NOxBOXi Nitric Oxide Delivery System is intended for use by healthcare professionals for the delivery and monitoring of a constant (user set) concentration of nitric oxide (NO) and the monitoring of NO2 and O2 in the inspiratory lines of a patient undergoing nitric oxide therapy (iNO).

The NOxBOXi Nitric Oxide Delivery System includes:

· The NOxBOXi head unit, which delivers NO gas while in the intelligent delivery mode.

· Continuous monitoring and alarms for NO, O2 and NO2.

• The integrated NOxMixer which provides a backup NO delivery capability that is intended to deliver a continuous flow of NO. mixed with O2, for iNO therapy and provides a continuous treatment option during transit and transfer conditions within hospitals.

The NOxBOXi Nitric Oxide Delivery System must only be used in accordance with the indications, warnings and precautions described in the nitric oxide drug packaging (currently neonates). Refer to this material prior to use.

Device Description

The NOxBOXi Nitric Oxide Delivery System (NOxBOXi) simultaneously delivers Nitric Oxide (NO) medical gas, while monitoring Nitric Oxide, Nitrogen Dioxide and Oxygen levels in the inspiratory limb of a ventilator for patients undergoing inhaled Nitric Oxide Therapy.

The system is designed for use by healthcare professionals to administer treatment to patients undergoing inhaled Nitric Oxide (iNO) therapy. The NOxBOXi will deliver nitric oxide in a synchronous manner to a single patient.

An integrated component to the NOxBOXi, the NOxMixer is intended to deliver a continuous flow of Nitric Oxide from the NOxBOXi, mixed in line with Oxygen (O2) for use in iNO therapy. The NOxMixer will be used in conjunction with manually bagging a patient.

The NOxBOXi includes the NOxBOXi Head Unit, a NOxFLOW sample line, two NO feed hoses, two regulators (connector type dependent on the gas supplier), a test circuit, NO, O₂ & NO₂ monitors, power supply, drainage syringe, Operating Manual & Technical Guide.

Optional accessories include 4 separate NOxKITs (22mm, 12 mm, & 10mm), one way valve for HFOV (High Frequency Oscillatory Ventilation), bagging kits (hyperinflation & selfinflating) and circuit reducers (22f - 15m).

AI/ML Overview

This document describes a Special 510(k) submission (K201339) for the NOxBOXi Nitric Oxide Delivery System. This submission is specifically for adding compatibility claims for additional ventilators and does not involve product changes or changes to the indications for use. Therefore, the validation and acceptance criteria primarily refer to the original K171696 clearance.

Here's the breakdown of the requested information based on the provided text:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly present a table of acceptance criteria with corresponding reported device performance values in the typical format of a clinical study or performance verification. Instead, it refers to broad categories of performance and compliance with standards. The "Comparison of Characteristics With Changes From Device Cleared in K171696" table shows that no changes were made to the core technical parameters of the device concerning its primary functions (NO administration, monitoring accuracy, battery backup, etc.). The acceptance criterion for this specific submission (K201339) is that the device, with the added ventilator compatibility, continues to meet safety and effectiveness standards, as demonstrated by non-clinical testing.

The acceptance criteria for the original device (K171696) can be inferred from the tests performed:

Acceptance Criteria Category/Parameter (Inferred from testing)	Reported Device Performance (Implied successful completion of tests)
NOxBOXi Core Performance (from K171696)
NO & NO2 monitoring accuracy	+/- 2% or 0.2ppm
NO dosing Accuracy in manual mode (5-80 ppm)	± 20% or 2 ppm, whichever is the greater
NO dosing Accuracy in manual mode (0 to < 5 ppm or > 80 to 185 ppm)	+/-40% or 4 ppm, whichever is the greater
Backup accuracy (5-80 ppm)	± 20% or 2 ppm, whichever is the greater
Backup accuracy (0 to < 5 ppm or > 80 to 185 ppm)	+/-40% or 4 ppm, whichever is the greater
Battery Backup capability	4 hours without AC power
Response of NO delivery to external perturbations and user changes	Successfully met (implied by FDA guidance compliance)
Purity of NO drug delivery	Successfully met (implied by FDA guidance compliance)
Acceptable/minimal production of NO2	Successfully met (implied by FDA guidance compliance)
Control of excess NO2	Successfully met (implied by FDA guidance compliance)
Biological safety (biocompatibility)	Meets ISO 10993-1, -5, -10 standards (K171696)
Electrical safety and essential performance	Meets IEC 60601-1 standard (K171696)
Electromagnetic compatibility (EMC)	Meets IEC 60601-1-2 standard (K171696)
Usability/Human Factors	Meets IEC 62366 and FDA guidance (K171696)
Respiratory Gas Monitor Performance	Meets ISO 80601-2-55 standard (K171696)
Software Life Cycle Processes	Meets IEC 62304 standard (K171696)
VOC and Particulate levels in delivered gas	VOC levels three orders of magnitude below OSHA PELs; Particulate levels well below EPA's maximum limits (K171696)
K201339 Specific Acceptance Criteria
Compatibility with additional ventilators	No effect on ventilator functionality, and no new questions of safety or effectiveness raised ("Equivalent; testing shows no new questions raised regarding safety and effectiveness")

2. Sample size used for the test set and the data provenance

For the K201339 submission, the testing was limited to non-clinical bench testing to verify compatibility with additional ventilators. There is no mention of a human patient test set or sample size in this document for this specific submission. The provenance is internal testing performed by the manufacturer or their agents. The nature of this submission is purely technical validation without clinical data.

For the original K171696, while biological and performance standards were met, specific "sample sizes" for patient data are not detailed, as these are typically bench and engineering tests rather than clinical trials with patient cohorts.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

This information is not provided in the document. Given that the testing for this submission was non-clinical (ventilator compatibility), the "ground truth" would have been established through engineering and performance specifications, likely by the manufacturer's R&D and quality assurance teams, rather than medical experts for clinical ground truth.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

This information is not provided and is generally not applicable to the type of non-clinical, bench testing described for this device. Adjudication methods like 2+1 or 3+1 are used for establishing ground truth in clinical reading studies, which were not performed for this submission.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is a nitric oxide delivery system, not an AI-assisted diagnostic or therapeutic tool for which such studies would be relevant. The document explicitly states: "No clinical testing was required to support substantial equivalency of this medical device."

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

This question is not applicable as the NOxBOXi system is a medical device for delivering and monitoring nitric oxide, not an algorithm or AI system. It operates with a "human-in-the-loop" as healthcare professionals operate and monitor the device.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

For the specific K201339 submission, the "ground truth" for ventilator compatibility was established through engineering specifications and verification testing to ensure that the device's interaction with the additional ventilators did not compromise their functionality or the safety and effectiveness of the NOxBOXi system. This is based on objective measurements and compliance with applicable standards, not clinical ground truth like pathology or outcomes data.

For the core device (K171696), the ground truth for its performance characteristics (e.g., accuracy of gas delivery and monitoring) would have been established against calibrated reference standards and established measurement methodologies during verification and validation testing.

8. The sample size for the training set

This information is not applicable as the device is not described as an AI/machine learning system that requires a training set.

9. How the ground truth for the training set was established

This information is not applicable as the device is not described as an AI/machine learning system that requires a training set and associated ground truth.

Summary

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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the FDA name and title on the right. The symbol on the left is a stylized representation of a human figure, while the text on the right reads "FDA U.S. FOOD & DRUG ADMINISTRATION" in blue letters.

Praxair, Inc. % Sarah Fitzgerald Senior Consultant, Ouality and Regulatory Affairs Emergo Global Consulting, LLC 2500 Bee Cave Road, Building 1, Suite 300 Austin, Texas 78746

Re: K201339

Trade/Device Name: The NOxBOXi Nitric Oxide Delivery System Regulation Number: 21 CFR 868.5165 Regulation Name: Nitric Oxide Administration Apparatus Regulatory Class: Class II Product Code: MRN, MRO, MRP, MRQ, CCL Dated: May 13, 2020 Received: May 20, 2020

Dear Sarah Fitzgerald:

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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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

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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); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; 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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

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/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). 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 (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Todd Courtney Assistant Director DHT1C: Division of ENT, Sleep Disordered Breathing, Respiratory and Anesthesia Devices OHT1: Office of Ophthalmic, Anesthesia, Respiratory, ENT and Dental Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K201339

Device Name NOxBOXi Nitric Oxide Delivery System

Indications for Use (Describe)

NOxBOXi Nitric Oxide Delivery System is intended for use by healthcare professionals for the delivery and monitoring of a constant (user set) concentration of nitric oxide (NO) and the monitoring of NO2 and O2 in the inspirator lines of a patient undergoing nitric oxide therapy (iNO).

The NOxBOXi Nitric Oxide Delivery System includes:

· The NOxBOXi head unit, which delivers NO gas while in the intelligent delivery mode.

· Continuous monitoring and alarms for NO, O2 and NO2.

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


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

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Special 510(k) Summary

NOxBOXi Nitric Oxide Delivery System

1. Submission Sponsor

Praxair Distribution, Inc. (PDI) 10 Riverview Drive Danbury, CT 06810 USA Phone: (412) 874.3315 Dave Loflin Director of Quality and FDA Regulations

2. Submission Correspondent

Emergo Global Consulting, LLC 2500 Bee Cave Road Building 1, Suite 300 Austin, TX 78746 Office Phone: (512) 327.9997 Sarah Marie Fitzgerald, RAC Senior Consultant, Quality and Regulatory Affairs

3. Date

June 18, 2020

4. Device Identification

Trade/Proprietary Name:	NOxBOXi Nitric Oxide Delivery System
Classification Names:	Nitric Oxide administration apparatus, back-up and gas analyzer
Common/Usual Name:	Nitric Oxide administration apparatus - primaryNitric Oxide administration apparatus - backupNitric Oxide AnalyzerNitrogen Dioxide AnalyzerOxygen Gas Analyzer
Classification Regulationand Product Code:	21 CFR 868.5165 – primary delivery system	MRN
Additional Regulationsand Product Codes:	21 CFR 868.5165 – backup delivery system21 CFR 868.2380 – Nitric Oxide Analyzer21 CFR 868.2385 - Nitrogen Dioxide Analyzer21 CFR 868.1720 - Oxygen Gas Analyzer	MROMRPMRQCCL
Device Class:	Class II
Classification Panel:	Anesthesiology

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5. Legally Marketed Predicate Device

NOxBOXi Nitric Oxide Delivery System, K171696.

6. Device Description

7. Indication for Use Statement

NOxBOXi Nitric Oxide Delivery System is intended for use by healthcare professionals for the delivery and monitoring of a constant (user set) concentration of nitric oxide (NO) and the monitoring of NO2 and O2 in the inspiratory ventilator lines of a patient undergoing nitric oxide therapy (iNO).

The NOxBOXi Nitric Oxide Delivery System includes:

The NOxBOXi head unit, which delivers NO gas while in the intelligent delivery mode.
Continuous monitoring and alarms for NO, O2 and NO2.
The integrated NOxMixer which provides a backup NO delivery capability that is intended to deliver a continuous flow of NO, mixed with O2, for iNO therapy and provides a continuous treatment option during transit and transfer conditions within hospitals.

The NOxBOXi Nitric Oxide Delivery System must only be used in accordance with the indications, contraindications, warnings and precautions described in the nitric oxide drug packaging inserts and labeling (currently neonates). Refer to this material prior to use.

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8. Substantial Equivalence Discussion

The following table compares the NOxBOXi to the predicate device with respect to intended use, technological characteristics and principles of operation.

Comparison of Characteristics With Changes From Device Cleared in K171696

	Subject: NOxBOXi Nitric OxideDelivery System	Predicate: NOxBOXi Nitric OxideDelivery System	Comparison
510(k) Number	K201339	K171696	N/A
Manufacturer	Praxair Distribution, Inc.		No Change
Regulatory & Indications for Use
Product Code	MRN, MRO, MRP, MRQ, CCL		No Change
Regulation Numbers	21 CFR 868.5165, .2380, .2385, .1720		No Change
Regulation Name	Nitric Oxide administration apparatus, back-up and gas analyzers		No Change
Indications for Use	NOXBOXi Nitric Oxide Delivery System is intended for use by healthcareprofessionals for the delivery and monitoring of a constant (user set)concentration of nitric oxide (NO) and the monitoring of NO2 and O2 in theinspiratory ventilator lines of a patient undergoing nitric oxide therapy (iNO).The NOxBOXi Nitric Oxide Delivery System includes:The NOxBOXi head unit, which delivers NO gas while in the intelligent delivery mode.Continuous monitoring and alarms for NO, O2 and NO2.The integrated NOxMixer which provides a backup NO delivery capability that is intended to deliver a continuous flow of NO, mixed with O2, for iNO therapy and provides a continuous treatment option during transit and transfer conditions within hospitals.The NOxBOXi Nitric Oxide Delivery System must only be used in accordance with the indications, contraindications, warnings and precautions describedin the nitric oxide drug packaging inserts and labeling (currently neonates).Refer to this material prior to use.
	Refer to this material prior to use.
Technical
NO administration	NO blended with O2 in the patient's inhalation circuit		No Change
NO flow rate (sample flowrate)	225 ml/min		No Change
NO concentrationprovided	0.0 TO 80ppm		No Change
NO monitor	Yes		No Change
O2 monitor	Yes		No Change
Monitoring accuracy	NO & NO2 - +/- 2% or 0.2ppm		No Change
NO2 monitor & alarm	Yes		No Change
Battery Backup capability	4 hours without AC power		No Change
	Subject: NOxBOXi Nitric OxideDelivery System	Predicate: NOxBOXi Nitric OxideDelivery System	Comparison
Manual bagging & backup system	NOxMIXER®	NOxMIXER®	No Change
NO dosing range inmanual mode		0 - 185ppm on 800ppm cylinders	No Change
NO dosing Accuracy inmanual mode		$± 20% or 2 ppm, whichever is the greater for NO doses from 5 - 80 ppm (800 ppm drug cylinder) and O2 flow rates of 5 - 14 L/min$ $* +/-40% or 4 ppm, whichever is the greater; for NO doses from 0 to < 5 ppm or > 80 to 185 ppm (800 ppm drug cylinder) and O2 flow rates of 2 to < 5 L/min or > 14 to 25 L/min$	No Change
NO flow in manual mode		Adjustable 50 – 600 mL/min of NO/N2	No Change
O2 flow range in manualbagging mode		2 to 25 L/min of O2	No Change
Oxygen inlet pressure		3.5 – 4.5 bar	No Change
NO delivery pressure		1.65bar from manual control valve	No Change
Manual bagging & backup system	NOxMIXER®		No Change
Dimensions		65 mm (W) X 185 mm (H) x 60.8 mm (D)	No Change
Pre-use set up time		Instant set-up	No Change
Monitoring during manualbagging		Yes	No Change
Alarms active duringbagging		Yes	No Change
Stand alone vs Built-in		Built-in	No Change
Can be used as a back-upfunction		Yes	No Change
Back-up accuracy		$± 20% or 2 ppm, whichever is the greater for NO doses from 5 - 80 ppm (800 ppm drug cylinder), * +/-40% or 4 ppm, whichever is the greater; for NO doses from 0 to < 5 ppm or > 80 to 185 ppm (800 ppm drug cylinder)$	No Change
	Ventilator Compatibility
Compatible Ventilators	Various models from the followingmanufacturers:● Bunnel● Carefusion● Carefusion / SensorMedics● Drägerwerk● Fisher & Paykel Healthcare● Hamilton Medical● Maquet● Newport (Covidien)● Philips Respironics● Puritan Bennett (Covidien)	Various models from the followingmanufacturers:● Bunnel● Carefusion● Carefusion / SensorMedics● Drägerwerk● (N/A)● Hamilton Medical● Maquet● Newport (Covidien)● Philips Respironics● Puritan Bennett (Covidien)	Equivalent;testingshows nonewquestionsraisedregardingsafety andeffectiveness

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9. Non-Clinical and Usability Performance Data

NOxBOXi has been verified and validated to ensure that it meets its functional, performance, and usability specifications and requirements. The device has been tested in compliance to international standards and US FDA guidance documents including the following:

FDA guidance "Use of International Standard ISO 10993-1, "Biological evaluation of . medical devices – Part 1: Evaluation and testing within a risk management process" (K171696)
FDA guidance "Premarket Notification Submissions for Nitric Oxide Delivery Apparatus, Nitric Oxide Analyzer and Nitrogen Dioxide Analyzer" including accuracy of NO delivery, response of NO delivery to external perturbations and user changes, purity of NO drug delivery, acceptable / minimal production of NO2, NO analyzer accuracy, NO2 analyzer accuracy, control of excess NO2, backup testing, and compatibility testing (effects on ventilator functionality) of ventilators listed in the product labeling, as applicable (K171696 and K201339)
FDA guidance "Content of Premarket Submissions for Software Contained in Medical ● Devices" (K171696)
FDA guidance "Applying Human Factors and Usability Engineering to Medical Devices." (K171696)
ISO 10993-1: Biological Evaluation of Medical Devices Part 1: Evaluation and Testing Within a Risk Management Process (K171696)
ISO 10993-5: Biological Evaluation of Medical Devices Part 5: Tests for In Vitro Cytotoxicity (K171696)
. ISO 10993-10: Biological Evaluation of Medical Devices Part 10: Tests for Irritation and Skin Sensitization (K171696)
. IEC 60601-1: Medical Electrical Equipment – Part 1: General Requirements for Basic Safety and Essential Performance (K171696)
IEC 60601-1-2: Medical Electrical Equipment – Part 1-2: General Requirements for Basic Safety and Essential Performance - Collateral Standard: Electromagnetic Disturbances -Requirements and Tests (K171696)
. IEC 62366: Medical Devices – Application of Usability Engineering to Medical Devices (K171696)
. ISO 80601-2-55: Medical Electrical Equipment – Part 2-55: Particular Requirements for the Basic Safety and Essential Performance of Respiratory Gas Monitors (K171696)
. IEC 62304: Medical Device Software – Software Life Cycle Processes (K171696)
. ISO 15223-1: Medical Devices - Symbols to be Used With Medical Device Labels, Labelling, and Information to be Supplied – Part 1: General Requirements (K171696)

Additionally, gases delivered through the NOxBOXi system were analyzed for the presence of volatile organic compounds (VOC) and particulate matter. Measurement of the resulting VOC concentrations resulted in levels that were three orders of magnitude below OSHA permissible exposure levels. Particulate testing determined that the gas delivered by the NOxBOXi system

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contained particulate levels well below the EPA's maximum limits for total suspended particulates. (K171696)

Testing for this submission was limited to the aspects that could be affected by including compatibility with additional ventilators. No additional usability testing was conducted for this submission. No clinical testing was required to support substantial equivalency of this medical device.

10. Conclusions/Statement of Substantial Equivalence

This submission is for the addition of compatibility claims for specific ventilators and is not related to product changes. There are no changes to the indications for use of the product and there are no significant design changes. The above-described non-clinical data support the substantial equivalence of the device and the compatibility with additional ventilators. The NOxBOXi passed all testing and no different questions of safety or effectiveness were raised. The information provided within this premarket notification supports substantial equivalence to the predicate device.

Regulation Number and Section

§ 868.5165 Nitric oxide administration apparatus.

(a)
Identification. The nitric oxide administration apparatus is a device used to add nitric oxide to gases that are to be breathed by a patient. The nitric oxide administration apparatus is to be used in conjunction with a ventilator or other breathing gas administration system.(b)
Classification. Class II. The special control for this device is FDA's “Guidance Document for Premarket Notification Submissions for Nitric Oxide Administration Apparatus, Nitric Oxide Analyzer, and Nitrogen Dioxide Analyzer.”