Development process for this product are included in this submission.

# 5.0 Intended use

### 5.1 Indications for Use :

The ABX MICROS ES 60 (OT and CT models) is a quantitative multi-parameter, automated hematology analyzer for in vitro diagnostic use in clinical laboratories to identify and enumerate the following parameters: WBC, RBC, HGB, HCT, MCV, MCH, MCHC, RDW, PLT, MPV, LYM%, LYM#, MON%, MON#, GRA%, GRA#, in K2EDTA and K3EDTA anticoagulated venous whole blood samples of adult patient population. It is not intended to be used for pediatric subjects.

# 5.2 Special Conditions for Use Statements:

For prescription use only

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# 6.0 Substantial Equivalence Information :

The following tables show the similarities and differences between the candidate device and its predicate device identified below.

### 6.1 Predicate Device Name and 510(k) number:

| Candidate device | Predicate device | Manufacturer | 510(k) number |
|------------------|------------------|----------------|---------------|
| ABX MICROS ES 60 | ABX MICROS 60 | HORIBA ABX SAS | k030799 |

#### 6.2 Comparison with predicate Device : Similarities

| Item | Candidate<br>(ABX MICROS ES 60) | Predicate k030799<br>(ABX MICROS 60) |
|-------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | The ABX MICROS ES 60 (OT<br>and CT models) is a quantitative<br>multi-parameter, automated<br>hematology analyzer for in vitro<br>diagnostic use in clinical<br>laboratories to identify and<br>enumerate the following<br>parameters: WBC, RBC, HGB,<br>HCT, MCV, MCH, MCHC,<br>RDW, PLT, MPV, LYM%,<br>LYM#, MON%, MON#, GRA%,<br>GRA#, in K2EDTA and K3EDTA<br>anticoagulated venous whole<br>blood samples of adult patient<br>population. It is not intended to be<br>used for pediatric subjects. | The ABX MICROS 60<br>Hematology Analyzer is a fully<br>automated (microprocessor<br>controlled) hematology analyzer<br>used for the in vitro diagnostic<br>testing of whole blood specimens<br>or blood cell concentrates. It<br>operates in complete blood count<br>(CBC) mode. |
| Principles of Measurement | | |
| RBC, PLT, HCT, MPV | Impedance | Same |
| HGB | Spectrophotometry | Same |
| WBC, WBC Differential<br>(LYM, MON, GRA)) | Impedance | Same |
| RDW, MCV, MCH, MCHC | Calculation | Same |
| Reagents | | |
| Diluent | ABX Minidil LMG | Same |
| Lyse | ABX Minilyse LMG or ABX<br>Alphalyse 360 | Same |
| Cleaner | ABX Miniclean | Same |
| Reagent Pack | ABX Minipack LMG | Same |
| Concentrated cleaning reagent | ABX Minoclair | Same |
| Quality Controls | ABX Minotrol 16<br>(3 levels) | Same |
| Calibrator | ABX Minocal | Same |
| System configuration | Bench top | Same |

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| Item | Candidate<br>(ABX MICROS ES 60) | Predicate k030799<br>(ABX MICROS 60) |
|-----------------------------|----------------------------------------------------------------------------------------------------|--------------------------------------|
| | Handheld barcode reader<br>(optional)<br>Integrated barcode reader (CT<br>version only)<br>Printer | |
| Sampling mechanism | Single tube presentation – open<br>and closed vial sampling | Same |
| Aspiration pathway | Single sampling probe and<br>common aspiration pathway used<br>for all sample presentation modes | Same |
| Minimum Sample Volume | 50 μL | Same |
| Specimen sample volume | 10 μL | Same |
| Counting aperture diameters | | |
| RBC/PLT | 50 μm | Same |
| WBC | 80 μm | Same |
| Dilution ratios | | |
| RBC/PLT chamber | 1/15000 | Same |
| Performance claims | | |
| Precision | | |
| WBC | < 2.5 % | Same |
| RBC | < 2.0 % | Same |
| HGB | < 1.5 % | Same |
| HCT | < 2.0 % | Same |
| PLT | < 5.0 % | Same |
| Accuracy | | |
| WBC | R2 > 95% | Same |
| RBC | R2 > 95% | Same |
| HGB | R2 > 95% | Same |
| HCT | R2 > 95% | Same |
| PLT | R2 > 95% | Same |

# 6.3 Comparison with predicate Device : Differences

| Item | Candidate<br>(ABX MICROS ES 60) | Predicate k030799<br>(ABX MICROS 60) |
|------------------------|-------------------------------------------------------------|-------------------------------------------------------------------------------------------|
| User Interface Display | Automated instrument with 8"<br>LCD touch screen display | Automated instrument with 3"<br>LCD display |
| Software application | Linux-based software application | Internally developed software<br>application |
| Analytical cycle | 1) Draining sequence done by<br>vacuum<br>2) No air bubble. | 1) Draining sequence<br>movement<br>2) Presence of air bubble at<br>the end of all cycles |

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| Item | Candidate<br>(ABX MICROS ES 60) | Predicate k030799<br>(ABX MICROS 60) |
|-----------------------|------------------------------------------|-------------------------------------------------|
| Sample types | Whole blood samples only | Whole blood samples and blood cell concentrates |
| Dilution ratios | | |
| WBC chamber | 1/260 | 1/250 |
| Throughput | OT / CT models: 60 / 50 samples per hour | OT / CT model: approx. 60 / 55 samples per hour |
| Dimensions | OT / CT models: 43 x 36 x 36 cm | OT / CT models:44 x 36 x 33 cm |
| Weight | OT model: 14 kg<br>CT model: 17 kg | OT model: 14 kg<br>CT model: 14 kg |
| Performance claims | | |
| High Linearity limit | | |
| WBC (10³/mm³) | 100 | Same |
| RBC (10⁶/mm³) | 8.0 | Same |
| HGB (g/dL) | 24 | 26 |
| HCT (%) | 70 | 80 |
| PLT (10³/mm³) | 2200 | Same |
| Limit Of Quantitation | | |
| WBC (10³/mm³) | 0.8 | Not available |
| RBC (10⁶/mm³) | 0.7 | Not available |
| HGB (g/dL) | 0.6 | Not available |
| HCT (%) | 8.0 | Not available |
| PLT (10³/mm³) | 42 | Not available |
| Carry-over | | |
| WBC | < 1% | < 0.5% |
| RBC | < 1% | < 0.5% |
| HGB | < 1% | < 0.5% |
| PLT | < 1% | < 0.5% |

### 7.0 Special Control/Guidance Document Referenced :

### 7.1 Standards Followed

- . CLSI EP05-A2: Evaluation of Precision Performance of Quantitative Measurement Methods - 2004
- CLSI EP06-A: Evaluation of the Linearity of Quantitative Measurement ● Procedure: A Statistical Approach - 2003
- CLSI EP07-A2: Interference Testing in Clinical Chemistry - 2005
- . CLSI EP09-A3: Measurement Procedure Comparison and Bias Estimation Using Patient Samples - 2013
- . CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures - 2012
- . CLSI EP28-A3c: Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory - 2008

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- CLSI H20-A2: Reference Leukocyte (WBC) Differential Count (Proportional) and Evaluation of Instrumental Methods - 2007
- CLSI H26-A2: Validation, Verification and Quality Assurance of Automated ● Hematology Analyzers - 2010
- IEC61010-1, IEC61010-2-081, IEC61010-2-101, UL61010-1, CAN/CSA-● C22.2 No. 61010-1-12. CAN/CSA-C22.2 No. 61010.2.081-04. CAN/CSA-C22.2 No. 61010-2-101-04: Safety requirements for electrical equipment for measurement, control, and laboratory use
- . EN61326-1, EN61326-2-6: Electrical equipment for measurement, control and laboratory use - EMC requirements
- ISO14971: Medical devices Application of risk management to medical ● devices

# 7.2 FDA Guidances Followed

- Guidance for Industry and FDA Staff : Format for Traditional and Abbreviated ● 510(k)s - 2005
- Final Guidance for Industry and FDA: Class II Special Controls Guidance ● Document: Premarket Notifications for Automated Differential Cell Counters for Immature or Abnormal Blood Cells - 2001
- Guidance for Industry and FDA Staff : Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices – 2005
- Guidance for Industry, FDA Reviewers and Compliance on Off-The-Shelf Software Use in Medical Devices - 1999
- . Draft Guidance for Industry and Food and Drug Administration Staff on the Content of Premarket Submissions for Management of Cybersecurity in Medical Devices - 2013

# 8.0 Summary of Performance Data :

# 8.1 Analytical Performance

# 8.1.1 Analytical Limits at Low Level

# Limit of Blank (LoB)

Plasma samples, obtained by centrifugation of normal samples, were used as blank samples, in order to be as close as possible as the blood sample matrix.

To estimate the LoB, a total of 60 repeated measurements of different plasma are run in the same series (5 different samples run 12 times).

This test is performed on 2 instruments with two reagents lots.

Results on Micros ES60 OT and Micros ES60 CT were similar and met specifications.

LoB obtained from 60 repeated measurements of 5 different plasma samples, are:

| Measurand | LoB |
|-----------|------------------|
| WBC | $0.1x10^3/mm^3$ |
| RBC | $0.01x10^6/mm^3$ |
| HCT | 0.1 % |
| PLT | $1x10^3/mm^3$ |

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# Limit of Detection (LoD)

A set of six samples with very low parameter concentration (i.e. in the range LoB and 4 x LoB) are run 10 times over several days.

To estimate the LOD, take 60 results and calculate the pooled standard deviation (SDs). This test is performed on 2 instruments with two reagents lots.

Results on Micros ES60 OT and Micros ES60 CT were similar and met specifications.

LoD obtained from 10 runs of 6 low samples on each instrument are:

| Measurand | LoD |
|-----------|--------------|
| WBC | 0.2x103/mm3 |
| RBC | 0.01x106/mm3 |
| HGB | 0.5 g/dL |
| HCT | 0.2 % |
| PLT | 4x103/mm3 |

### Limit of Quantitation (LoQ)

To estimate the limit of quantitation, several ranges of linearity in low concentrations are prepared. Between 3 to 6 samples by level are prepared and run at least 5 times each, 40 replicates by level are necessary. The LoQ data are considered acceptable when the % Total-error is smaller than the desired total error for each measurand.

This test is performed on 2 instruments with two reagents lots.

Results on Micros ES60 OT and MicrosES60 CT were similar and passed acceptance limits.

LoQ obtained from at least 40 runs of 4 samples by level are:

| Measurand | LoQ |
|-----------|-------------|
| WBC | 0.8x103/mm3 |
| RBC | 0.7x106/mm3 |
| HGB | 0.6 g/dL |
| HCT | 8% |
| PLT | 42x103/mm3 |

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# 8.1.2 Precision(Repeatability/Reproducibility)

# Imprecision (Repeatability)

Repeatability was performed using 12 normal and 10 abnormal fresh whole blood samples collected into tubes containing K2EDTA anticoagulant. Each sample was run 10 consecutive times on two models of the Micros ES60 (ES60 OT and ES 60 CT), in a single day and all runs were completed within 8 hours of sample collection.

The size of the standard deviation was compared with the mean value of each parameter. This standard deviation divided by the mean is known as the Coefficient of Variation (CV) and is expressed as a percentage: CV% = (100*[Standard Deviation/Mean])

The results obtained were in the specifications.

| | Precision (Repeatability) Acceptance Criteria | | |
|--|-----------------------------------------------|--|--|
|--|-----------------------------------------------|--|--|

| | WBC | RBC | HGB | HCT | PLT | LYM% | MON% | GRA% |
|-----|------|-----|------|-----|-----|------|------|------|
| %CV | <2.5 | <2 | <1.5 | <2 | <5 | <10 | <20 | <4 |

# Imprecision (Reproducibility)

Reproducibility was assessed on three Micros ES60 instruments at three sites, each with its own operator. On each site; High, Normal, and Low levels of one single lot of Minotrol control material were run in duplicate, twice each day, during a minimum of 18 days.

Total standard deviation and CV% were calculated for each measurand and results obtained were in the specifications.

| Acceptable Total CV Claim (%) | Low Level<br>Control | Normal Level<br>Control | High Level<br>Control |
|-------------------------------|----------------------|-------------------------|-----------------------|
| WBC | 7.0 | 5.0 | 4.0 |
| RBC | 4.0 | 3.0 | 3.0 |
| HGB | 5.0 | 4.0 | 3.0 |
| HCT | 5.0 | 4.5 | 4.0 |
| MCV | 4.0 | 3.0 | 2.5 |
| MCH | 7.0 | 4.5 | 4.0 |
| MCHC | 7.0 | 4.5 | 4.0 |
| RDW | 5.0 | 5.0 | 5.0 |
| PLT | 15.0 | 10.5 | 7.0 |
| LYM% | 8.0 | 8.0 | 8.0 |
| MON% | 15.0 | 14.0 | 11.0 |
| GRA% | 12.0 | 4.0 | 3.0 |
| LYM# | 8.0 | 8.0 | 8.0 |
| MON# | 15.0 | 14.0 | 11.0 |
| GRA# | 12.0 | 4.0 | 3.0 |

Precision (Reproducibility) Acceptance Criteria

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# 8.1.3 Linearity / Assay's Measuring (Reportable) Range

Commercial High and Full Range Linearity kits were used to perform the linearity studies. The expected values of the kit samples were considered the "true values". Each level was run in replicates of four (n=4) as recommended by the kit supplier. For each level, the 4 replicate results were plotted versus the theoretical value. The findings of the polynomial regression analysis indicate that the ABX Micros ES 60 exhibits linearity across the claimed range.

The Analytical Measuring Range is defined as the range comprised between the Limit of Quantitation and the High Linearity Limit determined for each parameter. The claimed AMR are therefore:

| Parameter | AMR on<br>Micros ES60 |
|---------------|-----------------------|
| WBC (10³/mm³) | 0.8 - 100 |
| RBC (10⁶/mm³) | 0.7 - 8 |
| PLT (10³/mm³) | 42 - 2200 |
| HGB (g/dL) | 0.6 - 24.0 |
| HCT (%) | 8.0 - 70.0 |

#### 8.1.4 Carryover

The potential for sample carryover was tested in duplicate on the ABX Micros ES 60 OT and CT instruments using alternating high and low concentrations samples.

The percentage of carryover is calculated using the formula below:

$$\boxed{Ct\%} = \frac{low4 - low6}{high3 - low6} \times 100 \bigg|$$

All carry-over results are within specifications for the ABX Micros ES OT and CT Systems.

| | Carry-over Limit<br>(%CV) |
|-----|---------------------------|
| WBC | <1% |
| RBC | <1% |
| HGB | <1% |
| PLT | <1% |

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# 8.1.5 Interfering substances

The interference effect is evaluated following two methodologies:

- By addition : evaluating the effect of potentially interfering substances added to the sample of interest:
A potential interfering substance is added to a sample and the bias relative to a control portion of the sample is evaluated ("paired-difference testing"). This bias was compared to the acceptance criteria.

For all tests performed with the following potential interferents, the bias remained below the acceptable limit and therefore, no significant interference was observed: urea, bilirubin, lipemia, and hemolysis.

An interference on WBC counts has been observed in presence of yeast in the sample.

- By comparison: evaluating the bias of individual specimen: -
Representative patient specimens and a control sample (without interferent) are run in duplicate in comparison to a comparative measurement procedure (Micros 60). Then the bias versus comparative measurement values was plotted for each specimen group. Both measurement procedures had 10 to 20 samples in each group to demonstrate sufficient precision.

A comparable effect was observed on the ABX Micros ES 60 and the reference device for the interferences from: WBC fragments, Myelocytes, nucleated RBC, RBC Inclusion, RBC Agglutinins / Cold Agglutinins / RBC Rouleaux, Dual RBC population, RBC fragments, Target cells, Platelet Aggregates, Platelet Satelitism, Macrothrombocytes / Large Platelets, Small RBC Leukocytosis.

Additionnally, Megakaryoctes and Parasites are potential interferents on respectively WBC and Monocytes counts that could not be tested, but that are well described in literature.

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# 8.1.6 Sample stability

11 whole venous blood specimens (collected in K2EDTA and K3EDTA) were analyzed on the ABX Micros ES 60 (OT model) at one site in France. Following the collection (TO), each specimen was divided in half, with one sample stored at ambient temperature (20-24°C) and the other stored under refrigerated conditions (2-8°C). Testing for stability was performed at 2, 6, 8, 10, 24, 36, 48, 60 and 72 hours after T0 The first aliquot of each specimen was run sequentially in any order. The second aliquot was run in reverse order to minimize the effects of carryover and drift. The acceptance criteria for sample stability is given as an acceptable maximum bias of the value at T with the value at T0. All data passed specifications.

| Parameters | Sample stability when<br>stored refrigerated (2-8°C) | Sample stability when<br>stored at room<br>temperature (20-24°C) |
|--------------------------------------------|------------------------------------------------------|------------------------------------------------------------------|
| WBC, RBC, HGB, HCT, MCV,<br>MCH, MCHC, PLT | 48 hours | 36 hours |
| RDW | 36 hours | 10 hours |
| MPV | 24 hours | 24 hours |
| LYM%, LYM#, MON%, MON#,<br>GRA%, GRA# | 24 hours | 8 hours |

# 8.2 Other supportive performance data using clinical specimens

In order to support the equivalence and comparability claims made for the ABX Micros ES 60 in vitro diagnostic hematology analyzer, some performance studies were done in external clinical laboratories with clinical blood specimens collected prospectively or not. These may be considered as "Clinical studies".

#### 8.2.1 Comparability with Predicate Device

A total of 179 whole blood specimens from adult patients were analyzed at four test sites in the US.

Each of the samples was analyzed in duplicate on the ABX Micros ES 60 (CT model) and on the predicate ABX Micros 60.

Bias was estimated at three points for each parameter: the low end of the distribution of observations, the mid-point, and the high end of the distribution. Bias was estimated separately for each replicate. Acceptance criteria were met for all measurands at all levels. These findings support the claim that the ABX Micros ES60 candidate device and the ABX Micros 60 predicate device are substantially equivalent, and demonstrate acceptable levels of bias.

#### 8.2.2 Comparability between Sampling methods

A total of 237 whole blood specimens from adult patients were analyzed at one test site in France.

Each of the samples was analyzed in duplicate on the ABX Micros ES 60 CT (Close Tube model) and on the ABX Micros ES 60 OT (Open Tube model).

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Bias was estimated at three points for each parameter: the low end of the distribution of observations, the mid-point, and the high end of the distribution. Bias was estimated separately for each replicate. Acceptance criteria were met for all measurands at all levels. These findings support the claim that both Open Tube and Close Tube models of ABX Micros ES60 device yield comparable performances across the analytical range for all the parameters.

### 8.2.3 Comparability between Anticoagulant types

A total of 52 normal and pathological blood specimens were analyzed on the ABX Micros ES60 (CT model) at three sites in the US. Different instruments and operators were used at each site. The specimens used in this study were venous blood specimens that were prospectively collected for this study specifically. Each subject provided blood collected in both K2EDTA and K3EDTA.

Each of the samples was analyzed in duplicate on the ABX Micros ES 60.

Bias was estimated at three points for each parameter: the low end of the distribution of observations, the mid-point, and the high end of the distribution. Bias was estimated separately for each replicate. Acceptance criteria were met for all measurands at all levels. These findings support the claim that K2EDTA and K3EDTA specimens give comparable results as measured on the ABX Micros ES60 hematology analyzer.

# 8.2.4 Clinical Sensitivity / Specificity

100 normal and 100 pathological samples preserved in K2EDTA covering the full analytic range of the ABX Micros ES60 were analyzed in duplicate on the ABX Micros ES60 (CT model) and ABX Micros ES60 (OT model). Samples used for this study were left-over samples from both hospital and private independent clinical laboratories in France. Two slides with May Grünwald Giemsa staining were prepared for each sample. Slide reviews were conducted as a gold standard reference and WBC differential counts were conducted using 400-cell reference differential count (200 cells per reader, 2 readers) on each sample following the procedure discussed in CLSI H20-A2.

Samples were classified into Normal or Abnormal samples for the ABX Micros ES60 OT, ABX Micros ES60 CT, and the reference method (manual slide microscopy for differential count and morphological appreciation; the predicate ABX Micros 60 for quantitative CBC parameters). Abnormal samples were subdivided into those with abnormal proportions of one or more cell types (quantitative), and those containing abnormal cells (morphological).

Method comparison studies were designed using the CLSI H20-A2 procedure by the construction of the "envelope" that takes into account the imprecision of both the test and the manual method (95% and 99% confidence interval respectively).

The ability to identify abnormal samples and listed pathologies was evaluated according the CLSI H20-A2 by creating predictive value tables for distributional and morphological classification. From these tables, the efficiency, sensitivity, specificity, positive predictive value, and negative predictive value were calculated.

For each cell type, the mean of the manual differential count is compared with the mean of the analyzer count.

For WBC differential count analysis, the scatter plot of the means of the test method (yi) vs. the means of the reference method (xi) for each sample (i) is traced. On each scatter

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plot, the 95% and 99% confidence intervals that take into account the imprecision of the test and reference methods are drawn.

The ABX Micros ES60 OT and CT models have shown acceptable performances in detecting an abnormal sample with good sensitivity. Positive predictive and negative predictive values are acceptable. Moreover, the WBC differential analysis comparison between the Micros ES60 and the manual microscopy slide observations (Gold Standard) show acceptable results. The data demonstrate the accuracy of the ABX Micros ES60 performance.

# 8.2.5 Reference Interval

275 (135 male and 140 female) normal adult samples (whole blood samples collected in K2EDTA) were analyzed in duplicate on the ABX Micros ES60 (OT model) and ABX Micros ES60 (CT model) at one test site in the US.

The nonparametric data analysis method was used, depending only on the ranks of the reference data arranged in order of increasing size. Per EP28-A3, the reference interval is determined to be between and including the lower and upper reference limits, which enclose 95% of the values from the reference population subjects. Confidence intervals for the reference limit were calculated using a 90% probability (90% CI).

Defined reference values are not significantly different between the ABX Micros ES60 OT and CT models. For each gender, a single reference interval applicable (Shared Interval) on both versions of the analyzers has been defined as described in the following table.

| MICROS ES60<br>Reference Interval | MALES<br>(N=135) | | FEMALES<br>(N=140) | |
|-----------------------------------|------------------|------|--------------------|------|
| | LOW | HIGH | LOW | HIGH |
| WBC (10³/mm³) | 4.3 | 9.6 | 4.2 | 10.3 |
| RBC (10⁶/mm³) | 4.1 | 5.7 | 4.0 | 5.1 |
| HGB (g/dl) | 12.6 | 16.7 | 11.6 | 15.1 |
| HCT (%) | 38.3 | 50.8 | 35.8 | 46.4 |
| MCV (µm³) | 83 | 97 | 83 | 98 |
| MCH (pg) | 26.7 | 32.3 | 26.8 | 32.5 |
| MCHC (g/dl) | 31.7 | 34 | 31.8 | 34.0 |
| RDW (%) | 11.1 | 14.4 | 11.3 | 13.9 |
| PLT (10³/mm³) | 156 | 370 | 181 | 393 |
| MPV (µm³) | 6.3 | 9.1 | 6.5 | 9.0 |
| LYM (10³/mm³) | 1.1 | 3.1 | 1.2 | 3.4 |
| MON (10³/mm³) | 0.1 | 0.6 | 0.1 | 0.6 |
| GRA (10³/mm³) | 2.6 | 7.0 | 2.7 | 7.4 |
| %LYM (%) | 16.5 | 44.7 | 17.7 | 45.2 |
| %MON (%) | 3.1 | 8.3 | 3.3 | 8.1 |
| %GRA (%) | 49.1 | 76.9 | 49.2 | 77.7 |

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Reference intervals have been established on ABX Micros ES60 OT and CT for each parameter, based on a CLSI EP28-A3 study. These intervals are given in the labeling of the Micros ES60.

However, expected values will vary with sample population and/or geographical location. Horiba highly recommends that each laboratory establishes its own normal ranges based upon its local population.

# 9.0 Proposed Labeling :

The labeling is written as per the recommendations given in standard EN18113-2. It takes into account the requirements of 21 CFR Part 809.10.

#### Conclusion : 10.0

As per 21CFR Part §807.92(b)(3), the nonclinical tests demonstrate that the ABX Micros ES 60 device is as safe, as effective, and performs as well as or better than the predicate device .

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