Sysmex Automated Blood Coagulation Analyzer CS-5100

K150678 · Siemens Healthcare Diagnostic Products GmbH · JPA · Jan 11, 2016 · Hematology

Device Facts

• Record ID: K150678
• Device Name: Sysmex Automated Blood Coagulation Analyzer CS-5100
• Applicant: Siemens Healthcare Diagnostic Products GmbH
• Product Code: JPA · Hematology
• Decision Date: Jan 11, 2016
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 864.5425
• Device Class: Class 2

Intended Use

The Sysmex® CS-5100 is a fully automated blood coagulation analyzer intended for in vitro diagnostic use using plasma collected from venous blood samples in 3.2% sodium citrate tubes to analyze clotting, chromogenic and immunoassay methods in the clinical laboratory. For determination of: - Prothrombin Time (PT) seconds and PT INR with Dade® Innovin® - Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL - Fibrinogen (Fbg) with Dade® Thrombin Reagent - Antithrombin (AT) with INNOVANCE® Antithrombin - D-dimer with INNOVANCE® D-Dimer The performance of this device has not been established in neonate and pediatric patient populations.

Device Story

Sysmex CS-5100 is a fully automated blood coagulation analyzer for clinical laboratories. It processes venous blood plasma samples collected in 3.2% sodium citrate tubes. The device utilizes clotting, chromogenic, and immunochemical methods to determine PT, PT INR, APTT, Fibrinogen, Antithrombin, and D-dimer levels. Samples are loaded into racks and automatically transported to aspiration positions; the system features random access, liquid level sensing, and barcode reading for samples and reagents. Analysis is performed using transmitted light detection (absorbance) via a halogen lamp. Results are displayed on an Information Processing Unit (IPU) touch panel, printed, or transmitted to a host computer. The device supports normal and micro-sample modes. By providing rapid, automated coagulation testing, the device assists clinicians in diagnosing and monitoring hemostatic disorders and excluding pulmonary embolism, thereby facilitating timely clinical decision-making.

Clinical Evidence

Clinical evidence includes a multi-center method comparison (n=469 for PT, n=361 for D-dimer) against the predicate, showing high correlation (r=0.996-0.999). Reproducibility studies (20-day, 3-site) demonstrated total CVs generally <7.5%. A prospective multi-center study (n=1467) evaluated D-dimer for Pulmonary Embolism (PE) exclusion, achieving 98.0% sensitivity and 99.7% NPV at a 0.50 mg/L FEU cutoff, confirming clinical performance comparable to the predicate.

Technological Characteristics

Automated coagulation analyzer; uses transmitted light detection (absorbance) at 340-800 nm via halogen lamp. Materials include pneumatic units, sample/reagent probes, and cuvette handling systems. Features include liquid level sensing, barcode readers, and bidirectional interface (CA, ASTM, CS protocols). Temperature control: detector 37°C ± 0.5°C; reagent probe 37.5°C ± 0.5°C. Reagent cooling: 4°C-15°C. Software manages automated pipetting, dilution, and analysis modes (normal/micro).

Indications for Use

Indicated for in vitro diagnostic use in clinical laboratories to analyze clotting, chromogenic, and immunoassay coagulation parameters (PT, PT INR, APTT, Fibrinogen, Antithrombin, D-dimer) using citrated human plasma. Performance not established for neonate or pediatric populations.

Regulatory Classification

Identification

A multipurpose system for in vitro coagulation studies is a device consisting of one automated or semiautomated instrument and its associated reagents and controls. The system is used to perform a series of coagulation studies and coagulation factor assays.

Special Controls

*Classification.* Class II (special controls). A control intended for use with a multipurpose system for in vitro coagulation studies is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

Predicate Devices

• Sysmex CA-1500 (K011235)

Submission Summary (Full Text)

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

January 11, 2016

Siemens Healthcare Diagnostics Products GmbH Ms. Donna Noeh Regulatory Manager, US Affairs Emil-von-Behring-Str. 76 35041 Marburg, Germany

Re: K150678

Trade/Device Name: Sysmex CS-5100 Regulation Number: 21 CFR 864.5425 Regulation Name: Multipurpose system for in vitro coagulation studies Regulatory Class: Class II Product Code: JPA Dated: December 10, 2015 Received: December 11, 2015

Dear Ms. Noah:

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 comply with all the Act's requirements, including, but not limited to: registration and listing (21

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CFR Part 807); labeling (21 CFR Parts 801 and 809); 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 yours.

# Leonthena R. Carrington -S

Leonthena R. Carrington, MS, MBA, MT(ASCP) Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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# Indications for Use

510(k) Number (if known) K150678

Device Name Sysmex CS-5100

#### Indications for Use (Describe)

The Sysmex® CS-5100 is a fully automated blood coagulation analyzer intended for in vitro diagnostic use using plasma collected from venous blood samples in 3.2% sodium citrate tubes to analyze clotting, chromogenic and immunoassay methods in the clinical laboratory.

For determination of:

- Prothrombin Time (PT) seconds and PT INR with Dade® Innovin®
- · Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL
- · Fibrinogen (Fbg) with Dade® Thrombin Reagent
- Antithrombin (AT) with INNOVANCE® Antithrombin
- · D-dimer with INNOVANCE® D-Dimer

The performance of this device has not been established in neonate and pediatric patient populations.

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

X Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

### PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON A SEPARATE PAGE IF NEEDED.

#### FOR FDA USE ONLY

Concurrence of Center for Devices and Radiological Health (CDRH) (Signature)

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Image /page/4/Picture/0 description: The image shows the word "SIEMENS" in a bold, sans-serif font. The color of the text is a teal or turquoise shade. The letters are evenly spaced and appear to be a logo or brand name.

# 510(k) Summary

This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of 21 CFR §807.92 and follows the FDA guidance "The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]", issued July 28, 2014.

## 1. Submitter

Siemens Healthcare Diagnostics Products GmbH Emil-von-Behring-Str. 76 35041 Marburg, Germany Contact Person: Donna Noeh Email: [e-mail] Phone: + 49 6421 39 5107 Facsimile: + 49 6421 39 4977 Date Prepared: January 7, 2016 2. Device Sysmex CS-5100 Name of Device: Common or Usual Name: Automated Coagulation Instrument Multipurpose system for in vitro coagulation studies (21 CFR Classification Name: 864.5425) Regulatory Class: 2 Product Code: JPA 510(k) Review Panel Hematology 3. Predicate Device Name of Device: Sysmex CA-1500 (K011235) Common or Usual Name: Automated Coagulation Instrument Classification Name: Multipurpose system for in vitro coagulation studies (21 CFR 864.5425) Regulatory Class: 2 Product Code: JPA Hematology 510(k) Review Panel

The predicate has not been subject to a design-related recall for any of the applications associated with this Premarket Notification.

No reference devices were used in this submission.

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# 4. Device Description / Test Principle

The Sysmex CS-5100 is an automated blood coagulation instrument which can analyze samples using clotting, chromogenic and immunoassay methods. Analysis results are displayed on the Information Processing Unit (IPU) screen. They can be printed on external printers or transmitted to a host computer. Sold separately from the instrument are the associated

- Reagents ●
- Controls
- Calibrators ●
- Consumable materials ●

The subject of this 510(k) notification are reagent applications which perform the coagulation tests Prothrombin Time (PT) seconds and PT INR with Dade® Innovin®; Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL; Fibrinogen (Fbg) with Dade® Thrombin Reagent; Antithrombin (AT) with INNOVANCE® Antithrombin; and D-dimer with INNOVANCE® D-Dimer.

The analysis principles used on the instrument are reflected by the reagent application testing provided in this 510(k) notification and is described in the below table.

| Table of Sysmex CS-5100 Analysis Principles | | |
|---------------------------------------------|------------------------------------------------|---------------------------------|
| Reagent | Application | Methodology |
| Dade® Innovin® | PT, Prothrombin Time<br>(seconds) | Clotting<br>(extrinsic pathway) |
| Dade® Innovin® | PT, Prothrombin Time (INR) | Clotting, calculated |
| Dade® Actin® FSL | APTT, Activated Partial<br>Thromboplastin Time | Clotting<br>(intrinsic pathway) |
| Dade® Thrombin<br>Reagent | Fibrinogen quantitation | Clotting<br>(common pathway) |
| INNOVANCE®<br>Antithrombin | Antithrombin quantitation | Chromogenic |
| INNOVANCE® D-<br>Dimer | D-dimer quantitation | Immunochemical |

The intended Environment of Use is a clinical central/hospital laboratory.

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# Front View of the Instrument

Image /page/6/Figure/2 description: This image shows a diagram of a machine with several parts labeled with numbers. The top part of the machine is labeled (1), and there are buttons labeled (4), (5), and (6). The middle section has a part labeled (7), and the bottom section has parts labeled (3) and (8), with a button labeled (2) on the side.

- (1) Light shield lid: Open this cover to set reagents, perform maintenance, etc.
- (2) Power switch: Turns the power ON/OFF.
- (3) Left door: Holds the Pneumatic Unit inside. Open this door to adjust the positive pressure (0.22 MPa).
- (4) Alarm indicator LED: Indicates the instrument status.
- (5) Mechanical stop switch: Press this switch to immediately stop the instrument's mechanical movement.
- (6) Start button: Press this button to immediately start an analysis. This button is the same as the [Start] button on the IPU toolbar.
- (7) Sampler: Automatically transports samples that are set in the sample rack to the aspiration position.
- (8) Right door: Open the door for maintenance or to discard cuvettes.

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# Informational Processing Unit

Image /page/7/Figure/2 description: The image shows a desktop computer with a monitor, CPU, keyboard, and mouse. The monitor is labeled as (1), the CPU is labeled as (2), the keyboard is labeled as (3), and the mouse is labeled as (4). The computer is a desktop model, with the CPU placed under the monitor and the keyboard and mouse connected to the CPU.

- (1) Touch panel display: Displays the IPU screen. It can also be used as a touch panel.
- (2) IPU Main Unit: This is the Main Unit of IPU.
- (3) Keyboard: Used to operate the IPU together with the touch panel.
- (4) Mouse: Used to operate the IPU together with the touch panel.

### Options and Accessories

Options and accessories that can be used for this instrument are as follows:

- (1) Waste tank (with float switch for waste tank): Waste fluids discharged from the Main Unit enter this tank.
- (2) Wand barcode reader: Reads barcodes to input sample numbers, rack numbers and reagent IDs.
- (3) 2D barcode reader: Reads barcodes to input calibrator's or reagent's assay sheet values, normal values and ISI values, and control's targets/limits.
- (4) IPU cart: The IPU (which includes the keyboard, PC and touch panel display), and the tanks for waste, rinse and CA Clean II can be placed on this cart.
- (5) External indicator light: The status of the instrument is indicated with a red, yellow or green light that can be seen when the operator is not directly in front of the instrument.
- (6) IPU holder: This is an optional holder for the IPU which includes the keyboard, PC and touch panel display which can be installed on the right side of the instrument to minimize the instrument footprint.

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The instrument is capable of measuring in the following analysis modes:

- (1) Normal mode: Samples for all the analyses including re-analyses are taken into the instrument at the same time and analyzed. In a normal mode, a capped sample tube analysis can be performed. Automatic re-analysis can also be performed.
- (2) Micro-sample mode: Samples set in the sampler or STAT holder are taken into the instrument for each analysis through a secondary dispensing sample probe. When measurements are to be performed in Micro mode, sample tubes must be uncapped. The instrument detects capped tubes automatically and displays an error message. This analysis mode can be performed with less sample volume than normal mode (consult instruction manual for further information). However, automatic re-analysis cannot be performed.

# 5. Intended Use / Indications for Use

The Sysmex CS-5100 is a fully automated blood coagulation analyzer intended for in vitro diagnostic use using plasma collected from venous blood samples in 3.2% sodium citrate tubes to analyze clotting, chromogenic and immunoassay methods in the clinical laboratory.

For determination of:

- Prothrombin Time (PT) seconds and PT INR with Dade® Innovin® ●
- Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL
- Fibrinogen (Fbg) with Dade® Thrombin Reagent ●
- Antithrombin (AT) with INNOVANCE® Antithrombin ●
- D-dimer with INNOVANCE® D-Dimer. ●

The performance of this device has not been established in neonate and pediatric patient populations.

### 6. Comparison of Technological Characteristics with the Predicate Device

Both the subject and predicate instruments employ the same technological characteristics in that they automatically analyze various clotting tests using reagents, calibrators and controls previously cleared for automated coagulation analyzers. The reagents perform at least equally well on both the subject and predicate instruments. At a high level, the devices have the following same technological elements:

### Similarities between the CS-5100 and CA-1500

| Similarities between Sysmex CS-5100 and Sysmex CA-1500 | | |
|--------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|
| Analyzer Component | Proposed Device<br>Sysmex CS-5100 | Predicate Device<br>Sysmex CA-1500 |
| Regulatory Classification | JPA, Class 2<br>System, Multipurpose for in<br>vitro coagulation studies | Same |
| Sample Type | Human plasma<br>3.2% sodium citrate | Same |
| Similarities between Sysmex CS-5100 and Sysmex CA-1500 | | |
| Analyzer Component | Proposed Device | Predicate Device |
| | Sysmex CS-5100 | Sysmex CA-1500 |
| Application type | Clotting Applications:<br>Prothrombin Time (PT) with<br>Dade® Innovin®;<br>Activated Partial Thromboplastin<br>Time (APTT) with Dade® Actin®<br>FSL;<br>Fibrinogen (Clauss) with Dade®<br>Thrombin Reagent<br><br>Chromogenic Application:<br>Antithrombin with<br>INNOVANCE® Antithrombin<br><br>Immuno-chemical Application:<br>D-dimer<br>with INNOVANCE® D-Dimer<br> | Same |
| Specimen Processing | Automatic Pipetting and Dilution | Same |
| Random Access | Yes | Same |
| Liquid Level Sensing | Yes - reagent and sample | Same |
| Bar code Reader | Sample + reagent | Same |
| STAT Testing | Yes | Same |
| Sampling Capabilities | Normal and Micro Mode | Same |
| Sample Volumes in Normal<br>Mode (Plasma) | PT with Dade® Innovin® 50 µL<br>APTT with Dade® Actin® FSL<br>50 µL<br>Fibrinogen with Dade®<br>Thrombin Reagent 10 µL<br>Antithrombin with<br>INNOVANCE® Antithrombin<br>10 µL<br>D-dimer with INNOVANCE® D-Dimer | Same |
| Similarities between Sysmex CS-5100 and Sysmex CA-1500 | | |
| Analyzer Component | Proposed Device | Predicate Device |
| | Sysmex CS-5100 | Sysmex CA-1500 |
| Sample Volumes in Micro<br>Mode (Plasma) | PT with Dade® Innovin® 50 µL<br>APTT with Dade® Actin® FSL<br>50 µL<br>Fibrinogen with Dade®<br>Thrombin Reagent 10 µL | Same |
| Rinse & Buffer Solutions | | |
| On-board | CA-CLEAN I | Same |
| External | CA-CLEAN II | Same |
| | Dade Owren's Buffer | Same |
| | Water | Same |
| Light Source | | |
| Chromogenic | Halogen Lamp | Same |
| Immuno-chemical | Halogen Lamp | Same |
| Wavelengths used in Analysis | Antithrombin with<br>INNOVANCE® Antithrombin<br>(405 nm) | Same |
| Temperature Control | Sample incubation well: 37℃ ±<br>1.0°C | Same |

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There are no technological differences between the subject and predicate devices. However the following minor changes exist between the subject and predicate devices:

| Differences between Sysmex CS-5100 and Sysmex CA-1500 | | |
|----------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Analyzer Component | Proposed Device | Predicate Device |
| | Sysmex CS-5100 | Sysmex CA-1500 |
| Intended Use Statement | The Sysmex CS-5100 is a fully<br>automated blood coagulation analyzer<br>intended for in vitro diagnostic use<br>using plasma collected from venous<br>blood samples in 3.2% sodium citrate<br>tubes to analyze clotting, chromogenic<br>and immunoassay methods in the<br>clinical laboratory.<br>For determination of:<br>• Prothrombin Time (PT) seconds and<br>PT INR with Dade® Innovin®<br>• Activated Partial Thromboplastin<br>Time (APTT) with Dade®<br>Actin® FSL<br>• Fibrinogen (Fbg) with Dade®<br>Thrombin Reagent<br>• Antithrombin (AT) with<br>INNOVANCE® Antithrombin<br>• D-dimer with INNOVANCE® D-<br>Dimer<br>The performance of this device has not<br>been established in neonate and<br>pediatric patient populations. | The intended use of the Sysmex CA-<br>1500 is as a fully automated,<br>computerized blood plasma<br>coagulation analyzer for in vitro<br>diagnostic use in clinical<br>laboratories.<br>The instrument uses citrated<br>human plasma to perform the<br>following parameters and<br>calculated parameters:<br>Clotting Analysis Prameters:<br>Prothrombin Time (PT); Activated<br>Partial Thromboplastin Time<br>(APTT); Fibrinogen (Clauss);<br>Batroxobin Time; Extrinsic Factors<br>(II, V, VII, X); Intrinsic Factors<br>(VIII, IX, XI, XII); Protein C.<br>Chromogenic Analysis<br>Parameters: Antithrombin III;<br>Factor VIII; Plasminogen;<br>Heparin; Protein C; α2-<br>Antiplasmin.<br>Immunologic Analysis Parameters:<br>D-dimer.<br>Calculated Parameters: PT Ratio;<br>PT INR; PT %; Derived Fibrinogen;<br>Factor Assays % Activity |
| Differences between Sysmex CS-5100 and Sysmex CA-1500 | | |
| | Proposed Device | Predicate Device |
| Analyzer Component | Sysmex CS-5100 | Sysmex CA-1500 |
| Operating Principle | | |
| Clotting | Transmitted Light Detection<br>(Absorbance) at 340, 405, 575, 660 or<br>800 nm. Wavelengths 340 and 575 are<br>technically available but not validated in<br>combination with the intended<br>applications. | Scattered Light Detection at 660 nm |
| Chromogenic | Transmitted Light Detection<br>(Absorbance) at 340, 405, 575, 660,<br>800 nm. Wavelengths 340, 575, 660,<br>and 800 are technically available but not<br>validated in combination with the<br>intended applications. | Transmitted Light Detection<br>(Absorbance) at 405, 575, 800 nm |
| Immuno-chemical | Transmitted Light Detection<br>(Absorbance) at 340, 405, 575, 660 or<br>800 nm. Wavelengths 340, 405, 575,<br>and 800 are technically available but not<br>validated in combination with the<br>intended applications. | Transmitted Light Detection<br>(Absorbance) at 405, 575, or 800 nm |
| Wavelengths* used in Analysis<br>*The default wavelength is normally<br>used to generate the reported value of<br>the measurement. The sub-wavelength | Clotting Applications:<br>PT (seconds) Dade® Innovin®<br>(Default = 660 nm; Sub-<br>Wavelength= 800 nm)<br><br>PT (INR) with Dade® Innovin®<br>(Default = 660 nm; Sub-Wavelength=<br>800 nm)<br><br>APTT with Dade® Actin® FSL<br>Activated PTT Reagent (Default =<br>660 nm; Sub-Wavelength= 800 nm) | Clotting Applications:<br>PT (seconds) with Dade®<br>Innovin® Default = 660 nm; Sub-<br>Wavelength= none)<br><br>PT (INR) with Dade® Innovin®<br>(Default = 660 nm; Sub-<br>Wavelength= none)<br><br>APTT with Dade® Actin® FSL<br>Activated PTT Reagent (Default<br>= 660 nm; Sub-Wavelength=<br>none) |
| is run in parallel. If a light intensity<br>error occurs by using the default<br>wavelength the value from the sub-<br>wavelength is used automatically. | Fibrinogen with Dade® Thrombin<br>Reagent (Default = 405 nm; Sub-<br>Wavelength= none)<br><br>Immuno-chemical Application:<br>D-dimer with INNOVANCE®<br>D-Dimer (Default = 660 nm; Sub-<br>Wavelength= none) | Fibrinogen with Dade® Thrombin<br>(Default = 660 nm;<br>Sub-Wavelength= none)<br><br>Immuno-chemical Application:<br>D-dimer with INNOVANCE® D-<br>Dimer (Default = 800 nm; Sub-<br>Wavelength= none) |
| Differences between Sysmex CS-5100 and Sysmex CA-1500 | | |
| Analyzer Component | Proposed Device<br>Sysmex CS-5100 | Predicate Device<br>Sysmex CA-1500 |
| Light Source<br>Clotting | Halogen Lamp | Light Emitting Diode |
| Probes | 2 Sample probes;<br>3 Reagent probes | 1 Sample probe;<br>1 Reagent probe |
| Cap Piercing | Cap Piercer only | Both options available:<br>Cap Piercer and Non-Cap Piercer |
| Temperature Control | -Detector : 37 °C ± 0.5 °C<br>-Reagent probe : 37.5 °C ± 0.5 °C | -Detector: 37°C ± 1.0°C<br>- Reagent probe: 37°C ± 1.0°C |
| Reagent Cooling | 10°C ± 2°C, when ambient temperature is 20°C - 28°C.<br>During operation 4°C -15°C, when ambient temperature is 15°C – 30°C | 15°C ± 2°C, when ambient temperature is 15°C - 30°C |
| Pipetting Capabilities | Reagent probe:<br>20 – 200 μL<br>Sample probe:<br>4 – 270 μL | Reagent probe:<br>3 – 200 μL<br>Sample probe:<br>5 – 450 μL |
| Sample Volumes in Micro<br>Mode (Plasma) | Antithrombin with INNOVANCE® Antithrombin 14 μL<br>D-dimer with INNOVANCE® D-Dimer 15 µL | Antithrombin with INNOVANCE® Antithrombin 10 μL<br>D-dimer with INNOVANCE® D-Dimer 13 µL |
| Bidirectional Interface<br>communication protocols | CA-, ASTM-, CS- Protocol | CA-, ASTM-Protocol |

# Differences between CS-5100 and CA-1500

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The above described differences do not raise new questions as to safety and effectiveness of the new device.

# 7. Performance Data

The following performance data were provided in support of the substantial equivalence determination.

#### 7.1 Method comparison

Method comparison studies designed according to EP09-A3 CLSI Guideline "Measurement Procedure Comparison and Bias Estimation Using Patient Samples" were conducted at three external sites in the United States, all sites using the same protocol.

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Samples were measured on both the predicate device (Sysmex CA-1500) as well as the new device (Sysmex CS-5100), in random order to eliminate any inherent bias. Results were compared by Passing-Bablok regression analysis as well as Bland-Altman plots. Results from each application met the pre-established acceptance criteria. The following summary of Passing-Bablok regression shows that the proposed and predicate devices provide equivalent results when used in a clinical setting.

| Sysmex CS-5100: Method Comparison Summary Table, Passing-Bablok regression | | | | |
|-------------------------------------------------------------------------------------------------------|--------------------------------------------|--------------------------------------------|--------------------------------------------|--------------------------------------------|
| Application<br>(measuring interval) | Site 01 | Site 02 | Site 03 | Sites Combined |
| Prothrombin<br>Time using<br>Dade® Innovin®<br>(8.7 - 90.0<br>seconds) | n=125<br>$y = 1.000x + 0.400$<br>r = 0.997 | n=209<br>$y = 1.000x + 0.000$<br>r = 0.999 | n=135<br>$y = 0.987x +0.374$<br>r = 0.999 | n=469<br>$y = 1.000x + 0.100$<br>r = 0.998 |
| Prothrombin<br>Time (INR) using<br>Dade® Innovin®<br>(0.93 - 8.00 INR) | n=122<br>$y = 1.044x - 0.037$<br>r = 0.997 | n=208<br>$y = 1.030x-0.038$<br>r = 0.999 | n=135<br>$y = 1.039x - 0.019$<br>r = 0.999 | n=465<br>$y = 1.047x-0.047$<br>r = 0.999 |
| Activated Partial<br>Thromboplastin<br>Time using<br>Dade® Actin®<br>FSL<br>(20.0 - 139.0<br>seconds) | n=126<br>$y = 1.029x - 1.112$<br>r = 0.994 | n=210<br>$y = 1.017x-1.203$<br>r = 0.998 | n=130<br>$y = 1.027x - 1.225$<br>r = 0.994 | n=466<br>$y = 1.026x - 1.315$<br>r = 0.996 |
| Fibrinogen<br>quantitation<br>using Dade®<br>Thrombin Reagent<br>(50 - 860 mg/dL) | n=145<br>$y = 1.052x -4.466$<br>r = 0.994 | n=91<br>$y = 1.028x + 5.491$<br>r = 0.996 | n=132<br>$y = 0.982x + 9.889$<br>r = 0.998 | n=368<br>$y = 1.018x + 4.633$<br>r = 0.995 |
| Antithrombin<br>quantitation<br>using<br>INNOVANCE®<br>Antithrombin<br>(9.0 - 128.0% of<br>norm) | n=135<br>$y = 0.990x-0.413$<br>r = 0.996 | n=120<br>$y = 0.957x + 1.825$<br>r = 0.994 | n=126<br>$y = 0.985x - 0.359$<br>r = 0.997 | n=381<br>$y = 0.980x + 0.222$<br>r = 0.996 |

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| Sysmex CS-5100: Method Comparison Summary Table, Passing-Bablok regression | | | | |
|---------------------------------------------------------------------------------------|---------------------------------|-----------------------------------|-----------------------------------|-----------------------------------|
| D-dimer<br>quantitation<br>using<br>INNOVANCE®<br>D-Dimer (0.19 –<br>35.20 mg/L FEU¹) | n=137 | n= 108 | n=116 | n=361 |
| | $y = 1.058x-0.013$<br>r = 0.997 | $y = 1.000x - 0.035$<br>r = 0.997 | $y = 1.000x + 0.000$<br>r = 0.998 | $y = 1.021x - 0.007$<br>r = 0.996 |

#### 7.2 Reproducibility Studies

Twenty-day precision studies were performed at two external sites in Germany and one external site in the United States. Testing followed the scheme of two runs per day, with two replicates per run, at each of the three sites according to CLSI EP05-A2 "Evaluation of Precision Performance of Quantitative Measurement Methods". The order of the analysis of parameter, samples and quality control samples for each run and day varied to avoid an inherent bias to the study. One calibration curve of each calibrated application was used in the study. Within Run, Between Run, Between Day, and Total With-in Site was calculated. The data is summarized in the following tables.

| Sysmex CS-5100: Reproducibility Summary Table, Within Run | | | | | |
|-------------------------------------------------------------------------------------------------|----------------------------------------|--------------------------------|--------------------------------|--------------------------------|----------------------------|
| Application<br>(CRR/<br>Clotting time range) | Sample<br>Range (mean<br>of all sites) | Site 01<br>Within Run<br>(%CV) | Site 02<br>Within Run<br>(%CV) | Site 03<br>Within Run<br>(%CV) | Sites<br>Combined<br>(%CV) |
| Prothrombin Time<br>using Dade® Innovin®<br>(8.7 - 90.0 seconds) | 9.27 - 79.67<br>seconds | 0.64 – 1.85 | 0.47 – 0.98 | 0.51 - 3.61 | 0.59 — 2.35 |
| Prothrombin Time<br>(INR) using Dade®<br>Innovin® (0.93 - 8.00<br>INR) | 1.02 - 7.76<br>INR | 0.62 - 2.21 | 0.45 - 0.92 | 0.44 - 1.31 | 0.51 - 1.50 |
| Activated Partial<br>Thromboplastin Time<br>using Dade® Actin®<br>FSL<br>(20.0 - 139.0 seconds) | 22.02 -<br>123.25<br>seconds | 0.71 - 5.51 | 0.51 - 3.05 | 0.56 - 2.67 | 0.76 - 3.93 |
| Fibrinogen<br>quantitation using<br>Dade® Thrombin<br>Reagent<br>(50 - 860 mg/dL) | 56.2 - 752.6<br>mg/dL | 1.14 - 6.18 | 0.99 - 3.27 | 1.41 - 2.72 | 1.20 - 4.20 |

¹ D-dimer results are reported in fibrinogen equivalent units (FEU).

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| Sysmex CS-5100: Reproducibility Summary Table, Within Run | | | | | |
|--------------------------------------------------------------------------------------------|-------------------------------|-------------|-------------|-------------|-------------|
| Antithrombin<br>quantitation using<br>INNOVANCE®<br>Antithrombin<br>(9.0 - 128.0% of norm) | 10.17 -<br>119.41% of<br>norm | 0.71 - 2.66 | 0.81 - 3.45 | 0.97 - 3.13 | 0.92 - 3.11 |
| D-dimer quantitation<br>using INNOVANCE®<br>D-Dimer (0.19 - 35.20<br>mg/L FEU) | 0.25 - 33.81<br>mg/L FEU | 0.91 - 2.15 | 0.80 - 1.56 | 1.27 – 2.51 | 1.08 – 2.07 |

| Sysmex CS-5100: Reproducibility Summary Table, Between Run | | | | | |
|-----------------------------------------------------------------------------------------------|----------------------------------------|---------------------------------|---------------------------------|---------------------------------|----------------------------|
| Application<br>(CRR/<br>Clotting time range) | Sample Range<br>(mean of all<br>sites) | Site 01<br>Between Run<br>(%CV) | Site 02<br>Between Run<br>(%CV) | Site 03<br>Between Run<br>(%CV) | Sites<br>Combined<br>(%CV) |
| Prothrombin Time<br>using Dade®<br>Innovin®<br>(8.7 - 90.0 sec) | 9.27 - 79.67<br>seconds | 0.12 - 1.73 | 0.00 - 1.15 | 0.00 - 1.45 | 0.35 - 1.42 |
| Prothrombin Time<br>(INR) using Dade®<br>Innovin® (0.93 –<br>8.00 INR) | 1.02 – 7.76<br>INR | 0.00 - 2.05 | 0.00 - 1.12 | 0.53 - 1.30 | 0.25 - 1.37 |
| Activated Partial<br>Thromboplastin<br>Time using Dade®<br>Actin® FSL<br>(20.0 - 139.0 sec) | 22.02 - 123.25<br>seconds | 0.00 - 0.97 | 0.00 - 2.50 | 0.29 - 2.66 | 0.34 - 2.40 |
| Fibrinogen<br>quantitation using<br>Dade® Thrombin<br>Reagent<…