The cobas m 511 integrated hematology analyzer is a quantitative, automated analyzer with cell locating capability. It is intended for in vitro diagnostic use by a skilled operator in the clinical laboratory. The system prepares a stained microscope slide from EDTA-anticoagulated whole blood. It utilizes computer imaging to count the formed elements of blood and provide an image-based assessment of cell morphology, which may be reviewed by the operator, and also allows for manual classification of unclassified cells. The instrument reports the following parameters: RBC, HGB, HCT, MCV, MCH, MCHC, RDW, RDW-SD, %NRBC, #NRBC, WBC, %NEUT, #NEUT, %LYMPH, #LYMPH, %MONO, #MONO, %EO, #EO, %BASO, #BASO, PLT, MPV, %RET, #RET, HGB-RET.

Device Description

The cobas m 511 system is a fully automated stand-alone hematology analyzer with integrated slide making capability and digital cell imaging. It provides a complete blood count, 5-part differential, and reticulocvte enumeration of samples of whole blood collected in K2 or K3 EDTA. It is designed for high throughput in the clinical laboratory environment.

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text.

Device: cobas m 511 integrated hematology analyzer
Predicate Devices: Sysmex® XN-Series (XN-10, XN-20) Automated Hematology Analyzer and CellaVision® DM1200 Automated Hematology Analyzer

It's important to note that the provided text is a 510(k) summary, which focuses on demonstrating substantial equivalence to predicate devices rather than directly outlining the acceptance criteria in a traditional sense (e.g., "sensitivity must be > X%, specificity > Y%"). Instead, the document describes performance studies and states that results "met acceptance criteria" or "were found to be acceptable," implying that specific internal acceptance criteria were used for each test. I will extract the performance results where available, and indicate where quantitative acceptance criteria are not explicitly stated but implied to have been met.

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document does not explicitly present a table of acceptance criteria. Instead, it presents performance data and states that "acceptance criteria were met." Where quantitative values are provided, they represent the reported device performance which implicitly met the underlying, but unstated, acceptance criteria for FDA clearance.

Performance Characteristic	Acceptance Criteria (Implied / Stated)	Reported Device Performance
Method Comparison (vs. Predicate Device)	Correlation and bias "found to be acceptable for all reportable parameters" based on CLSI EP09-A3 guidelines.	(See Table 3 in original document for full details. Below are examples for key parameters.)
WBC [10³/µL]	Implied to be acceptable.	Pearson's (r) = 0.999; Intercept = 0.02; Slope = 1.012; Bias at low/high limits: 0.03 - 0.07 [10³/µL], 1.26 - 1.7 [%].
RBC [10⁶/µL]	Implied to be acceptable.	Pearson's (r) = 0.974; Intercept = 0.02; Slope = 0.991; Bias at low/high limits: -0.41 - -0.56.
HGB [g/dL]	Implied to be acceptable.	Pearson's (r) = 0.970; Intercept = -0.33; Slope = 1.046; Bias at low/high limits: -0.12 - 0.14 [g/dL], 1.35 - 3.08 [%].
PLT [10³/µL]	Implied to be acceptable.	Pearson's (r) = 0.973; Intercept = -11.03; Slope = 1.020; Bias at low/high limits: -10.83 - 0.88.
%NEUT [%]	Implied to be acceptable.	Pearson's (r) = 0.989; Intercept = 1.62; Slope = 1.012; Bias at low/high limits: 3.06 - 5.21.
%LYMPH [%]	Implied to be acceptable.	Pearson's (r) = 0.989; Intercept = -0.23; Slope = 0.977; Bias at low/high limits: -2.66 - -0.81.
Flagging Capabilities (Clinical Sensitivity & Specificity)	For WBC messages (flags) vs. 400-cell reference method: met acceptance criteria for sensitivity and specificity.	Sensitivity = 92.9% (118/(118+9))Specificity = 96.8% (302/(302+10))
Precision (Repeatability - within-run)	"Repeatability results met their pre-defined acceptance criteria." (Based on CLSI EP05-A3 and H26-A2 standards).	(See Table 5 in original document for full details. Examples for WBC & PLT below.)
WBC [10³/μL] (All samples)	Implied to be acceptable.	Mean of Sample Means: 12.06; SD: 0.233; %CV: 1.93.
PLT [10³/μL] (All samples)	Implied to be acceptable.	Mean of Sample Means: 246.77; SD: 6.749; %CV: 2.73.
Reproducibility (Total Precision)	"Reproducibility for the three (3) levels of DigiMAC3 controls was calculated and found to be acceptable for all sites combined for all reportable parameters." (Consistent with CLSI EP05-A3).	(See Table 6 in original document for full details. Examples for WBC & PLT below.)
WBC [10³/µL] (L1 control)	Implied to be acceptable.	Mean: 16.93; Total (Reproducibility) SD: 0.404; %CV: 2.39.
PLT [10³/µL] (L1 control)	Implied to be acceptable.	Mean: 470.53; Total (Reproducibility) SD: 8.090; %CV: 1.72.
Linearity	Demonstrated to be linear from lower to upper limit; "all results met acceptance criteria." (Based on CLSI EP06-A).	(See Table 7 in original document for examples showing "Maximum Absolute Deviation (Relative)" met allowed deviation. e.g., WBC System 1: 0% dev (8%) vs. 0.5% allowed (15%))
Carryover	"Carryover results for the cobas m 511 system met acceptance criteria." (Based on ICSH guidelines and CLSI H26-A2).	White Blood Cells: 0.000%Red Blood Cells: 0.000%Platelets: 0.001%Blasts: 0.000%
Interfering Substances	No significant interference effects up to specific concentrations, except for noted thresholds (HGB/HCT with hemolysis, WBC/#LYMPH with lipemia).	Unconjugated/Conjugated Bilirubin: No significant effects up to 40 mg/dL.Hemolysis: No significant effects up to 1000 mg/dL, except HGB ≥ 672 mg/dL & HCT ≥ 792 mg/dL.Lipemia: No significant effects up to 3000 mg/dL, except WBC ≥ 1646 mg/dL & #LYMPH ≥ 2459 mg/dL.High WBC/PLT conc.: No significant effects up to 100.2 x 10⁹/uL (WBC) and 1166 x 10³/uL (PLT).
Specimen Stability	"The combined results demonstrated stability for normal and abnormal samples up to or beyond twenty-four (24) hours."	Samples stable up to and beyond 24 hours at ambient (15°C-25°C) and refrigerated (2℃-8℃).
Anticoagulant Comparison	"All acceptance criteria were met, demonstrating equivalency of results obtained from samples collected into K2 EDTA and K3 EDTA."	Equivalence established.
Venous and Capillary Blood Method Comparisons	"Overall, the data demonstrate comparable results between venous and capillary blood processed on the cobas m 511 system."	Comparability established.
Mode to Mode Analysis	"The results were found to be acceptable in that all twenty-six (26) reportable parameters that were evaluated met acceptance criteria."	Acceptance criteria met.
Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ)	(Based on CLSI EP17-A2 guidelines).	WBC: LoB = 0.05 x 10³/uL, LoD = 0.08 x 10³/uL, LoQ = 0.24 x 10³/uLPLT: LoB = 1 x 10³/uL, LoD = 3 x 10³/uL, LoQ = 6 x 10³/uL
Reference Intervals	"Normal reference ranges for adult and pediatric cohorts are consistent with those in the published literature."	Established for adult males, adult females, and six pediatric subgroups.

2. Sample Sizes and Data Provenance

Test Set Sample Size:
- Method Comparison: 1859-1864 samples (exact number varies slightly by parameter, presumably due to valid data points for each). Sample collection lasted "a minimum of two (2) weeks at each of four (4) clinical sites."
- Flagging Capabilities: 439 samples (for WBC flags).
- Precision (Repeatability): 144 samples (for primary parameters), with 31-143 individual samples processed for different parameter groups. Total observations were 4436 (for WBC, RBC, HGB, etc.) and 4405 (for PLT, MPV, %NRBC, etc.) derived from 31 consecutive runs.
- Reproducibility: 120 observations per control level (for 3 control levels per parameter).
- Linearity: Not explicitly stated as a single number but involved serial dilutions run for 6 replicates (5 for reticulocytes) on multiple systems.
- Carryover: 12 independent carryover experiments.
- Interfering Substances: Dose-response experiments using 6 incremental concentration samples for each substance.
- Specimen Stability: 31 normal samples, 14 abnormal samples.
- Anticoagulant Comparison: 44 healthy donor samples, 40 residual abnormal samples.
- Venous and Capillary Blood Method Comparisons: 40 healthy donor samples, 40 residual abnormal capillary samples.
- Mode to Mode Analysis: Not a specified sample size number, but compared results from closed-tube vs. open-tube modes.
- LoB, LoD, LoQ: "three (3) individual test days" for each.
Data Provenance: The studies were conducted at four (4) clinical sites. The document does not specify the country of origin of these sites but implies they are clinical laboratories. The studies are prospective in nature, as they involve testing samples on the newly developed cobas m 511 system and comparison to predicate devices/reference methods. The samples were "residual whole blood samples" (for some studies) or collected specifically for the studies ("from healthy volunteer donors," "apheresis samples").

3. Number of Experts and Qualifications for Ground Truth

Expert Usage: For Flagging Capabilities, the "400-cell reference method" refers to the combined results from two (2) 200-cell WBC differentials performed by individuals on two (2) separate blood smears. For Carryover, "slides from the LTV serum samples were reviewed by an external hematopathologist to determine cell carryover."
Number of Experts: At least two individuals performed the 200-cell WBC differentials for the flagging study. At least one external hematopathologist was used for the carryover study.
Qualifications: "Skilled operator in the clinical laboratory" is mentioned as the intended user. For the flagging study, "individuals" are implied to be laboratory professionals trained in WBC differentials. The carryover study explicitly mentions an "external hematopathologist," implying a medical doctor specializing in laboratory hematology, which suggests a high level of expertise.

4. Adjudication Method for the Test Set

Flagging Capabilities: The "400-cell reference method" involved two separate 200-cell differentials. The combination of these two suggests a form of consensus or combined result, but specific adjudication rules (e.g., if discrepancies, a third reader decides) are not detailed. It's presented as a direct summation or combination of two expert reads.
Other Studies: For quantitative parameter comparisons, the ground truth for the "reference method" (often the predicate device or a standardized laboratory method) is assumed to be the established truth, and formal adjudication among multiple readers is not explicitly mentioned as being part of the process for the device's numerical outputs.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was explicitly described in the provided text for comparing human reader performance with and without AI assistance. The device is an automated analyzer, and its primary comparison is to another automated analyzer (Sysmex XN-Series) and an automated cell locating device that assists a human operator (CellaVision DM1200).
The document implies that the cobas m 511 system provides images that may be reviewed by the operator and allows for manual classification of unclassified cells (%NEUT, %LYMPH, etc. are determined by the instrument). The comparison for "Flagging Capabilities" involves the device's flags against a human expert reference method, highlighting the device's ability to trigger review. However, this is not a study measuring the improvement of human readers with AI assistance.
Therefore, an effect size of how much human readers improve with AI vs. without AI assistance is not provided as such a study was not the focus of this 510(k) submission.

6. Standalone Performance Study

Yes, standalone performance (algorithm only without human-in-the loop performance) was extensively done. The "Analytical Performance" section (5.1) details multiple studies of the device's performance in measuring various blood parameters independently.
- Method Comparison: Compares the device's readings against a predicate device.
- Precision (Repeatability and Reproducibility): Measures the device's consistency.
- Linearity: Assesses the device's accuracy across its measuring range.
- Carryover, Interfering Substances, Specimen Stability, LoB/LoD/LoQ: All measure the inherent performance characteristics of the automated analyzer itself.
The device "utilizes computer imaging to count the formed elements of blood and provide an image-based assessment of cell morphology," and "reports the following parameters: RBC, HGB, HCT, MCV, MCH, MCHC, RDW, RDW-SD, %NRBC, #NRBC, WBC, %NEUT, #NEUT, %LYMPH, #LYMPH, %MONO, #MONO, %EO, #EO, %BASO, #BASO, PLT, MPV, %RET, #RET, HGB-RET." These are all automated measurements.

7. Type of Ground Truth Used

The type of ground truth used varies by study:

Method Comparison: The predicate device's measurements (Sysmex XN-Series) served as the comparator/ground truth for quantitative parameters.
Flagging Capabilities: A 400-cell reference method which involved expert consensus (two individuals performing 200-cell WBC differentials on separate smears) was used as ground truth for WBC flagging. This represents a type of expert consensus based on microscopy.
Precision and Reproducibility: Standardized quality control materials (DigiMAC3 controls) with known values, and repeated measurements of patient samples across ranges.
Carryover: Expert review by an external hematopathologist of slides to confirm cell carryover.
Linearity, Interfering Substances, Stability, LoB/LoD/LoQ: These studies establish the device's intrinsic performance characteristics, often relative to expected values or reference methods for their respective tests, rather than a single 'ground truth' in the diagnostic sense. For linearity, prepared samples with known (or expected) concentrations are typically used.
Reference Intervals: Based on statistical analysis of samples from normal healthy donors and comparison to published literature.

8. Sample Size for the Training Set

The document does not report the sample size for the training set for the AI/computer imaging components. This 510(k) summary focuses on the validation of the final device rather than its development. Details about the training data used for the "proprietary imaging algorithms" are typically considered proprietary and not required in a public 510(k) summary.

9. How the Ground Truth for the Training Set Was Established

Since the training set size and details are not provided, the method for establishing ground truth for the training set is also not discussed in this document. It is highly probable, given the nature of the device, that ground truth for training would involve extensive manual expert review and classification of blood cell images by trained morphologists or hematopathologists.

Summary

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March 2, 2018

Roche Diagnostics Hematology, Inc. Dan Bracco Head of Clinical and Regulatory Affairs 69 Milk Street, Suite 120 Westborough, Massachusetts 01581

Re: K171655

Trade/Device Name: cobas m 511 integrated hematology analyzer Regulation Number: 21 CFR 864.5220 Regulation Name: Automated differential cell counter Regulatory Class: Class II Product Code: GKZ, JOY Dated: June 2, 2017 Received: June 5, 2017

Dear Dan Bracco:

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 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR

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803); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Leonthena R. Carrington -S

Lea Carrington 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) K171655

Device Name

cobas m 511 integrated hematology analyzer

Indications for Use (Describe)

The cobas m 511 integrated hematology analyzer is a quantitative, automated analyzer with cell locating capability. It is intended for in vitro diagnostic use by a skilled operator in the clinical laboratory. The system prepares a stained microscope slide from EDTA-anticoagulated whole blood. It utilizes computer imaging to count the formed elements of blood and provide an image-based assessment of cell morphology, which may be reviewed by the operator, and also allows for manual classification of unclassified cells. The instrument reports the following parameters: RBC, HGB, HCT, MCV, MCH, MCHC, RDW, RDW-SD, %NRBC, #NRBC, WBC, %NEUT, %LYMPH, #LYMPH, %MONO, #MONO, %EO, #EO, %BASO, #BASO, PLT, MPV, %RET, #RET, HGB-RET.

Type of Use (Select one or both, as applicable)
Registration Use (Part 21 CFR 601 Subpart D) One-Time Study Use (21 CFR 601 Subpart C)	Registration Use (Part 21 CFR 601 Subpart D)	One-Time Study Use (21 CFR 601 Subpart C)
Registration Use (Part 21 CFR 601 Subpart D)
One-Time Study Use (21 CFR 601 Subpart C)

Prescription Use (Part 21 CFR 801 Subpart D)

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

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cobas m 511 integrated hematology analyzer 510(k) Summary

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

In accordance with 21 CFR 807.87, Roche Diagnostics Hematology, Inc. (RDH) hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).

The purpose of this traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the cobas m 511 integrated hematology analyzer (cobas m 511 system).

Submitter Name	Roche Diagnostics Hematology, Inc.
Address	69 Milk StreetSuite 120Westborough, MA 01581
Contact	Dan BraccoPhone: (508) 329-2455FAX: (508) 329-2486Email: dan.bracco@roche.com
Date Prepared	February 22, 2018
Proprietary Name	cobas m 511 integrated hematology analyzer
Common Name	Automated Differential Cell CounterAutomated Cell Locating Device
Classification Name	21 CFR 864.5220, Differential Cell Counter, Class II21 CFR 864.5260, Automated Cell Locating Device, Class II
Product Codes,Regulation Numbers	GKZJOY
Predicate Devices	Sysmex® XN-Series (XN-10, XN-20) Automated Hematology AnalyzerCellaVision® DM1200 Automated Hematology Analyzer
Establishment Registration	The establishment registration number for Roche Diagnostics Hematology hasnot yet been established.

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1. DEVICE DESCRIPTION

Instrument Components and Consumables 1.1.

The cobas m 511 system consists of the following major components:

The analyzer, with rack transport system for sample tubes .
Viewing stations, that can be configured as the control station or as a review station .
Associated consumables and components .

The cobas m 511 system major components:

cobas m 511 analyzer 1.1.1. -

The cobas m 511 analyzer is a stand-alone hematology analyzer with integrated slide making capability and digital cell imaging. It has five (5) processing stations: sample mixing, slide printing, slide staining, slide imaging (low and high magnification), and slide output. It also includes a separate compartment, which houses the necessary consumables and waste containers.

cobas m 511 viewing station 1.1.2. -

The viewing station hardware is a computer with custom software developed by RDH that provides the graphical user interface for the system. It is designed to interface with a standard Laboratory Information System (LIS) for results reporting.

DigiMAC3 stain pack 1.1.3. -

The DigiMAC3 stain pack is intended to fix and stain cells from a whole blood sample or control/calibrator material that have been applied to a slide by the cobas m 511 analyzer, in order to make the cells suitable for automated imaging or manual microscopy. The DigiMAC3 stain pack is comprised of the following four (4) separate solutions, which are individually applied to each processed slide: DigiMAC3 fix, DigiMAC3 eosin, DigiMAC3 methylene blue,

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and DigiMAC3 rinse. The application of these stain solutions results in a Romanowsky type stain such as typically used in hematologic evaluations of whole blood.

DigiMAC3 reticulocyte 1.1.4. -

DigiMAC3 reticulocyte is intended to stain a whole blood sample or control material before it is applied to a slide by the cobas m 511 analyzer, in order to make the reticulocytes suitable for automated imaging or manual microscopy. DigiMAC3 reticulocyte is a supravital stain consisting of an aqueous solution of Azure B dye as the critical component, which condenses the reticulum in red blood cells and allows visualization of reticulocytes. Unlike the stain pack solutions that stain a prepared slide, DigiMAC3 reticulocyte is mixed with the whole blood sample by the cobas m 511 analyzer prior to slide printing.

DigiMAC³ wash 1.1.5. -

DigiMAC3 wash is used to clean all specimen-contacting surfaces, including blood fluid pathways, following processing of each blood sample. This solution is unique to the cobas m 511 system and is comprised of detergent and preservative in an aqueous, buffered solution.

1.1.6. DigiMAC³ clean

DigiMAC3 clean is primarily a 0.7% sodium hypochlorite formulation, which is used to remove protein build-up from the surfaces of the cobas m 511 analyzer components that come in contact with blood samples.

DigiMAC3 slides 1.1.7.

The DigiMAC3 slide is a glass substrate on which a whole blood sample or control/calibrator material is applied and stained by the cobas m 511 analyzer, in order to enable automated imaging or manual microscopy.

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Principles of Operation 1.2.

The cobas m 511 system uses digital morphology from an automatically produced Romanowsky stained monolayer slide, to provide the standard set of hematology parameters for the complete blood count (CBC), automated white blood cell (WBC) differential, and the enumeration of reticulocytes. This is done through the use of proprietary imaging algorithms that locate, count and evaluate red and white blood cells, platelets and nucleated red blood cells.

The cobas m 511 system prints a consistent sample volume (a nominal 1 uL) onto a glass microscope slide using a precision application method. In the stainer module, four reagents are applied to the cells on the slide: a fixative, an eosin stain, a methylene blue stain, and a rinse. Following staining, the slide is imaged at low magnification using a 10x lens to locate, image, and count white and red blood cells, nucleated red blood cells, and platelets. The system selects a specific number of white blood cell locations and provides their coordinates to the high magnification module for additional analysis. In the high magnification module a 50x lens is used to classify white blood cell types, evaluate red blood cells, and platelets and to evaluate cellular morphology. The white blood cells are categorized into the five (5) normal types or as unclassified cells by the instrument. This allows a skilled technologist to review images of the cells on the viewing station or to perform a full microscopic review of the slide. This 50x magnification is also used to identify and count the reticulocytes when a reticulocyte test is requested. For reticulocyte processing, an additional slide is produced from blood in the sample cup that is first incubated with a supravital stain. The cells are then printed onto the slide, stained using DigiMAC3 stain and imaged to determine the number and percentage of reticulocytes and reticulocyte hemoglobin.

Following processing, results and images can be viewed on the viewing station. The viewing station allows the operator to monitor system processes and status, and to view sample processing and results. The viewing station also allows a skilled medical technologist to perform a full white blood cell differential and a morphological review of white blood cells, red blood cells and platelets for samples requiring further review.

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1.3. -Modes of Operation

Closed-tube (automated rack) mode .
Open-tube (manual) mode .

Specimen Identification 1.4.

Specimen identification is performed automatically by the cobas m 511 system through an integrated barcode reader; or manually by the operator through the use of a hand-held barcode reader or keypad.

Specimen Sampling and Handling 1.5.

Samples can be introduced onto the cobas m 511 system using either the closed-tube (automated rack mode) or open-tube modes. In the closed-tube mode the sample tubes into a custom rack. The rack is then mechanically transported into the cobas m 511 system for processing. In this mode the cobas m 511 system automatically mixes, aspirates, and analyzes samples while the sample caps remain intact. In the open-tube mode, the operator mixes the samples tubes individually by hand and then introduces the sample to the open-port aspiration probe presented by the cobas m 511 system. The operator will position the tube such that the aspiration probe is immersed into the approximate center of the blood volume.

1.6. Calibration

The DigiMAC3 calibrator is used for calibration of the cobas m 511 system. The calibrator is a stable suspension of cells of human or animal origin. It is used for calibrating the following hematology parameters of the cobas m 511 system: WBC, RBC, MCH, MCV, PLT, and MPV.

Quality Control 1.7.

DigiMAC3 controls are used to monitor the performance of the cobas m 511 system. These hematology quality control (OC) materials consist of stable suspensions of cells of human or animal origin. They are used for evaluating the accuracy and precision of all hematology parameters of the cobas m 511 analyzer. There are three (3) levels of controls (11, L2 and L3), which are used in conjunction with each other for monitoring the performance of the cobas m 511 analyzer.

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1.8. Software

FDA has reviewed applicant's Hazard Analysis and Software Development processes for this line of product types: Yes

INTENDED USE 2.

Indication(s) for Use 2.1.

The cobas m 511 integrated hematology analyzer is a quantitative, automated analyzer with cell locating capability. It is intended for in vitro diagnostic use by a skilled operator in the clinical laboratory. The system prepares a stained microscope slide from EDTA-anticoagulated whole blood. It utilizes computer imaging to count the formed elements of blood and provide an imagebased assessment of cell morphology, which may be reviewed by the operator, and also allows for manual classification of unclassified cells. The instrument reports the following parameters: RBC, HGB, HCT, MCV, MCH, MCHC, RDW, RDW-SD, %NRBC, #NRBC, WBC, %NEUT, #NEUT, %LYMPH, #LYMPH, %MONO, #MONO, %EO, #EO, %BASO, #BASO, PLT, MPV, %RET, #RET, HGB-RET.

2.2. Special Conditions for Use Statement(s):

For prescription use only

SUBSTANTIAL EQUIVALANCE INFORMATION 3.

Predicate Device Names(s) and 510(k) numbers 3.1.

Sysmex® XN-Series (XN-10, XN-20) Automated Hematology Analyzer (Sysmex Analyzer) -K112605

CellaVision® DM1200 Automated Hematology Analyzer (CellaVision Analyzer) – K092868

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3.2. Comparison with Predicate Device

Table 1 compares the cobas m 511 system with its predicate device.

ltem	Submitted Device:	Predicate Device:
Indications for use	cobas m 511 systemThe cobas m 511 integrated hematologyanalyzer is a quantitative, automatedanalyzer with cell locating capability. It isintended for in vitro diagnostic use by askilled operator in the clinical laboratory.The system prepares a stainedmicroscope slide from EDTA-anticoagulated whole blood. It utilizescomputer imaging to count the formedelements of blood and provide an image-based assessment of cell morphology,which may be reviewed by the operator,and also allows for manual classification of IRF, RET-He and has a Body Fluid modeunclassified cells. The instrument reportsthe following parameters: RBC, HGB,HCT, MCV, MCH, MCHC, RDW, RDW-SD, %NRBC, #NRBC, WBC, %NEUT,#NEUT, %LYMPH, #LYMPH, %MONO,#MONO, %EO, #EO, %BASO, #BASO,PLT, MPV, %RET, #RET, HGB-RET.	Sysmex AnalyzerThe XN-Series modules (XN-10, XN-20)are quantitative multi-parameter automatedhematology analyzers intended for in vitrodiagnostic use in screening patientpopulations found in clinical laboratories.The XN-Series modules classify andenumerate the following parameters inwhole blood: WBC, RBC, HGB, HCT,MCV,MCH, MCHC, PLT (PLT-I, PLT-F),NEUT%/#, LYMPH%/#, MONO%/#,E0%/#, BASO%/#, IG%/#, RDW-CV,RDW-SD, MPV, NRBC%/#, RET%/#, IPF,for body fluids. The Body Fluid modeenumerates the WBC-BF, RBC-BF,MN%/#, PMN%/#, and TC-BF# parametersin cerebrospinal fluid (CSF),serous fluids(peritoneal, pleural) and synovial fluids.Whole blood should be collected in K2 or K3EDTA anticoagulant and, Serous andSynovial fluids in K2 EDTA anticoagulant toprevent clotting of fluid. The use of
		anticoagulants with CSF specimens isneither required nor recommended.
Conditions for use	For prescription use.	Same
Principle of operation	Characterizes and identifies cells usingdigital imaging of stained cells on amicroscope slide.	Characterizes and identifies cells basedon detection of direct-current resistancelight scatter, fluorescence, and adaptivecluster analysis.
	Low magnification location and imaging ofwhite and red blood cells and plateletsusing a 10x objective, combined withillumination optics and a camera.High magnification imaging of white bloodcell types and cell morphology using a 50xobjective, combined with illumination opticsand a camera.	Flow cytometry method using asemiconductor laser to analyzephysiological and chemical characteristicsof cells and other biological particlesHydro Dynamic Focusing (DC Detection)with aperture to count the RBC and PLTand calculate the HCT via the RBC pulseheight detection method.
	Hemoglobin measurement using LED lightabsorption	SLS-Hemoglobin Method usinghemoglobin absorption after chemicallysing and LED light.
Item	Submitted Device:cobas m 511 system	Predicate Device:Sysmex Analyzer
	Automatically classifies cells from wholeblood and carries out all processes fromaspiration of sample to outputting ofresults.	Automatically classifies cells from wholeblood and carries out all processesautomatically from aspiration of the sampleto outputting of results.
	Displays analysis results and graphics ona computer screen.	Same
	Results can be printed on available printeror transmitted to a host computer.	Same
Modes of operation	Closed-tube (automated rack) modeOpen-tube (manual) mode	Sampler Analysis Mode (Closed Cap)Manual Analysis Mode (Closed and OpenCap)Pre-dilute Analysis ModeLow WBC Analysis ModeBody Fluid Mode
Methodology	Performs automated analyses of wholeblood cells using a combination of low andhigh magnification computer imaging ofstained cells.	Performs hematology analyses accordingto the Hydro Dynamic Focusing (DCDetection), flow cytometry method (usingsemiconductor laser), and SLS-hemoglobinmethod.
Sample identification	Automated barcode reading of sample tubeidentifier.Manual keyboard entry.Bi-directional instrument to LIS interface:patient demographics, orders, results.	Same
Calibrator	Calibration and verification of calibrationusing stabilized whole blood calibrator.	Same
	DigiMAC³ calibrator	XN CAL (for WBC, RBC, HGB, HCT, PLTand RET)XN CAL PF (for PLT-F)
Quality control	Three (3) stabilized whole blood controllevels of varying componentconcentrations.	Same
	DigiMAC³ control L1DigiMAC³ control L2DigiMAC³ control L3	XN Check (3 levels)
Sample types	Whole blood	SameBody Fluids
Anticoagulant	K2 and K3 ethylenediaminetetraacetic acid(EDTA)	Same
Sample collection device	Evacuated blood collection tube containingEDTA as an anticoagulant.	Same
Quality controltechniques	Levey-Jennings control chartX-bar charting	Same
Item	Submitted Device:cobas m 511 system	Predicate Device:Sysmex Analyzer
Intended use population	All whole blood samples from anyindividual sent to laboratory for analysis.	Same, also including body fluids
Sample aspirationvolume	30µL (closed-tube and open-tube mode)	88µL (Sampler Mode-Whole Blood)88µL (Manual Mode- Whole Blood)70µL (Manual Mode- Diluted Blood)
Service diagnostics	On-board system diagnosticsManufacturer can perform web-baseddiagnostics.	Same
Throughput	Approximately 60 samples/hour maximum	Approximately 100 samples/hour maximum
Reagents	DigiMAC3 stain pack, including:DigiMAC3 fix (fixative)DigiMAC3 eosin (stain)DigiMAC3 methylene blue (stain)DigiMAC3 rinse (rinse)DigiMAC3 reticulocyte (stain)	CELLPACK DCL (Diluent)CELLPACK DFL (Diluent)LYSERCELL WNR (Lyse)LYSERCELL WDF (Lyse)LYSERCELL WPC (Lyse)FLUOROCELL WNR (Stain)FLUOROCELL WDF (Stain)FLUOROCELL RET (Stain)FLUOROCELL PLT (Stain)FLUOROCELL WPC (Stain)SULFOLYSER (Lyse)
Cleaning solutions	DigiMAC3 washDigiMAC3 clean	CELLCLEAN AUTO
Software	Analyzer OS: LinuxViewing Station OS: MacOS	Microsoft Windows
	Proprietary cobas m 511 software	Proprietary Sysmex software
Analysis technique	Instrument measures targeted parametersautomatically.Examiner can assess results via viewingscreen or printed report.	Same
Number of samples	Multiple maintained in queue.One sample result presented at a time.	Same
Number of individualsrepresented per sample	One	Same
Presentation ofabnormal samples	Results reported numerically with flags.	Same
Analyte targets	Components of cells such as DNA, RNAand proteins	Same
Sample preparationprocedure	Printing of blood onto a microscope slidefollowed by staining of the slide.	Flow analysis after dilution and mixing withreagents.
Light sources	Light Emitting Diodes (LEDs)	Semiconductor Laser
Operational conditions	18 to 27°C ambient temperature20-60% relative humidity	15 to 30°C ambient temperature20-85% relative humidity
ltem	Submitted Device:cobas m 511 system	Predicate Device:Sysmex Analyzer
Automation	Transportation of racks of sample tubes onconveyor.	Same
Sample handling system	Individual sample tubes are automaticallyremoved from rack to be processed.Manual open-tube mode.	Same
Reagent access	Reagent (cleaning solution) and slidesstored within the instrument and remainingreagents stored in a drawer within theinstrument below the analyticalcomponents.	Reagents stored within the top front coverof the instrument and in a cabinet below theanalyzer.
Reagent bottle/Cartridgeidentification	Barcodes	Barcode or reagent specific cassetteposition
Reagent mixing	No reagent mixing required.	Same
Information transfer toand from instrument	Through LIS or manual entry on a computerscreen.	Same
Probe cleaning	Automatically for each specimen andperiodically with special clean reagent.	Same
Host interface	LIS or middleware	Same
Calibration intervals	Performed by manufacturer at installationand as needed.	Same
Stain types	Absorbent dyes, hemoglobin absorptionwith LED light.	Fluorescent dyes, hemoglobin absorptionwith chemical lysing and semiconductorlaser beam light.
User management	Allows setting of user assignment andlevel of access.	Same
Flagging of errors orsample conditions	System and sample errors and messagesare configurable, displayed and reportedby system to the LIS.	Same

Table 1: Comparison with Predicate Device

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Table 2 compares the cobas m 511 system with its predicate device, CellaVision Analyzer.

Item	Submitted Device:cobas m 511 system	Predicate Device:CellaVision Analyzer
Indications for use	The cobas m 511 integrated hematologyanalyzer is a quantitative, automatedanalyzer with cell locating capability. It isintended for in vitro diagnostic use by askilled operator in the clinical laboratory.The system prepares a stainedmicroscope slide from EDTA-anticoagulated whole blood. It utilizescomputer imaging to count the formedelements of blood and provide an image-based assessment of cell morphology,which may be reviewed by the operator,and also allows for manual classificationof unclassified cells. The instrumentreports the following parameters: RBC,HGB, HCT, MCV, MCH, MCHC, RDW,RDW-SD, %NRBC, #NRBC, WBC,%NEUT, #NEUT, %LYMPH, #LYMPH,%MONO, #MONO, %EO, #EO, %BASO,#BASO, PLT, MPV, %RET, #RET, HGB-RET.	DM1200 is an automated cell-locatingdevice. DM1200 automatically locates andpresents images of blood cells onperipheral blood smears. The operatoridentifies and verifies the suggestedclassification of each cell according to type.DM1200 is intended to be used by skilledoperators, trained in the use of the deviceand in recognition of blood cells.
Principle of operation	Low magnification location and imaging ofwhite and red blood cells and platelets.High magnification imaging of white bloodcell types and cell morphology.Displays analysis results, graphics, andimages on a computer screen.Results can be printed on available printeror transmitted to a host computer.	The analysis process consists of anoverview image processing and a cell-location step. The overview image is used tofind cells of interest and to obtain an overallimpression of the sample. The overviewimage can have one 10x zoom level or both10x and 50x zoom levels. The cell-locationstep uses the optical unit and a camera toobtain images of the identified images andstores the images in a database.
Methodology	Performs automated analyses of wholeblood cells using a combination of low andhigh magnification imaging of stained cellson a glass microscope slide, withsubsequent operator review ofcomputerized images or glass microscopeslide for flagged cases.	Same
Sample identification	Automated barcode reading of sampleidentifier.Manual keyboard entry.	Same
Specimen types	Whole Blood	SameBody Fluids
Item	Submitted Device:cobas m 511 system	Predicate Device:CellaVision Analyzer
Sample preparation	Automated slide preparation and staining.	Automated or manual slide preparation and staining.
Stains	Romanowsky type stain	Same
Analysis technique	Locates, identifies, and counts the varioustypes of white blood cells under theautomated microscope.Red blood cells and platelets and plateletmorphology can be assessed by examiner.	Same
Presentation of samples	Results reported numerically.Cells can be observed on a computerdisplay.Cells can be observed through amicroscope.	Same
Handling of abnormalsamples	Images automatically made available forreview.Slides available as needed for subsequentreview.	Same
Analyte targets	Stained components of cells such as DNA,RNA, and proteins.	Same
Light sources anddetector	LED light sources with specific Blue,Green, Yellow and Red wavelengths.Black and White cameras.	White light source.Color camera with RGB filters on individualpixels.
Automation	Slides moved automatically throughsystem.	Same
Sample identification	Analyzer tracks slide location in systemand prints alphanumeric sampleidentification on slide.	Barcode identification on slide.
Measurement principle	Numeric morphologic features from digitalimages and cell type computerclassification.	Same
Information transferto/from instrument	Through LIS or manual entry on acomputer screen.	Same
Internal qualitymanagement system	System performs self-testing and lightadjustment.Quality control samples run daily.	Same
Calibration intervals	Performed at installation and as needed.	Same
Display	Restricted to Apple iMac computer withspecific integrated display size, resolution,and color specifications.	Various
Intrinsic colorcompensation	Algorithms and classifiers tolerate stainvariations.	Same
Item	Submitted Device:cobas m 511 system	Predicate Device:CellaVision Analyzer
	Display color cannot be adjusted.	Display color can be adjusted.
Software	Analyzer OS: LinuxViewing Station OS: MacOS	Microsoft Windows
	Proprietary cobas m 511 software	Proprietary software
Result and imagestorage	Stores results and images in a localdatabase.	Same

Comparison with CellaVision Analyzer Table 2:

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4. SPECIAL CONTROL/GUIDANCE DOCUMENT REFERENCED (IF APPLICABLE)

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

CLSI EP05-A3	Evaluation of Precision of Quantitative Measurement Procedures;Approved Guideline - Third Edition
CLSI EP06-A	Evaluation of the Linearity of Quantitative Measurement Procedures:A Statistical Approach; Approved Guideline
CLSI EP07-A2	Interference Testing In Clinical Chemistry; Approved Guideline -Second Edition
CLSI EP09-A3	Measurement Procedure Comparison and Bias Estimation UsingPatient Samples; Approved Guideline - Third Edition
CLSI EP10-A3-AMD	Preliminary Evaluation of Quantitative Clinical LaboratoryMeasurement Procedures, Approved Guideline - Third Edition
CLSI EP17-A2	Evaluation of Detection Capability for Clinical Laboratory MeasuremenProcedures; Approved Guideline - Second Edition
CLSI EP28-A3c	Defining, Establishing, and Verifying Reference Intervals in theClinical Laboratory: Approved Guideline - Third Edition

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CLSI H20-A2 Reference Leukocyte (WBC) Differential Count (Proportional) and Evaluation of Instrumental Methods: Approved Standard -Second Edition
Validation, Verification, and Quality Assurance of Automated CLSI H26-A2 Hematology Analyzers; Approved Standard - Second Edition
Safety requirements for electrical equipment for measurement, control, IEC 61010-1:2010 and laboratory use - Part 1: General requirements
IEC 61010-2-101:2015 Safety requirements for electrical equipment for measurement, control, and laboratory use - Part 2-101: Particular requirements for in vitro diagnostic (IVD) medical equipment
IEC 61326-1:2012 Electrical equipment for measurement, control and laboratory use -EMC requirements - Part 1: General requirements
IEC 61326-2-6:2012 Electrical equipment for measurement, control and laboratory use -EMC requirements - Part 2-6: Particular requirements - In vitro diagnostic (IVD) medical equipment
IEC 62304:2006 Medical device software - Software life cycle processes
ISO 14971:2007 Medical devices – Application of risk management to medical devices

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PERFORMANCE CHARACTERESTICS 5.

Analytical Performance 5.1.

Method Comparison 5.1.1.

A method comparison study was performed to compare results of residual whole blood samples that were randomly collected for a minimum of two (2) weeks at each of four (4) clinical sites. Specific interference samples and medical decision level samples were also included at each site. Each sample was processed on the cobas m 511 system and the predicate device within eight (8) hours of venipuncture. Correlation and bias between the cobas m 511 system and the comparator analyzer were determined in accordance with the CLSI EP09-A3 guideline based on the results of either a Passing-Bablok or Deming regression model. For the %NRBC and #NRBC parameters the mean difference was used to calculate bias in accordance with the CLSI EP09-A3 guideline. If a parameter has mixed acceptance criteria comprised of both an absolute bias limit and a proportional bias limit, the bias been reported at the crossover point where the two (2) bias limits are equal. In these cases the crossover point is listed in both absolute and proportional terms for the same value. Because bias is calculated using a linear model, if the calculated bias was found to be acceptable at the low bias limit, high bias limit, and crossover point (if required), the bias is considered acceptable at all points in between. The results of the Method Comparison evaluation were found to be acceptable for all reportable parameters. The results for all sites combined are shown in Table 3.

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Parameter[Units]	N	Pearson's(r)	Intercept(95% CI)	Slope (95% CI)	SampleRange	Evaluation Range			Bias (95% CI)			At HighLimit
WBC[103/µL]	1859	0.999	0.02(-0.01, 0.05)	1.012(1.007, 1.017)	(0.04, 247.04)	0.50	4.00	30.00	0.03(0.00, 0.05)	0.07(0.05, 0.08)[103/µL]	1.7(1.34, 2.09)[%]	1.26(0.87, 1.69)
RBC[106/µL]	1859	0.974	0.02(-0.01, 0.04)	0.991(0.985, 1.000)	(1.15, 7.21)	4.00	N/A	5.50	-0.41(-0.59, -0.25)	N/A		-0.56(-0.82, -0.18)
HGB[g/dL]	1853	0.970	-0.33(-0.41, -0.24)	1.046(1.039, 1.053)	(4.20, 21.20)	4.50	10.00	21.20	-0.12(-0.17, -0.07)	0.14(0.11, 0.15)[g/dL]	1.35(1.15, 1.53)[%]	3.08(2.70, 3.42)
HCT [%]	1859	0.953	-0.72(-1.06, -0.35)	1.043(1.033, 1.053)	(13.50, 66.00)	14.00	N/A	66.00	-0.87(-2.40, 0.71)	N/A		3.20(2.68, 3.68)
MCV [fL]	1859	0.887	-3.03(-5.06, -0.87)	1.060(1.035, 1.083)	(58.20, 119.20)	80.00	N/A	100.00	2.25(1.97, 2.58)	N/A		3.01(2.65, 3.36)
MCH[pg]	1844	0.956	1.37(0.73, 1.80)	0.974(0.960, 0.996)	(17.58, 40.75)	28.00	N/A	34.00	2.33(2.14, 2.52)	N/A		1.47(1.19, 1.76)
MCHC[g/dL]	1844	0.559	15.71(14.73, 16.45)	0.522(0.500, 0.552)	(26.59, 36.80)	32.00	N/A	36.00	1.26(1.09, 1.43)	N/A		-4.19(-4.44, -3.92)
RDW [%]	1859	0.913	2.46(2.15, 2.74)	0.870(0.848, 0.892)	(10.70, 29.40)	12.00	N/A	14.60	7.43(6.98, 7.86)	N/A		3.78(3.39, 4.11)
RDW-SD[fL]	1859	0.912	5.48(4.48, 6.46)	0.940(0.917, 0.963)	(31.70, 97.10)	40.00	N/A	60.00	7.70(7.31, 8.13)	N/A		3.13(2.42, 3.90)
PLT [103/µL]	1808	0.973	-11.03(-13.21, -8.94)	1.020(1.008, 1.031)	(1.00, 1061.00)	10.00	75.00	1000.0	-10.83(-12.94, -8.85)	-9.54(-11.04, -8.10)[103/µL]	-12.73(-14.72, -10.80) [%]	0.88(-0.08, 1.84)
MPV [fL]	1678	0.772	-0.91(-1.40, -0.20)	1.063(1.000, 1.111)	(8.00, 13.00)	8.00	N/A	10.20	-5.08(-6.62, -2.50)	N/A		-2.63(-3.03, -1.96)
						Evaluation Range			Bias (95% CI)
Parameter[Units]	N	Pearson's(r)	Intercept(95% CI)	Slope (95% CI)	SampleRange	LowEnd	CrossoverPoint	HighEnd	At Low Limit	Crossover Point		At HighLimit
%NRBC[/100 WBC]	1862	0.981	N/A	N/A	(0.00, 186.10)	0.00	N/A	1.50	-0.03(-0.06, 0.01)	N/A		(meandifference)
#NRBC[103/µL]	1864	0.995	N/A	N/A	(0.00, 9.59)	0.00	N/A	0.10	0.00(0.00, 0.00)	N/A		(meandifference)
%NEUT [%]	1585	0.989	1.62(1.12, 2.15)	1.012(1.004, 1.019)	(10.10, 94.00)	40.00	N/A	85.00	5.21(4.60, 5.84)	N/A		3.06(2.82, 3.30)
%LYMPH[%]	1648	0.989	-0.23(-0.37, -0.08)	0.977(0.971, 0.983)	(0.70, 83.00)	25.00	40.00	65.00	-0.81(-0.91, -0.70)	-1.15(-1.32, -0.98)[%LYMPH]	-2.89(-3.30, -2.44)[%]	-2.66(-3.13, -2.15)
%MONO[%]	1648	0.913	-0.60(-0.82, -0.50)	1.000(1.000, 1.026)	(0.60, 24.50)	2.00	N/A	10.00	-0.60(-0.78, -0.50)	N/A		-0.60(-0.70, -0.50)
%EO [%]	1702	0.973	-0.08(-0.13, -0.03)	1.042(1.030, 1.054)	(0.00, 32.90)	0.00	N/A	5.00	-0.08(-0.13, -0.03)	N/A		0.13(0.09, 0.17)
%BASO [%]	1788	0.721	-0.30(-0.35, -0.25)	1.649(1.576, 1.723)	(0.00, 3.10)	0.00	N/A	1.00	-0.30(-0.35, -0.25)	N/A		0.35(0.31, 0.39)
#NEUT[103/µL]	1585	0.994	0.12(0.09, 0.15)	1.027(1.021, 1.033)	(0.37, 37.66)	1.00	1.50	10.00	0.15(0.12, 0.17)	0.16(0.14, 0.19)[103/µL]	10.98(9.18, 12.37)[%]	3.92(3.43, 4.36)
#LYMPH[103/µL]	1648	0.990	-0.06(-0.07, -0.05)	1.032(1.022, 1.042)	(0.02, 12.66)	0.50	1.50	3.00	-0.04(-0.05, -0.03)	-0.01(-0.02, 0.00)[103/µL]	-0.71(-1.30, -0.16)[%]	1.26(0.58, 1.87)
#MONO[103/µL]	1648	0.940	-0.03(-0.04, -0.02)	1.000(0.976, 1.000)	(0.01, 6.14)	0.10	N/A	1.50	-0.03(-0.04, -0.02)	N/A		-0.03(-0.06, -0.03)
#EO[103/µL]	1702	0.976	-0.01(-0.01, 0.00)	1.071(1.060, 1.083)	(0.00, 7.17)	0.00	N/A	0.50	-0.01(-0.01, 0.00)	N/A		0.03(0.03, 0.04)
#BASO[103/µL]	1788	0.680	-0.02(-0.03, -0.02)	1.661(1.577, 1.744)	(0.00, 0.46)	0.00	N/A	0.10	-0.02(-0.03, -0.02)	N/A		0.04(0.04, 0.05)
%RET [%]	1842	0.964	-0.36(-0.39, -0.32)	1.094(1.072, 1.116)	(0.05, 12.93)	0.50	1.67	2.50	-0.31(-0.34, -0.28)	-0.20(-0.21, -0.18)[%RET]	-11.91(-12.75, -10.83) [%]	-4.84(-5.80, -3.81)
Parameter[Units]	N	Pearson's(r)	Intercept(95% CI)	Slope (95% CI)	SampleRange	Evaluation Range			Bias (95% CI)
						Low End	Crossover Point	High End	At Low Limit	Crossover Point	At High Limit
#RET[106/µL]	1834	0.924	-0.01(-0.01, -0.01)	1.070(1.047, 1.092)	(0.00, 0.42)	0.02	N/A	0.15	-0.01(-0.01, -0.01)	N/A	0.00 (0.00, 0.00)
HGB-RET[pg]	1701	0.793	-3.29(-4.69, -1.94)	1.141(1.100, 1.184)	(16.23, 45.00)	23.00	N/A	40.00	-0.23(-2.11, 1.61)	N/A	5.84 (4.94, 6.83)

Table 3: Summary of cobas m 511 system vs. Predicate Device for All Sites Combined

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5.1.2. Flaqqing Capabilities

Clinical sensitivity studies were conducted at the four (4) clinical sites to evaluate cobas m 511 system messages (flags) for white blood cells versus a 400-cell reference method. The 400-cell reference method according to the CLSI H20-A2 standard refers to the combined results from two (2) 200-cell WBC differentials performed by individuals on two (2) separate blood smears. The samples used represented a variety of abnormal conditions. The results obtained from comparison of cobas m 511 system messages versus the 400-cell reference method met the acceptance criteria for sensitivity and specificity. These results are summarized in Table 4.

Clinical Sensitivity Analysis – cobas m 511 system Messages for All Sites Table 4: Combined

cobas m 511 system
	Positive (Flagged Abnormal)	Negative (Normal)	Total
Reference Method	Positive (Abnormal)	118	9	127
	Negative (Normal)	10	302	312
Total		128	311	439

Sensitivity = 118/(118+9) x 100% = 92.9%, Specificity = 302/(302+10) x 100% = 96.8%

5.1.3. Precision

Precision studies were performed at the four (4) clinical sites to evaluate repeatability (i.e., within-run precision) when whole blood samples were processed thirty-one (31) consecutive times on the cobas m 511 system, as recommended in the CLSI H26-A2 standard. Residual K2 EDTA whole blood samples spanning the upper and lower limit of the analytical measuring range generally encountered in the laboratory were selected for the WBC, RBC, HGB and PLT parameters. In addition, samples at medical decision levels of anemia, thrombocytopenia, severe leukopenia, and nucleated red blood cells were evaluated. The mean, standard deviation (SD), and coefficient of variation (CV) were calculated for each sample per the CLSI EP05-A3 guideline. Repeatability results met their pre-defined acceptance criteria. The results of the individual assessments by parameter for all sites combined are shown in Table 5.

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Parameter[Units]	Sample Range	Sample Size(N)	Observations(N)	Range ofSampleMeans	Mean ofSampleMeans	Repeatability
						SD(95% CI)	%CV(95% CI)
WBC[10³/μL]	All	144	4436	(1.98, 130.75)	12.06	0.233(0.229, 0.238)	1.93(1.89, 1.97)
WBC[10³/μL]	< 4.0 x 10³/μL	17	520	(1.98, 3.95)	3.19	0.096(0.090, 0.102)	3.01(2.84, 3.21)
WBC[10³/μL]	≥ 4.0 x 10³/μL	127	3916	(4.00, 130.75)	13.24	0.246(0.241, 0.252)	1.85(1.81, 1.90)
RBC[10⁶/μL]	All	144	4436	(1.92, 6.40)	4.10	0.034(0.034, 0.035)	0.84(0.82, 0.86)
HGB[g/dL]	All	144	4436	(5.98, 20.26)	12.37	0.135(0.132, 0.137)	1.09(1.06, 1.11)
HCT[%]	All	144	4436	(18.39, 65.15)	37.81	0.373(0.365, 0.381)	0.99(0.97, 1.01)
MCV[fL]	All	144	4436	(66.36, 109.80)	92.64	0.600(0.588, 0.613)	0.65(0.63, 0.66)
MCH[pg]	All	144	4436	(20.16, 36.19)	30.29	0.189(0.185, 0.193)	0.62(0.61, 0.64)
MCHC[g/dL]	All	144	4436	(30.22, 34.47)	32.69	0.142(0.139, 0.145)	0.43(0.42, 0.44)
RDW[%]	All	144	4436	(12.23, 27.18)	15.24	0.277(0.272, 0.283)	1.82(1.78, 1.86)
RDW-SD[fL]	All	144	4436	(40.26, 83.41)	50.71	0.872(0.854, 0.891)	1.72(1.68, 1.76)
	Sample Range	Sample Size(N)	Observations(N)	Range of	Mean of	Repeatability
Parameter[Units]				SampleMeans	SampleMeans	SD(95% CI)	%CV(95% CI)
	All	143	4405	(14.74, 936.84)	246.77	6.749(6.609, 6.895)	2.73(2.67, 2.79)
PLT[103/µL]	< 150 x 103/μL	31	950	(14.74, 149.61)	103.71	3.364(3.217, 3.525)	3.24(3.10, 3.40)
	≥ 150 x 103/μL	112	3455	(152.71, 936.84)	286.36	7.413(7.240, 7.595)	2.59(2.53, 2.65)
MPV t【门】	All	141	4347	(8.76, 14.91)	10.74	0.170(0.167, 0.174)	1.58(1.55, 1.62)
	All	143	4405	(0.00, 4.09)	0.12	0.082(0.080, 0.084)	66.68(65.29, 68.13)
%NRBC *[/100 WBC]	< 4%	142	4374	(0.00, 0.97)	0.09	0.080(0.079, 0.082)	85.04(83.27, 86.90)
	≥ 4%	1	31	(4.09, 4.09)	4.09	0.197(0.157, 0.263)	4.80(3.84, 6.42)
	All	144	4436	(0.00, 1.32)	0.02	0.009(0.009, 0.009)	40.10(39.27, 40.97)
#NRBC[103/µL]	< 0.25 x 103/µL	142	4374	(0.00, 0.20)	0.01	0.007(0.007, 0.007)	61.46(60.17, 62.79)
	≥ 0.25 x 103/μL	2	62	(0.28, 1.32)	0.80	0.048(0.041, 0.059)	6.06(5.15, 7.38)
	All	142	4365	(4.82, 96.81)	68.17	1.598(1.564, 1.632)	2.34(2.29, 2.39)
%NEUT *[%]	< 33.3%	3	87	(4.82, 30.78)	20.80	1.749(1.520, 2.060)	7.99(6.94, 9.41)
	≥ 33.3%	139	4278	(35.19, 96.81)	69.19	1.594(1.561, 1.629)	2.30(2.26, 2.36)
	Sample Range	Sample Size(N)	Observations(N)	Range ofSampleMeans	Mean of	Repeatability
Parameter[Units]					SampleMeans	SD(95% CI)	%CV(95% CI)
	All	142	4365	(1.43, 89.38)	20.94	1.406(1.377, 1.437)	6.74(6.60, 6.89)
%LYMPH *[%]	< 13.3%	43	1329	(1.43, 13.28)	7.47	0.913(0.879, 0.949)	12.21(11.76, 12.70)
	≥ 13.3%	99	3036	(13.47, 89.38)	26.79	1.575(1.535, 1.616)	5.89(5.74, 6.05)
	All	142	4365	(1.36, 21.30)	7.84	0.959(0.939, 0.980)	12.25(12.00, 12.52)
%MONO *[%]	< 6.67%	56	1717	(1.36, 6.65)	4.88	0.760(0.735, 0.786)	15.56(15.05, 16.11)
	≥ 6.67%	86	2648	(6.69, 21.30)	9.76	1.069(1.040, 1.099)	10.97(10.68, 11.28)
	All	142	4365	(0.00, 14.66)	2.42	0.534(0.523, 0.546)	21.96(21.50, 22.44)
%E0 *[%]	< 4%	115	3529	(0.00, 3.97)	1.46	0.418(0.408, 0.428)	28.61(27.95, 29.31)
	≥ 4%	27	836	(4.09, 14.66)	6.53	0.867(0.826, 0.911)	13.27(12.65, 13.95)
%BASO *[%]	All	142	4365	(0.01, 2.34)	0.61	0.278(0.272, 0.284)	45.28(44.33, 46.26)
#NEUT *[103/µL]	All	142	4365	(0.87, 49.70)	7.86	0.243(0.238, 0.248)	3.08(3.02, 3.15)
#LYMPH *[103/µL]	All	142	4365	(0.21, 116.87)	2.45	0.173(0.170, 0.177)	7.52(7.36, 7.68)
#MONO *[103/µL]	All	142	4365	(0.03, 7.32)	0.79	0.132(0.129, 0.135)	16.90(16.55, 17.27)
Parameter[Units]	Sample Range	Sample Size(N)	Observations(N)	Range ofSampleMeans	Mean ofSampleMeans	Repeatability
						SD(95% CI)	%CV(95% CI)
#EO *[103/µL]	All	142	4365	(0.00, 0.87)	0.19	0.050(0.049, 0.051)	26.15(25.61, 26.72)
#BASO *[103/µL]	All	142	4365	(0.00, 0.25)	0.05	0.028(0.028, 0.029)	55.84(54.67, 57.06)

Table 5: Repeatability Results for All Sites Combined

{23}------------------------------------------------

{24}------------------------------------------------

{25}------------------------------------------------

Only samples with ≥ 2.0x 10³/µL WBC are used for calculation of repeatability of differential parameters.

† Only samples with ≥ 20 x 10¾µL PLT are used for calculation of repeatability of MPV.

{26}------------------------------------------------

5.1.4. Reproducibility

Studies were performed to evaluate reproducibility (total precision) at the four (4) clinical sites using three (3) levels of stabilized quality control material (DigiMAC3 control L1, L2 and L3), consistent with Chapter 4 of the CLSI EP05-A3 guideline. The assessment utilized a 4 × 5 × 2 × 3 design, where: 4 = number of clinical sites, 5 = number of run days, 2 = number of runs (i.e., batches) per day, 3 = number of replicates per run. The data generated from this study were used to calculate various components of precision, including the following: Within-Run (Repeatability), Between-Run, Between-Day, Between-Laboratory (Site), Total (Reproducibility). Acceptance criteria were applied to the Total (Reproducibility) component. Reproducibility for the three (3) levels of DigiMAC3 controls was calculated and found to be acceptable for all sites combined for all reportable parameters. The results of this assessment for all sites combined are shown in Table 6.

{27}------------------------------------------------

Parameter[Units]	ControlLevel	N	Mean	Within-Run(Repeatability)		Between-Run		Between-Day		BetweenLaboratory(Site)		Total(Reproducibility)
				SD(95% CI)	%CV(95% CI)	SD	%CV	SD	%CV	SD	%CV	SD(95% CI)	%CV(95% CI)
WBC[103/µL]	L1	120	16.93	0.259(0.224, 0.306)	1.53(1.32, 1.81)	0.000	0.00	0.151	0.89	0.272	1.61	0.404(0.290, 0.669)	2.39(1.71, 3.95)
WBC[103/µL]	L2	120	8.00	0.209(0.181, 0.248)	2.62(2.27, 3.10)	0.022	0.28	0.065	0.82	0.158	1.97	0.271(0.208, 0.391)	3.39(2.60, 4.88)
WBC[103/µL]	L3	120	2.64	0.150(0.130, 0.177)	5.66(4.91, 6.70)	0.000	0.00	0.077	2.93	0.096	3.64	0.194(0.154, 0.261)	7.34(5.85, 9.88)
RBC[106/µL]	L1	120	2.56	0.018(0.016, 0.022)	0.72(0.62, 0.85)	0.006	0.25	0.019	0.75	0.064	2.50	0.070(0.042, 0.200)	2.72(1.63, 7.81)
RBC[106/µL]	L2	120	4.29	0.053(0.046, 0.062)	1.23(1.06, 1.45)	0.000	0.00	0.039	0.92	0.102	2.38	0.121(0.077, 0.280)	2.83(1.80, 6.53)
RBC[106/µL]	L3	120	5.58	0.056(0.049, 0.066)	1.00(0.87, 1.19)	0.000	0.00	0.052	0.94	0.116	2.08	0.139(0.089, 0.319)	2.50(1.59, 5.72)
HGB[g/dL]	L1	120	6.26	0.058(0.050, 0.068)	0.92(0.80, 1.09)	0.014	0.22	0.050	0.79	0.216	3.45	0.230(0.136, 0.701)	3.67(2.17, 11.19)
HGB[g/dL]	L2	120	12.31	0.143(0.124, 0.169)	1.16(1.01, 1.37)	0.019	0.15	0.112	0.91	0.374	3.04	0.417(0.254, 1.117)	3.38(2.06, 9.08)
HGB[g/dL]	L3	120	17.45	0.216(0.187, 0.256)	1.24(1.07, 1.46)	0.000	0.00	0.145	0.83	0.461	2.64	0.530(0.330, 1.311)	3.04(1.89, 7.51)
Parameter[Units]	ControlLevel	N	Mean	Within-Run(Repeatability)		Between-Run		Between-Day		BetweenLaboratory(Site)		Total(Reproducibility)
				SD(95% CI)	%CV(95% CI)	SD	%CV	SD	%CV	SD	%CV	SD(95% CI)	%CV(95% CI)
	L1	120	18.11	0.154(0.134, 0.183)	0.85(0.74, 1.01)	0.065	0.36	0.144	0.79	0.409	2.26	0.465(0.287, 1.192)	2.57(1.58, 6.58)
HCT[%]	L2	120	34.95	0.406(0.352, 0.480)	1.16(1.01, 1.37)	0.118	0.34	0.283	0.81	0.639	1.83	0.817(0.541, 1.651)	2.34(1.55, 4.72)
	L3	120	49.24	0.596(0.516, 0.705)	1.21(1.05, 1.43)	0.000	0.00	0.331	0.67	0.735	1.49	1.003(0.690, 1.828)	2.04(1.40, 3.71)
MCV[fL]	L1	120	70.77	0.305(0.264, 0.361)	0.43(0.37, 0.51)	0.265	0.37	0.226	0.32	0.268	0.38	0.535(0.417, 0.744)	0.76(0.59, 1.05)
	L2	120	81.47	0.342(0.297, 0.405)	0.42(0.36, 0.50)	0.356	0.44	0.239	0.29	0.474	0.58	0.725(0.522, 1.188)	0.89(0.64, 1.46)
	L3	120	88.27	0.413(0.358, 0.488)	0.47(0.41, 0.55)	0.285	0.32	0.464	0.53	0.499	0.56	0.846(0.624, 1.316)	0.96(0.71, 1.49)
	L1	120	24.48	0.129(0.112, 0.153)	0.53(0.46, 0.62)	0.087	0.36	0.115	0.47	0.288	1.18	0.347(0.222, 0.784)	1.42(0.91, 3.20)
MCH[pg]	L2	120	28.68	0.110(0.095, 0.130)	0.38(0.33, 0.45)	0.114	0.40	0.110	0.38	0.232	0.81	0.301(0.200, 0.602)	1.05(0.70, 2.10)
	L3	120	31.28	0.134(0.116, 0.158)	0.43(0.37, 0.51)	0.092	0.29	0.102	0.33	0.216	0.69	0.289(0.196, 0.549)	0.92(0.63, 1.75)
	L1	120	34.58	0.122(0.106, 0.145)	0.35(0.31, 0.42)	0.110	0.32	0.213	0.62	0.448	1.29	0.522(0.326, 1.285)	1.51(0.94, 3.72)
MCHC[g/dL]	L2	120	35.20	0.107(0.093, 0.126)	0.30(0.26, 0.36)	0.116	0.33	0.138	0.39	0.441	1.25	0.489(0.296, 1.340)	1.39(0.84, 3.81)
	L3	120	35.43	0.097(0.084, 0.115)	0.28(0.24, 0.33)	0.084	0.24	0.171	0.48	0.415	1.17	0.467(0.285, 1.242)	1.32(0.80, 3.51)
Parameter	ControlLevel	N	Mean	Within-Run(Repeatability)		Between-Run		Between-Day		BetweenLaboratory(Site)		Total(Reproducibility)
[Units]				SD(95% CI)	%CV(95% CI)	SD	%CV	SD	%CV	SD	%CV	SD(95% CI)	%CV(95% CI)
	L1	120	15.62	0.277(0.240, 0.328)	1.77(1.54, 2.10)	0.090	0.57	0.060	0.38	0.236	1.51	0.379(0.284, 0.572)	2.43(1.82, 3.66)
RDW[%]	L2	120	13.18	0.248(0.215, 0.294)	1.88(1.63, 2.23)	0.203	1.54	0.000	0.00	0.107	0.81	0.338(0.287, 0.410)	2.56(2.18, 3.11)
	L3	120	13.12	0.277(0.240, 0.328)	2.11(1.83, 2.50)	0.000	0.00	0.028	0.21	0.112	0.86	0.300(0.256, 0.363)	2.29(1.95, 2.76)
RDW-SD[fL]	L1	120	39.79	0.587(0.508, 0.694)	1.48(1.28, 1.75)	0.307	0.77	0.263	0.66	0.744	1.87	1.030(0.715, 1.837)	2.59(1.80, 4.62)
	L2	120	38.65	0.628(0.544, 0.743)	1.63(1.41, 1.92)	0.487	1.26	0.000	0.00	0.480	1.24	0.929(0.734, 1.266)	2.40(1.90, 3.28)
	L3	120	41.71	0.759(0.658, 0.898)	1.82(1.58, 2.15)	0.000	0.00	0.211	0.51	0.449	1.08	0.907(0.731, 1.196)	2.18(1.75, 2.87)
	L1	120	470.53	4.611(3.994, 5.455)	0.98(0.85, 1.16)	1.885	0.40	3.705	0.79	5.187	1.10	8.090(5.856, 13.074)	1.72(1.24, 2.78)
PLT[10³/µL]	L2	120	215.97	3.213(2.783, 3.802)	1.49(1.29, 1.76)	0.771	0.36	2.524	1.17	2.262	1.05	4.734(3.734, 6.468)	2.19(1.73, 2.99)
	L3	120	76.69	1.281(1.110, 1.516)	1.67(1.45, 1.98)	0.916	1.19	0.697	0.91	0.935	1.22	1.960(1.562, 2.632)	2.56(2.04, 3.43)
	L1	120	7.65	0.089(0.077, 0.106)	1.17(1.01, 1.38)	0.000	0.00	0.020	0.27	0.042	0.55	0.101(0.084, 0.126)	1.32(1.10, 1.64)
MPV[fL]	L2	120	7.49	0.103(0.089, 0.122)	1.38(1.19, 1.63)	0.039	0.52	0.045	0.60	0.058	0.77	0.133(0.109, 0.170)	1.77(1.45, 2.27)
	L3	120	7.36	0.173(0.150, 0.205)	2.35(2.04, 2.78)	0.028	0.39	0.000	0.00	0.043	0.58	0.180(0.159, 0.209)	2.45(2.16, 2.84)
Parameter[Units]	ControlLevel	N	Mean	Within-Run(Repeatability)		Between-Run		Between-Day		BetweenLaboratory(Site)		Total(Reproducibility)
				SD(95% CI)	%CV(95% CI)	SD	%CV	SD	%CV	SD	%CV	SD(95% CI)	%CV(95% CI)
%NRBC[/100 WBC]	L2	120	18.30	0.931(0.806, 1.101)	5.09(4.41, 6.02)	0.250	1.37	0.000	0.00	1.185	6.48	1.528(1.028, 2.958)	8.35(5.62, 16.17)
	L3	120	8.84	1.011(0.876, 1.196)	11.44(9.91, 13.54)	0.266	3.01	0.000	0.00	0.427	4.83	1.129(0.961, 1.370)	12.78(10.87, 15.51)
#NRBC[103/µL]	L2	120	1.46	0.067(0.058, 0.079)	4.59(3.97, 5.43)	0.023	1.59	0.000	0.00	0.110	7.50	0.131(0.084, 0.293)	8.94(5.73, 20.02)
	L3	120	0.23	0.027(0.023, 0.032)	11.62(10.07, 13.75)	0.008	3.42	0.000	0.00	0.016	6.65	0.032(0.026, 0.042)	13.82(11.25, 17.93)
%NEUT[%]	L1	120	58.35	1.734(1.502, 2.051)	2.97(2.57, 3.52)	0.161	0.28	0.432	0.74	1.247	2.14	2.185(1.689, 3.096)	3.74(2.89, 5.31)
	L2	120	59.79	1.867(1.617, 2.209)	3.12(2.70, 3.69)	0.000	0.00	1.010	1.69	1.256	2.10	2.466(1.948, 3.364)	4.13(3.26, 5.63)
	L3	120	58.65	1.957(1.695, 2.315)	3.34(2.89, 3.95)	0.485	0.83	0.856	1.46	1.133	1.93	2.466(2.004, 3.206)	4.20(3.42, 5.47)
%LYMPH[%]	L1	120	39.37	1.667(1.444, 1.972)	4.23(3.67, 5.01)	0.000	0.00	0.266	0.68	1.280	3.25	2.119(1.608, 3.107)	5.38(4.08, 7.89)
	L2	120	37.32	1.798(1.558, 2.127)	4.82(4.17, 5.70)	0.000	0.00	1.078	2.89	1.252	3.35	2.442(1.918, 3.362)	6.54(5.14, 9.01)
	L3	120	37.47	1.997(1.730, 2.363)	5.33(4.62, 6.31)	0.000	0.00	0.721	1.93	1.088	2.90	2.386(1.953, 3.069)	6.37(5.21, 8.19)
Parameter[Units]	ControlLevel	N	Mean	Within-Run(Repeatability)		Between-Run		Between-Day		BetweenLaboratory(Site)		Total(Reproducibility)
				SD(95% CI)	%CV(95% CI)	SD	%CV	SD	%CV	SD	%CV	SD(95% CI)	%CV(95% CI)
%MONO[%]	L1	120	2.02	0.584(0.506, 0.691)	28.89(25.02, 34.18)	0.000	0.00	0.000	0.00	0.227	11.21	0.626(0.537, 0.752)	30.99(26.55, 37.21)
%MONO[%]	L2	120	2.45	0.663(0.574, 0.784)	27.02(23.41, 31.97)	0.167	6.80	0.096	3.90	0.279	11.39	0.744(0.633, 0.903)	30.35(25.82, 36.84)
%MONO[%]	L3	120	3.12	0.761(0.659, 0.900)	24.43(21.16, 28.90)	0.093	2.99	0.181	5.80	0.244	7.85	0.825(0.716, 0.972)	26.47(22.99, 31.22)
%EO[%]	L1	120	0.17	0.141(0.122, 0.167)	81.81(70.86, 96.79)	0.040	23.27	0.061	35.50	0.085	49.39	0.180(0.146, 0.237)	104.57(84.48, 137.28)
%EO[%]	L2	120	0.31	0.191(0.166, 0.226)	62.20(53.88, 73.59)	0.076	24.60	0.062	20.21	0.110	35.63	0.241(0.197, 0.311)	78.43(64.12, 101.03)
%EO[%]	L3	120	0.68	0.351(0.304, 0.415)	51.26(44.40, 60.65)	0.000	0.00	0.078	11.41	0.247	36.13	0.436(0.338, 0.614)	63.74(49.43, 89.76)
%BASO[%]	L1	120	0.09	0.127(0.110, 0.151)	136.58(118.30, 161.59)	0.000	0.00	0.000	0.00	0.059	62.89	0.140(0.118, 0.174)	150.36(126.25, 185.94)
%BASO[%]	L2	120	0.13	0.129(0.112, 0.153)	102.85(89.09, 121.68)	0.039	30.78	0.037	29.69	0.083	66.07	0.163(0.130, 0.219)	129.51(103.30, 173.66)
%BASO[%]	L3	120	0.08	0.114(0.099, 0.135)	139.61(120.93, 165.18)	0.000	0.00	0.041	50.61	0.021	25.95	0.123(0.108, 0.143)	150.75(132.53, 174.84)
#NEUT[103/µL]	L1	120	9.87	0.307(0.266, 0.363)	3.11(2.69, 3.68)	0.052	0.52	0.103	1.04	0.090	0.92	0.340(0.296, 0.400)	3.44(3.00, 4.05)
#NEUT[103/µL]	L2	120	4.78	0.191(0.166, 0.226)	4.00(3.47, 4.73)	0.040	0.84	0.091	1.90	0.073	1.54	0.228(0.194, 0.276)	4.76(4.06, 5.77)
#NEUT[103/µL]	L3	120	1.55	0.098(0.085, 0.116)	6.31(5.47, 7.47)	0.000	0.00	0.058	3.76	0.035	2.28	0.119(0.101, 0.145)	7.70(6.54, 9.35)
Parameter[Units]	ControlLevel	N	Mean	Within-Run(Repeatability)		Between-Run		Between-Day		BetweenLaboratory(Site)		Total(Reproducibility)
				SD(95% CI)	%CV(95% CI)	SD	%CV	SD	%CV	SD	%CV	SD(95% CI)	%CV(95% CI)
#LYMPH[103/µL]	L1	120	6.67	0.314(0.272, 0.371)	4.71(4.08, 5.57)	0.000	0.00	0.076	1.14	0.321	4.81	0.455(0.322, 0.775)	6.83(4.83, 11.62)
#LYMPH[103/µL]	L2	120	2.99	0.167(0.144, 0.197)	5.58(4.83, 6.60)	0.000	0.00	0.089	2.99	0.151	5.05	0.242(0.179, 0.373)	8.10(5.99, 12.47)
#LYMPH[103/µL]	L3	120	0.99	0.078(0.067, 0.092)	7.85(6.80, 9.29)	0.000	0.00	0.027	2.72	0.062	6.24	0.103(0.078, 0.152)	10.39(7.86, 15.33)
#MONO[103/µL]	L1	120	0.34	0.098(0.085, 0.116)	28.72(24.88, 33.98)	0.000	0.00	0.000	0.00	0.032	9.46	0.104(0.090, 0.122)	30.24(26.26, 35.64)
#MONO[103/µL]	L2	120	0.20	0.054(0.047, 0.064)	27.46(23.78, 32.49)	0.009	4.64	0.007	3.55	0.017	8.89	0.058(0.050, 0.068)	29.45(25.59, 34.68)
#MONO[103/µL]	L3	120	0.08	0.022(0.019, 0.026)	26.57(23.01, 31.43)	0.000	0.00	0.006	7.35	0.005	6.43	0.023(0.020, 0.027)	28.30(24.84, 32.91)
#EO[103/µL]	L1	120	0.03	0.023(0.020, 0.028)	78.03(67.59, 92.32)	0.007	22.07	0.011	35.94	0.013	42.81	0.029(0.024, 0.038)	98.49(80.80, 126.18)
#EO[103/µL]	L2	120	0.02	0.015(0.013, 0.018)	62.27(53.94, 73.67)	0.007	28.12	0.005	22.02	0.008	35.11	0.019(0.016, 0.025)	79.91(65.61, 102.25)
#EO[103/µL]	L3	120	0.02	0.010(0.009, 0.012)	55.09(47.72, 65.18)	0.000	0.00	0.002	10.14	0.006	35.78	0.012(0.009, 0.016)	66.47(52.47, 90.72)
#BASO[103/µL]	L1	120	0.02	0.021(0.018, 0.024)	125.97(109.11, 149.04)	0.005	28.13	0.000	0.00	0.010	59.59	0.023(0.019, 0.029)	142.16(119.16, 176.27)
#BASO[103/µL]	L2	120	0.01	0.010(0.009, 0.012)	96.05(83.20, 113.64)	0.004	34.14	0.003	25.88	0.006	61.24	0.013(0.010, 0.017)	121.70(97.41, 162.24)
#BASO[103/µL]	L3	120	0.00	0.004(0.003, 0.004)	219.09(189.77, 259.21)	0.000	0.00	0.001	52.44	0.001	70.12	0.004(0.003, 0.005)	235.94(204.89, 278.17)
Parameter[Units]	ControlLevel	N	Mean	Within-Run(Repeatability)		Between-Run		Between-Day		BetweenLaboratory(Site)		Total(Reproducibility)
				SD(95% CI)	%CV(95% CI)	SD	%CV	SD	%CV	SD	%CV	SD(95% CI)	%CV(95% CI)
%RET	L1	120	7.46	0.525(0.455, 0.621)	7.03(6.09, 8.32)	0.310	4.16	0.155	2.07	0.397	5.32	0.744(0.583, 1.029)	9.97(7.81, 13.79)
[%]	L2	120	3.28	0.261(0.226, 0.309)	7.97(6.90, 9.43)	0.180	5.50	0.000	0.00	0.199	6.05	0.375(0.295, 0.515)	11.42(8.98, 15.69)
#RET[106/µL]	L1	120	0.19	0.014(0.012, 0.017)	7.40(6.41, 8.76)	0.008	4.06	0.004	2.09	0.010	4.99	0.019(0.015, 0.026)	10.03(8.02, 13.39)
	L2	120	0.14	0.012(0.011, 0.014)	8.66(7.50, 10.25)	0.006	4.41	0.005	3.23	0.010	7.01	0.017(0.013, 0.025)	12.42(9.55, 17.75)
HGB-RET[pg]	L1	120	25.22	0.320(0.277, 0.379)	1.27(1.10, 1.50)	0.213	0.84	0.000	0.00	0.327	1.30	0.504(0.370, 0.794)	2.00(1.47, 3.15)
	L2	120	26.11	0.369(0.320, 0.437)	1.41(1.23, 1.67)	0.146	0.56	0.149	0.57	0.362	1.39	0.557(0.407, 0.883)	2.14(1.56, 3.38)

Reproducibility Test Case Results for All Sites Combined Table 6:

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5.1.5. -Linearity

Linearity studies were conducted for WBC, RBC, HGB, HCT, PLT, and RET parameters. Serial dilutions of known high concentration of K2 EDTA whole blood samples and whole blood components, which spanned the full measuring range for each of the aforementioned parameters, were run in both closed-tube mode and open-tube mode on multiple cobas m 511 systems. Each concentration from each dilution series was run for six (6) replicates [five (5) replicates for the reticulocyte series]. Results were analyzed in accordance with the CLSI EP06-A guideline. The method has been demonstrated to be linear from the lower limit to the upper limit and all results met acceptance criteria. Results for closed-tube mode are shown in Table 7. Open-tube mode results were comparable.

Parameter	Units	Intercept	Slope	MaximumAbsoluteDeviation(Relative)	MaximumAllowableDeviation(Relative)	Range
System 1
WBC	103/μL	-0.040	1.022	0 (8%)	0.5 (15%)	(0.07, 404.8)
System 2
WBC	103/μL	0.041	0.897	0.01 (11.3%)	0.5 (15%)	(0.04, 561.1)
System 3
WBC	103/μL	0.011	0.984	0 (5%)	0.5 (15%)	(0.06, 460.5)
PLT	103/μL	-1.287	0.902	0.16 (6.9%)	20 (15%)	(9, 5000)
PLT	103/μL	-1.246	1.117	0.01 (4.1%)	20 (15%)	(5, 5020)
PLT	103/μL	0.374	0.963	N/A*	N/A*	(1, 5000)
PLT	103/μL	0.672	1.002	N/A*	N/A*	(0, 5130)
RET	%	0.010	0.789	0.01 (2.1%)	0.05 (20%)	(0.02, 0.63)
System 4
RBC	106/μL	-0.072	0.990	0.03 (1.5%)	0.2 (10%)	(0.37, 8.26)
HGB	g/dL	-0.305	1.017	0.11 (1.1%)	0.5 (10%)	(1.1, 24.2)
HCT	%	-0.307	1.033	0.06 (2.4%)	1 (10%)	(3.2, 72.2)
PLT	103/μL	-2.149	0.884	0.03 (3.1%)	20 (15%)	(9, 5000)
RET	%	0.005	0.839	0 (5.5%)	0.05 (20%)	(0.03, 0.75)

Table 7: Whole Blood Linearity

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Parameter	Units	Intercept	Slope	MaximumAbsoluteDeviation(Relative)	MaximumAllowableDeviation(Relative)	Range
System 5
RBC	106/µL	-0.053	0.979	0.03 (2.2%)	0.2 (10%)	(0.37, 8.26)
HGB	g/dL	-0.199	1.016	0.1 (2.3%)	0.5 (10%)	(1.1, 24.2)
HCT	%	-0.329	1.019	0.1 (4.4%)	1 (10%)	(3.2, 72.2)
PLT	103/µL	-1.654	0.945	0.01 (1.8%)	20 (15%)	(9, 5000)
RET	%	0.000	0.616	N/A*	N/A*	(0.01, 0.75)
System 6
RBC	106/µL	-0.045	0.971	N/A*	N/A*	(0.37, 8.26)
HGB	g/dL	-0.113	1.007	0.04 (0.6%)	0.5 (10%)	(1.1, 24.2)
HCT	%	-0.196	1.027	0.1 (2%)	1 (10%)	(3.2, 72.2)

*No deviation from linearity since the linear model was the best fit.

5.1.6. Carryover

Carryover was studied at each of the four (4) clinical sites for white and red blood cells and platelets consistent with the International Council for Standardization in Haematology (ICSH) guidelines for the evaluation of blood cell analyzers and CLSI H26-A2 standard. Samples with high percentages of blasts were also added to this evaluation, although not required by the ICSH guidelines or CLSI standard. In this evaluation, for each of the four (4) sample types, three (3) independent carryover experiments were conducted using residual high target value (HTV) whole blood samples. Filtered serum samples were used as low target value (LTV) samples. At each site and on each run day, HTV samples were run three (3) consecutive times immediately followed by three (3) LTV serum samples. Slides from the LTV serum samples were reviewed by an external hematopathologist to determine cell carryover from the HTV samples. Carryover results for the cobas m 511 system met acceptance criteria and are shown in Table 8.

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Sample Type	Sample Size (N)	Mean Percent Carryover
White Blood Cells	12	0.000%
Red Blood Cells	12	0.000%
Platelets	12	0.001%
Blasts	12	0.000%

Summary of Carryover Results for All Sites Combined Table 8:

Interfering Substances 5.1.7.

Studies were conducted to evaluate potential interference effects of hemolysis, lipemia and icterus (i.e., conjugated bilirubin and unconjugated bilirubin) and high concentrations of white blood cells (WBC) and platelets (PLT) on the cobas m 511 system. For hemolysis, lipemia and icterus, dose-response experiments were conducted using the ASSURANCE™ Interference Test Kit (Sun Diagnostics, New Gloucester, ME, USA) and whole blood donor samples. For the high concentrations of white blood cells and platelets, dose-response experiments were conducted using apheresis samples with matched whole blood from donors. Each interfering substance was tested in a series of six (6) incremental concentration samples. Results were analyzed using regression analysis in accordance with the CLSI EP07-A2 guideline. The results showed no significant interference effects of unconjugated bilirubin or conjugated bilirubin up to the maximum tested concentration of 40 mg/dL for each of the parameters that were evaluated. There were no significant hemolysis interference effects up to the maximum tested concentration of 1000 mg/dL for the parameters that were evaluated with the exception of clinically significant hemolysis interference effects observed at ≥ 672 mg/dL for HGB and ≥ 792 mg/dL for HCT. There were no significant lipemia interference effects up to the maximum tested concentration of 3000 mg/dL for the parameters that were evaluated with the exception that clinically significant lipemia interference effects were observed at ≥ 1646 mg/dL for WBC and ≥ 2459 mg/dL for #LYMPH. For all evaluated parameters, there were no significant interference effects of high concentrations of white blood cells up to the maximum tested concentration of 100.2 x 10°/uL and high concentrations of platelets up to maximum tested concentration of 1166 x 103/uL.

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Specimen Stability 5.1.8.

A study of normal samples was conducted using thirty-one (31) whole blood samples from healthy volunteer donors. Samples were processed in duplicate at each of the following time points: baseline [time zero (0)] and after 9, 20, 26, 38, and 50 hours in both ambient (15°C-25°C) and refrigerated (2℃-8℃) storage conditions.

A study of the abnormal samples was conducted using fourteen (14) residual de-identified whole blood samples at targeted medical decision levels. Samples were processed in duplicate at each of the following time points: baseline [time zero (0)] and after 9, 26, and 50 hours in both ambient (15°C-25°C) and refrigerated (2°C-8°C) storage conditions.

The data from both normal and abnormal samples were combined in order to determine the extent of changes in all reported parameters over an extended period of time up to fifty (50) hours. Each parameter was analyzed separately at both ambient and refrigerated temperatures. For each time point, results were compared to the respective [zero (0) hour] results. The combined results demonstrated stability for normal and abnormal samples up to or beyond twenty-four (24) hours.

Anticoagulant Comparison Study 5.1.9.

Studies were conducted to demonstrate comparability between whole blood samples collected into K2 and K3 EDTA. Forty-four (44) whole blood samples from healthy volunteer donors and forty (40) residual whole blood samples that included thirty (30) targeted abnormal samples were evaluated. Samples from healthy donors were collected via venipuncture into separate K2 and K3 EDTA blood collection tubes as recommended in the CLSI H26-A2 standard. Each tube was processed on a single cobas m 511 system and the K2 EDTA results compared to K3 EDTA results for all reportable parameters. Residual whole blood samples collected into K3 EDTA were processed on a cobas m 511 system and the predicate device. Results from the cobas m 511 system and the predicate device were compared for all reportable parameters. Correlation and bias were assessed in accordance with the CLSI EP09-A3 guideline. All acceptance criteria were met, demonstrating equivalency of results obtained from samples collected into K2 EDTA and K3 EDTA.

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5.1.10. Venous and Capillary Blood Method Comparisons

Studies were conducted to demonstrate comparability between whole blood samples collected via venipuncture (venous) and finger-stick (capillary), as recommended in the CLSI H26-A2 standard. Forty (40) whole blood samples from healthy volunteer donors were utilized. Blood was drawn twice from each healthy donor, once via venipuncture and once via finger-stick. Additionally, forty (40) residual whole blood capillary samples, which included thirty (30) targeted abnormal samples, were evaluated in a method comparison analysis with the predicate device. All samples were processed in the open-tube mode on the predicate device and the cobas m 511 system. Results from the cobas m 511 system and the predicate device were compared for all reportable parameters. Correlation and bias were assessed in accordance with the CLSI EP09-A3 guideline. Overall, the data demonstrate comparable results between venous and capillary blood processed on the cobas m 511 system.

5.1.11. Mode to Mode Analysis

A study was conducted at the four (4) clinical sites to compare results from samples processed in the cobas m 511 system open-tube mode versus the closed-tube mode. For this study, samples processed in the closed-tube mode were automatically mixed on the cobas m 511 system, while samples processed in the open-tube mode were manually mixed prior to processing. Correlation and bias between the closed-tube and open-tube mode results were determined in accordance with the CLSI EP09-A3 guideline based on the results of either a Passing-Bablok or Deming regression model. For the %NRBC and #NRBC parameters the mean difference was used to calculate bias in accordance with the CLSI EP09-A3 guideline. The results were found to be acceptable in that all twenty-six (26) reportable parameters that were evaluated met acceptance criteria.

5.1.12. Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ)

A study was conducted to evaluate LoB, LoD and LoQ for the cobas m 511 system according to the CLSI EP17-A2 guideline. To determine LoB, testing was performed on three (3) individual test days using preserved RBC samples. The calculated LoB for WBC is 0.05 x 103/uL and for PLT is 1 x 103/uL. To determine LoD, residual whole blood samples with targeted low level values that were greater than the LoB were used. Testing was performed on three (3) individual

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test days, using two (2) residual whole blood samples with targeted low level values for WBC and PLT parameters on each day. The calculated LoD for WBC is 0.08 x 103/uL and for PLT is 3 x 103/μL. To determine LoQ, residual whole blood samples with targeted low level values that were greater than the LoD were required. Testing was performed on three (3) individual test days for WBC and PLT samples. The calculated LoQ for WBC is 0.24 x 103/uL and for PLT is 6 x 10³/μL.

5.1.13. Reference Intervals

Reference ranges from normal healthy donors were established for adult males, adult females, and the following six (6) pediatric subgroups: 0 to <6 months, 6 to <24 months, 2 to <6 years, 6 to <12 years, 12 to <18 years (female), and 12 to <18 years (male). For each targeted population, normal reference ranges for all parameters reported by the cobas m 511 system were calculated in accordance with the CLSI EP28-A3c guideline. Adult reference ranges were established using data from four (4) sites, while the pediatric data was established using data from a single site. The normal reference ranges for adult and pediatric cohorts are consistent with those in the published literature. Reference intervals may differ because of differences in sex. age, diet, fluid intake, or geographic location. Therefore, it is recommended that each laboratory establish its own expected reference intervals based upon their individual patient populations.

6. PROPOSED LABELING

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

CONCLUSIONS 7.

The information provided in this Premarket Notification 510(k) supports a determination of substantial equivalence for the cobas m 511integrated hematology analyzer.

Regulation Number and Section

§ 864.5220 Automated differential cell counter.

(a)
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.(b)
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.”